Immunosuppressants with low molecular weight.
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"5083",leadTitle:null,fullTitle:"Significance, Prevention and Control of Food Related Diseases",title:"Significance, Prevention and Control of Food Related Diseases",subtitle:null,reviewType:"peer-reviewed",abstract:"Food-borne diseases are major causes of morbidity and mortality in the world. 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Whizar-Lugo",coverURL:"https://cdn.intechopen.com/books/images_new/6221.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"169249",title:"Prof.",name:"Víctor M.",middleName:null,surname:"Whizar-Lugo",slug:"victor-m.-whizar-lugo",fullName:"Víctor M. Whizar-Lugo"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"10692",leadTitle:null,title:"Critical Systems - Towards Antifragility",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tAs the world becomes ever more complex, connected and automated, the challenge of designing and operating critical systems increases exponentially. The Covid-19 pandemic has demonstrated that many critical systems – from healthcare to just-in-time supply chains to societal lockdown compliance – are remarkably fragile. If we are to learn anything from the pandemic it is that our critical systems need to become a lot more resilient. The ability of complex critical systems to survive unpredicted stresses and perturbations is one thing, but when solutions are responsible for the wellbeing of potentially millions of people, what is really needed, and this book proposes, are systems that are antifragile. That is, the more they are stressed the stronger they become.
\r\n\r\n\tAntifragility is a property found in many natural systems, but almost never in today’s human-engineered systems. Achieving antifragility demands new and better ways of specifying, designing and operating the world’s critical systems. More specifically, it demands the management and resolution of three overarching contradictions:
\r\n\r\n\t1) The divergence between system complexity of operating environments and the design capability of those tasked with creating such systems
\r\n\t2) The divergence between the levels of reliability required (twelve-9’s are not uncommon requirements) and the ability to identify or test failure modes that are increasingly unknown and unknowable
\r\n\t3) The divergence between the vulnerability of critical systems and the amount of damage that an individual ‘bad actor’ is able to inflict.
\r\n\t
\r\n\tThe book examines pioneering work to address these challenges and to ensure the timely arrival of antifragile critical systems into a world that currently sees humanity at the edge of a precipice.
Many undesired side-effects or therapeutic failures of drugs are the results of differences or changes in drug metabolism. A patient’s drug metabolizing capacity, highly influenced by genetic variations or alterations in the expression and activities of drug-metabolizing enzymes, can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity [1]. Even if the routine clinical practice applies blood concentration guided dosing, the interindividual variability in drug metabolism calls for personalized medication primarily for drugs with narrow therapeutic index [2, 3]. The identification of genetic and nongenetic factors that can potentially affect the pharmacokinetics of a particular drug is a prerequisite of tailored pharmacotherapy [4, 5].
CYP enzymes are the key players in the metabolism of most drugs; therefore, interindividual and intraindividual variations in CYP activities are of significant importance in clinical practice. The pharmacokinetic variability can divide the population into poor, intermediate, extensive, and ultra-rapid metabolizer phenotypes. The loss-of-function mutations in CYP genes result in permanent poor metabolism, whereas nongenetic (internal or environmental) factors can substantially modify the expression and activities of CYP enzymes, evoking transient poor or extensive/ultra-rapid metabolism [6, 7]. The clinical relevance for many CYP genetic variants, regarding drug efficacy, adverse drug reactions, or dose requirement, has been clearly evidenced [6, 7, 8, 9]; however, the heritable genetic polymorphisms are not the only determinant factors in interindividual differences in drug metabolism. CYP genotype determines the potential for the expression of functional or nonfunctional enzymes; and nongenetic host factors (age, sex, and disease states) and environmental factors (nutrition, medication, smoking, and alcohol consumption) can alter the expression and activities of CYP enzymes [10]. Homozygous wild genotype, predicted to be translated to functional CYP enzyme, can be transiently switched into poor or extensive metabolizer phenotype, due to phenoconversion [1, 11]. Consequently, both the CYP genotype and the current CYP expression or activity should be considered for the estimation of a patient’s drug-metabolizing capacity.
The prevalence of loss-of-function or gain-of-function alleles is generally 1–10%; however, the distribution of the common CYP variants varies among different ethnic populations. CYP3A enzymes, responsible for the metabolism of approximately 40% of the drugs on the market, including many immunosuppressant agents, display great genetic and nongenetic variations. For CYP3A5, substantial interethnic differences in allelic variants have been demonstrated. The prevalence of CYP3A5*3 allele (6986A > G), resulting in splicing defect and nonfunctional CYP3A5 protein, is 88–97% in white (Caucasian), 66% in Asian, and 12–35% in African populations; consequently, a higher average proportion of functional CYP3A5 in the total hepatic CYP3A pool is expected in subjects of black origin [7, 12]. On the other hand, the enormous, even more than 100-fold interindividual variability in the expression and activity of CYP3A4 is attributed to nongenetic factors rather than genetic polymorphisms [13]. CYP3A4*1B allele, which has a frequency of 3–5% in white populations, but a much higher frequency in African population (50–82%) has been reported to result in increased transcription; however, the clinical significance of CYP3A4*1B to CYP3A4 function seems to be doubtful [14, 15]. CYP3A4*22 allele with the prevalence of 2.5–8% in white and of 4% in Asian populations displays low hepatic CYP3A4 expression and results in decreased CYP3A4 activity [16]. Although the association between CYP3A4 genotype and pharmacokinetic behavior of CYP3A-substrates has been extensively studied, no clear phenotype-genotype relationship has been described for CYP3A4.
Beside the genetic polymorphisms, one of the major sources of interindividual or intraindividual variability in drug metabolism is concomitant medication and co-morbidities, evoking phenoconversion, notably CYP induction and enzyme inhibition [17]. CYP induction leads to an increase in the expression and activity of CYP enzymes and contributes to the increased elimination of drugs metabolized by the particular enzyme. Several pathways involving the activation of various nuclear receptors (PXR pregnane X receptor, CAR constitutive androstane receptor, and glucocorticoid receptor) have been reported to enhance the transcription of CYP3A genes and to contribute to the complex regulation of CYP3A enzymes by drugs such as rifampicin, phenobarbital, carbamazepine, and synthetic or natural steroids [18, 19, 20, 21]. Reduced drug concentration as a consequence of CYP3A induction leads to the lack of the pharmacological effect and drug failure. Phenoconversion converting genotypic extensive metabolism into phenotypic poor metabolism of drugs may occur during inflammation (sterile or infection-induced inflammation). Elevated release of proinflammatory cytokines (IL-6, IL-1β, TNF-α) has been associated with downregulation of several drug-metabolizing CYPs, including CYP3A enzymes. The mechanism of downregulation is the repression of PXR and CAR that are involved in transcriptional regulation of CYP3A expression [22, 23, 24, 25, 26]. As a consequence, transient poor metabolizer phenotype is developed, significantly increasing the risk of adverse drug reactions and impacting the clinical outcome [1, 27]. Likewise, co-medication can also give rise to poor metabolism. Several drugs or food components (e.g., bergamottin) are known to inhibit the function of drug-metabolizing CYPs; therefore, the concomitant treatment with a CYP inhibitor is expected to increase the exposure of those pharmacons that are metabolized by the particular enzyme. As a consequence of CYP inhibition, the risk of increased exposure and drug-induced adverse reactions can be anticipated, primarily for drugs with narrow therapeutic index, such as tacrolimus and ciclosporin.
By recognizing individual differences in drug metabolism, personalized drug therapy adjusted to the patient’s drug-metabolizing capacity can help to avoid the potential side effects of drugs. The graft and recipient survival are highly influenced by drug-metabolizing capacity of the liver, and it is essential to predict potential drug-drug interactions and to tailor medication at both early and late postoperative periods.
In recent decades, transplantation (liver, kidney, heart, and lung) has become a routine procedure for patients with end stage disease. Advances in surgical techniques and postoperative therapy have led to increasing numbers of transplantation and extended survival among these patients. The final outcome of transplantation and the long-term graft function have been improved mainly due to the development of potent and specific immunosuppressive drugs. Immunosuppressants efficiently decrease the risk of rejection, blocking the recipient’s immune system and protecting the transplanted organ. Because of the narrow therapeutic indexes and increased risk of adverse drug reactions, it is essential to apply personalized immunosuppressive therapy adjusted to patient’s drug-metabolizing capacity.
Immunosuppressants are generally classified according to their molecular mode of action; however, in terms of metabolic drug interactions, two main categories must be distinguished according to their molecular weights (agents with low or high molecular weights). High-molecular-weight agents, such as polyclonal and monoclonal antibodies (e.g., thymoglobulin, basiliximab, belatacept), that are not substrates for drug-metabolizing enzymes, are metabolized in common protein degradation pathways (intracellular catabolism by endosomal-lysosomal system) [28]; therefore, they are not subjects of metabolic drug interactions and not subjects of this review. In the metabolism of immunosuppressants with low molecular weight, drug-metabolizing CYP enzymes are involved which may entail metabolic drug interactions (Table 1).
Immunosuppressant | Pharmacology | Adverse effects | Enzymes responsible for the metabolism |
---|---|---|---|
Calcineurin inhibitors: | |||
Ciclosporin | Selective inhibition of T-cell dependent immune response: Calcineurin inhibition, Inhibition of cytokine production | Nephrotoxicity, hepatotoxicity, Hyperlipidaemia, hypertension, Tremor, hyperkalaemia, hypomagnaesemia, Hypertrichosis, gingiva hyperplasia | CYP3A4/5 |
Tacrolimus | Selective inhibition of T-cell dependent immune response: Calcineurin inhibition, Inhibition of cytokine production | Nephrotoxicity, hypertension, diabetes, cholestasis, diarrhea, Tremor, hyperkalaemia, hypomagnaesemia | CYP3A4/5 |
mTOR inhibitors: | |||
Sirolimus | Inhibition of B- and T-cell proliferation | Thrombocytopenia, anaemia, leukopenia, lymphocele, pneumonitis Hyperlipidaemia, Stomatitis aphtosa, wound-healing complications | CYP3A4/5 |
Everolimus | Inhibition of B- and T-cell proliferation | Thrombocytopenia, anaemia, leukopenia, lymphocele, pneumonia Hyperlipidaemia, hypertonia, wound-healing complications | CYP3A4/5 |
Purine analogues: | |||
Azatioprin | Inhibition of purine metabolism | Bone marrow suppression, leukopenia, anaemia, thrombocytopenia, myeloid dysplasia, Cholestasis, hepatotoxicity | Thiopurine S-methyl-transferase, Xantine oxidase |
Inosine monophosphate dehydrogenase inhibitors: | |||
Mycofenolate mofetil Mycofenolate | Selective inhibition of inosine monophosphate dehydrogenase, Inhibition of B- and T-cell proliferation | Vomiting, diarrhea, abdominal pain muscle weakness, Anaemia, leucopenia | UDP-glucuronyl transferase, CYP3A4/5 |
Corticosteroids: | |||
Prednisone Methyl-prednisolone | Inhibition of T-cell migration and production of T-cell lymphokines | Adrenal cortex suppression Hypercholesterolemia, diabetes, hypertension, osteoporosis, osteonecrosis, cataracta, skin atrophy | CYP3A4/5 |
Immunosuppressants with low molecular weight.
For solid organ transplant recipients, the mainstay of the immunosuppressive regimens is calcineurin inhibitor (CNI) therapy with ciclosporin or tacrolimus which selectively blocks several signaling processes, resulting in the inhibition of T-cell activation and proliferation (Figure 1) [29, 30]. These drugs effectively treat allograft rejection; however, they display large interindividual variability in their pharmacokinetics, requiring monitoring of blood concentrations for optimal safety and therapeutic efficacy.
Molecular action of calcineurin inhibitors and corticosteriods. AP-1 activator protein 1, CAR constitutive androstane receptor, CSA ciclosporin, FKBP tarcolimus binding protein, GR glucocoticoid receptor, IL-2 interleukin 2, JNK c-Jun N-terminal kinase, MAP3K mitogen-activated protein 3 kinase, MPK-1 mitogen-activated protein kinase 1, NFAT nuclear factor of activated T-cells, PXR pregnane X receptor, Tacr tacrolimus.
Ciclosporin A is an 11-amino acid cyclopeptide that blocks the production of IL-2 by inhibition of calcineurin and, as a consequence, the activation of T-cells (Figure 1) [31]. Ciclosporin undergoes extensive metabolism by CYP3A enzymes, producing more than 30 metabolites. The major metabolic pathways are N-demethylation to 4-N-demethyl ciclosporin, hydroxylation at several positions (1-, 6-, 9-monohydroxy and 1,9- or 6,9-dihydroxy-metabolites), and oxidation to carboxylic acid [32]. Some of the metabolites (e.g., 1,9-dihydroxy-ciclosporin, 1c9-dihydroxy-ciclosporin, 1-carboxy-ciclosporin) are toxic contributing to the nephrotoxic and hepatotoxic properties of the parent compound [33, 34]. Consequently, high CYP3A activity increases the rate of ciclosporin metabolism and decreases the immunosuppressive effect, which requires dose modification [35]. However, high CYP3A activity also increases the toxic metabolite formation and the risk of nephrotoxicity and hepatotoxicity. Therefore, immunosuppressive strategy must consider the blood concentrations of both ciclosporin and the toxic metabolites, especially if they are accompanied with symptoms indicating nephrotoxicity or hepatotoxicity.
Immunosuppressive properties of tacrolimus are similar to ciclosporin; however, for the same pharmacological effect, significantly lower blood concentration of tacrolimus is required than that of ciclosporin. Tacrolimus, the 23-membered macrocyclic lactone, is converted by demethylation, hydroxylation, and ring rearrangement to at least 15 metabolites, and only a minor proportion of tacrolimus dose is eliminated as unchanged parent drug [36]. Metabolism of tacrolimus leads to the inactivation of the molecule, except for the major 13-O-demethyl and the minor 31-O-demethyl metabolites. The 13-O-demethyl-tacrolimus possesses some immunosuppressive effect; however, it is about one tenth as active as tacrolimus, whereas the 31-O-demethyl metabolite displays an immunosuppressive activity comparable to tacrolimus [37, 38]. On the other hand, high blood concentration of 15-O-demethyl-tacrolimus metabolite has been reported to be associated with nephrotoxicity and myelotoxicity and with higher incidence of infections [39]. Similarly to ciclosporin, tacrolimus is metabolized by CYP3A enzymes, anticipating great interindividual and intraindividual differences in pharmacokinetics of tacrolimus: (1) CYP3A activity of enterocytes contributes to the first-pass metabolism of tacrolimus; (2) substantial interindividual differences in hepatic CYP3A activity result in great variability in the rate of tacrolimus metabolism, which requires continuous drug monitoring and dose modification primarily in the early postoperative period; (3) concomitant treatment with CYP3A inhibitors is the potential source of metabolic drug interactions; (4) genetic polymorphisms of CYP3A5 also contribute to the high interindividual variability. Since the relative contribution of CYP3A5 to tacrolimus biotransformation is significantly higher than that of CYP3A4 [40], the recipients carrying wild type CYP3A5*1 allele or transplanted with liver grafts carrying CYP3A5*1 are able to metabolize tacrolimus more rapidly than CYP3A5 nonexpressers [35, 41].
The mTOR inhibitors prevent cell proliferation by blocking cell cycle progression from the G1-phase to the S-phase. The immunosuppressive activity is mediated via blocking mTOR protein kinases, resulting in inhibition of growth factor–mediated T-cell proliferation in response to IL-2 trigger [42]. Sirolimus is a 31-membered macrolide, whereas everolimus is a sirolimus derivative having a 2-hydroxyethyl chain substitution at position 40. Although the chemical structures of sirolimus and everolimus are similar to that of tacrolimus, the mechanism of action of mTOR inhibitors is distinct from calcineurin inhibitors, which allows the application of combination regimens. Additionally, the main advantages of mTOR inhibitors are their nonnephrotoxic properties; therefore, mTOR inhibitors in combination with reduced dose calcineurin inhibitors can augment the calcineurin inhibitor–induced nephrotoxicity [43, 44, 45].
The structural similarities can explain some common metabolic pathways of mTOR inhibitors and tacrolimus, such as O-dealkylation and hydroxylation at several positions [42]. Sirolimus is primarily metabolized by CYP3A enzymes and by CYP2C8 at lower extent, producing hydroxylated and O-demethylated metabolites (e.g., 12-hydroxy-, 16-O-demethyl-, 39-O-demethyl-, 27–39-O-didemethyl- and dihydroxy-sirolimus as major metabolites) [46, 47]. The metabolism of sirolimus leads to inactivation, despite the fact that some metabolites display some pharmacological activity less than one tenth of the parent drug. Everolimus is also metabolized by CYP3A and CYP2C8 enzymes; however, the elimination rate of everolimus is more rapid than sirolimus (with 30 h vs. 62 h elimination half-lives, respectively). Everolimus is O-demethylated and hydroxylated at several positions (forming both mono- and dihydroxy-metabolites); furthermore, a ring-opened metabolite is also formed from everolimus [46]. Everolimus-induced adverse effects are associated with the exposure rather to the parent compound than to its metabolites.
One of the oldest agents with immunosuppressive activity introduced for kidney transplant recipients was the purine analogue 6-mercaptopurine, which acts by inhibiting purine nucleotide synthesis and, as a consequence, cell proliferation. The prodrug of 6-mercaptopurine, azathioprine with more favorable side-effect profile was later introduced to prevent rejection. Azathioprine is converted to 6-mercaptopurine by nonenzymatic cleavage of the thioether in enterocytes and hepatocytes or in erythrocytes. The major active metabolites, 6-thioguanine nucleotides, are formed via 6-thioinosine monophosphate in natural purine synthetic pathways. Inhibition of cell proliferation is mediated by incorporation of the thiopurine nucleotide analogues into DNA (and RNA), causing DNA damage [48]. 6-Mercaptopurine, independently from either direct administration or production from azathioprine, undergoes metabolic inactivation by xanthine oxidase and thiopurine S-methyl transferase and is excreted in the urine, leaving less parent compound available to form thiopurine nucleotides [49]. Due to genetic polymorphism, the thiopurine S-methyl transferase activity is highly variable in patients; namely, those subjects who carry one or two nonfunctional thiopurine S-methyl transferase alleles are unable to tolerate normal doses of azathioprine and can experience serious myelosuppression [50]. Therefore, genotyping assay is recommended before starting azathioprine therapy to identify high-risk patients, and dosage reduction or alternative therapy is recommended for these patients.
Mycophenolic acid is a selective inhibitor of inosine monophosphate dehydrogenase, which is responsible for de novo biosynthesis of guanosine monophosphate, one of the building blocks of DNA. Depletion of the guanosine pool in the cell arrests the lymphotic cell proliferation and suppresses the subsequent immune response triggered by allogenic transplanted organ [51]. In several rapidly dividing cells (e.g. enterocytes), an alternative salvage pathway exists for purine synthesis in addition to de novo synthetic pathway; however, lymphocytes seem to be dependent on the de novo pathway. Consequently, mycophenolic acid is able to selectively block proliferation of T- and B-cells. Mycophenolic acid is available as enteric-coated mycophenolate sodium and as mycophenolate mofetil ester prodrug that is extensively hydrolyzed to the active metabolite mycophenolic acid by carboxylesterases.
Mycophenolic acid is primarily metabolized by UDP-glucuronyl transferases (UGT1A7/8/9, UGT2B7), forming the major 7-O-mycophenolic glucuronide that is pharmacologically inactive and to the minor acil-glucuronide that has pharmacological activity comparable to the mycophenolic acid [52, 53]. The major proportion of the glucuronide conjugates is excreted in urine, whereas a smaller proportion that is eliminated via bile is metabolized by bacteria in the gut, and the deconjugated mycophenolic acid can be reabsorbed (enterohepatic circulation) [54]. Furthermore, in patients’ blood and urine, a minor demethylated metabolite (6-O-demethyl-mycophenolic acid) was also detected that was proved to be produced by CYP3A enzymes.
At the beginning of transplantation history, glucocorticosteroids were the primary immunosuppressive agents in the rejection prophylaxis strategy, and nowadays, they are still the first-line agents for treatment of graft rejection. The high-dose glucocorticoids given in peri-transplantation are tapered to low doses in the maintenance phase, aiming the steroid-free immunosuppression regimens because of serious adverse effects of glucocorticoids developing in long-term therapy. Acute rejection is generally treated with methylprednisolone, whereas the maintenance therapy applies either methylprednisolone or prednisone. Corticosteroids activate the cytosolic glucucorticoid receptor and modulate several cellular functions, including transcription of genes involved in proliferative and inflammatory processes. The activated receptor inhibits the transcription of NF-kB and activator protein 1 dependent genes, including proinflammatory cytokines (Figure 1). This process leads to the depletion of T-cells and macrophage dysfunction [55].
Regioselective and stereospecific hydroxylation of corticosteroids at several positions (at carbon 2, 6, 7, 15, 16, and 21) are catalyzed by CYP3A enzymes. Additionally, dual effect of corticosteroids on CYP3A enzymes has been demonstrated: (1) corticosteroids can competitively inhibit the function of CYP3A [56], and (2) they can induce CYP3A transcription. Activated glucocorticoid receptor upregulates the expression of nuclear receptors (PXR and CAR) that are involved in transcriptional regulation of CYP3A genes. Moreover, the proximal promoter region of CYP3A4 gene contains glucocorticoid responsive element, which directly binds activated glucocorticoid receptor [18, 57]. As a consequence of increased expression and activity of CYP3A enzymes, metabolic drug interactions can be expected upon concomitant treatment with drugs that require CYP3A activity for their metabolism.
Although calcineurin inhibitor–based immunosuppression efficiently prevents rejection, adverse reactions of ciclosporin and tacrolimus, primarily nephrotoxicity, prompt the discovery of novel agents with immunosuppressive activity [58]. Two investigational agents with low molecular weight should be mentioned: voclosporin and sotrastaurin. Voclosporin, a next-generation calcineurin inhibitor, is an analogue of ciclosporin with a single carbon extension added to the amino acid-1 of ciclosporin. Voclosporin displays higher binding affinity to cyclophillin A than ciclosporin leading to more potent inhibition of calcineurin [59]. Furthermore, it has a favorable safety property that it appears to be less toxic than currently available calcineurin inhibitors. Similarly to ciclosporin, voclospiron is a substrate for CYP3A enzymes, anticipating pharmacokinetic/metabolic drug interactions with those agents that interact with ciclosporin as well [60]. However, voclosporin is no longer pursed in transplantation. Sotrastaurin is protein kinase C inhibitor that effectively inhibits IL-2 production with the mechanism different from calcineurin or mTOR inhibition. Although sotrastaurin displayed some potential in preventing allograft rejection in animal studies, high efficacy and safety failure rate were observed in clinical trials involving kidney and liver transplant patients [61, 62]. Therefore, further development of sotrastaurin in transplantation has been halted.
Transplant recipients’ immunosuppressive therapy is often a multidrug therapy, primarily in the early postoperative period, which constitutes a challenge for clinicians to consider the complexity of drug interactions. Due to the fact that the metabolism of immunosuppressants with low molecular weight is catalyzed by the same enzymes (CYP3A4 and CYP3A5), the blood concentrations, elimination half-lives, and consequently, the efficacy or toxicity of certain immunosuppressant agents are expected to be modified during concomitant treatment. Therefore, during multidrug therapy or during withdrawal of any of the immunosuppressive drugs, special attention is required for optimal dosing for therapeutic concentrations. Each modification in immunosuppressive regimens can lead to changes in blood concentration of a drug (Table 2).
Immunosuppressant | Drug interactions | Consequences |
---|---|---|
Ciclosporin Tacrolimus | sirolimus, everolimus | Increased blood levels of ciclosporin and mTOR inhibitors; increased risk of nephrotoxicity |
prednisolone | Decreased blood levels due to enhanced metabolism of ciclosporin/tacrolimus, increased risk of rejection | |
Antifungals: | ||
ketoconazole | Increased blood levels of ciclosporin/tacrolimus; replacement of ketoconazole to other azole derivatives | |
fluconazole, voriconazole, itraconazole | Inhibition of CYP3A4; dose reduction of ciclosporin, tacrolimus is necessary | |
Antibiotics: | ||
clarithromycin, erythromycin, azithromycin | Irreversible inhibition of CYP3A4; increased blood levels of ciclosporin/tacrolimus | |
rifampicin | CYP3A4 induction; enhanced metabolism of ciclosporin, tacrolimus; increased risk of rejection | |
Antiviral agents: | ||
ritonavir | Irreversible inhibition of CYP3A4; increased blood levels of ciclosporin/tacrolimus | |
Lipid-lowering agents: | ||
fluvastatin, simvastatin, atorvastatin | Increased statin exposure by ciclosporin; incrased risk of myopathy and rhabdomyolysis | |
Antihypertensive agents: | ||
diltiazem, verapamil, amlodipine | Irreversible inhibition of CYP3A4, formation of metabolic intermediate complex; Increased blood levels of ciclosporin / tacrolimus | |
nifedipine | Reversible, competitive inhibition CYP3A4 | |
carvedilol | Inhibition of ABCB1 transporter; increase absorption of oral ciclosporin | |
Antidiabetic agents: | ||
troglitazone, rosiglitazone | CYP3A4 induction; enhanced metabolism of ciclosporin/tacrolimus; increased risk of rejection | |
Psychopharmacons: | ||
carbamazepine, valproic acid | CYP3A4 induction; enhanced metabolism of ciclosporin/tacrolimus; increased risk of rejection | |
fluvoxamine | Inhibition of CYP3A4; contraindicated | |
Herbs: | ||
St John’s wort | CYP3A4 induction; enhanced metabolism of ciclosporin/tacrolimus; increased risk of rejection | |
grapefruit, pomelo | Irreversible inhibition of CYP3A4; increased blood levels of ciclosporin/tacrolimus | |
Sirolimus Everolimus | ciclosporin | Increased blood levels of ciclosporin and mTOR inhibitors; increased risk of nephrotoxicity |
prednisolone | Decreased blood levels due to enhanced metabolism of sirolimus/everolimus, increased risk of rejection | |
Antifungals: | ||
ketoconazole | Increased blood levels of mTOR inhibitors; replacement of ketoconazole to other azole derivatives | |
fluconazole, voriconazole, itraconazole | Inhibition of CYP3A4; dose reduction of sirolimus, everolimus is necessary; voriconazole – sirolimus combination is contraindicated | |
Antibiotics: | ||
clarithromycin, erythromycin, azithromycin | Irreversible inhibition of CYP3A4; increased blood levels of sirolimus/everolimus | |
rifampicin | CYP3A4 induction; enhanced metabolism of sirolimus/everolimus; increased risk of rejection | |
Antiviral agents: | ||
ritonavir | Irreversible inhibition of CYP3A4; increased blood levels of sirolimus/everolimus | |
Antihypertensive agents: | ||
diltiazem, verapamil, amlodipine | Irreversible inhibition of CYP3A4, formation of metabolic intermediate complex; Increased blood levels of sirolimus/everolimus; verapamil-sirolimus combination is associated with increased blood levels of verapamil | |
Antidiabetic agents: | ||
troglitazone, rosiglitazone | CYP3A4 induction; enhanced metabolism of sirolimus/everolimus; increased risk of rejection | |
Psychopharmacons: | ||
carbamazepine, valproic acid | CYP3A4 induction; enhanced metabolism of sirolimus/everolimus; increased risk of rejection | |
Herbs: | ||
St John’s wort | CYP3A4 induction; enhanced metabolism of sirolimus/everolimus; increased risk of rejection | |
grapefruit, pomelo | Irreversible inhibition of CYP3A4; increased blood levels of sirolimus/everolimus | |
6‑mercaptopurine Azathioprine | allopurinol | Inhibition of xantine oxidase; myelotoxicity |
Mycophenolate | Ciclosporin | Inhibition of enterohepatic circulation, decrease in blood levels of mycophenolic acid |
Antiviral agents: | ||
ganciclovir, valganciclovir | Mycophenolate-glucuronide inhibits renal tubular secretion of ganciclovir; increased blood levels of ganciclovir and increased risk of toxicity (nephrotoxicity, neutropenia, leukopenia) | |
Prednisolone Methylprednisolone | Antifungals: | |
ketoconazole, fluconazole, voriconazole, itraconazole | Increased blood levels of corticosteroids Inhibition of CYP3A4 | |
Antibiotics: | ||
rifampicin | CYP3A4 induction; enhanced metabolism of corticosteroids | |
Antiviral agents: | ||
ritonavir | Irreversible inhibition of CYP3A4; increased blood levels of corticosteroids |
Clinically relevant pharmacokinetic drug interactions with immunosuppressants.
Calcineurin inhibitors are often applied in combination with mTOR inhibitors. Since both mTOR inhibitors and calcineurin inhibitors are substrates of CYP3A enzymes and can inhibit CYP3A activities, reduction of calcineurin inhibitor doses is recommended. Standard doses of ciclosporin were observed to decrease the clearance of sirolimus or everolimus more substantially than the doses of tacrolimus [45]. The major drawback of calcineurin inhibitor therapy is the risk of nephrotoxicity which appears to be dose dependent. The combination of low calcineurin inhibitor doses with mTOR inhibitors was found to be beneficial regarding retaining low rejection rates and lowering the risk of nephrotoxicity [44, 63]. To avoided renal dysfunction, the complete substitution of calcineurin inhibitors for mTOR inhibitors was attempted; however, the substitution showed an increase in graft failure in patients treated with merely mTOR inhibitors [64].
Corticosteroids have been demonstrated to induce the expression of the efflux pump transporter ABCB1 (P-glycoprotein) playing a main role in intestinal drug absorption and of CYP3A enzymes responsible for the metabolism of the majority of drugs [18, 65]. Therefore, the concomitant treatment of calcineurin inhibitors or mTOR inhibitors with corticosteroids can be expected to decrease the blood concentrations of tacrolimus/ciclosporin or of sirolimus/everolimus. Although the evidence for clinically significant interactions between corticosteroids and ciclosporin or mTOR inhibitors is limited, clear clinical effect of corticosteroids on tacrolimus exposure has been demonstrated [66, 67]. This also implies that dose reduction or cessation of corticosteroids leads to an increase in blood concentrations of tacrolimus, requiring dose adjustment [68]. Interestingly, CYP3A5 nonexpressers with CYP3A5*3/*3 genotype are more susceptible to glucocorticoid induction than CYP3A5*1 carriers [69]; thus, more pronounced increase in tacrolimus exposure can be expected in CYP3A5 nonexpressers after glucocorticoid withdrawal.
Clinically significant interaction between mycophenolic acid, the active metabolite of mycophenolate mofetil, and ciclosporin has been reported [70]. The mycophenolate-glucuronide metabolite eliminated into bile undergoes enterohepatic cycling because of intestinal bacterial metabolism and reabsorption of mycophenolic acid. The enterohepatic circulation, contributing to overall pharmacokinetics of mycophenolic acid by 37% in human, is inhibited by concomitant administration of ciclosporin but does not interfere with tacrolimus or sirolimus [71, 72]. In ciclosporin-mycophenolate combination therapy, the reduced blood concentration of mycophenolic acid is necessary to ameliorate by increasing dose of mycophenolate mofetil. Furthermore, special attention on optimal dosing is required during switching ciclosporin-mycophenolate to tacrolimus-mycophenolate therapy and vice versa.
Environmental circumstances and immune deficiencies due to immunosuppression therapy make recipients susceptible for infections that are one of the leading complications after organ transplantation; therefore, prevention and management of infections is a major task primarily in the early postoperative period. Since fungal infections are a threatening cause of morbidity and mortality, the antifungal prophylaxis is an important element of posttransplant medication. The antifungal azole-derivatives are potent (some of them are very strong) CYP3A inhibitors, predicting potential metabolic drug interactions with calcineurin inhibitors, mTOR inhibitors, or corticosteroids. The most potent CYP3A inhibitor is ketoconazole, able to increase blood concentrations (AUC) of ciclosporin (> 4-fold), tacrolimus (> 2-fold), sirolimus (11-fold), everolimus (15-fold), and methylprednisolone (> 2-fold) [73, 74]. Because of the substantial increase in blood concentrations of several immunosuppressants that can be avoided by drastic reduction of immunosuppressant doses and because of other adverse effects of ketoconazole, the concomitant medication is discouraged. Fluconazole, itraconazole, and voriconazole are alternative regimens for antifungal therapy or prophylaxis; however, all three drugs are azole derivatives and have the capability to inhibit CYP3A function, albeit at a lower extent than ketoconazole [75, 76, 77]. Although the continuous immunosuppressant monitoring is highly recommended and dose adjustment (reduction) is generally required, the antifungal treatment with fluconazole, itraconazole, or voriconazole can be safely applied except for voriconazole-sirolimus combination [78]. Because of an extreme (7-fold) increase of sirolimus blood concentrations as a consequence of concomitant use of voriconazole, this combination is contraindicated. Amphotericin B, the nonazole type antifungal agent, does not influence CYP activities; therefore, no metabolic drug interactions can be expected in concomitant treatment with immunosuppressants. However, the widespread use of amphotericin B is limited because of its toxicity profile, primarily because its nephrotoxic side-effect can contribute to the renal injury by ciclosporin or tacrolimus.
Organ transplant patients are at high risk for developing bacterial infections that occur in 20–40% of transplants. Potential sources of infection are from hospital and community exposures, as well as from endogenous flora of patients. Among the antibiotics used for treatment of infections, the macrolide erythromycin and clarithromycin have been reported to interact with immunosuppressive agents. These macrolides are CYP3A substrates and bind to CYP3A4 enzymes, leading to a complex formation that completely inactivates CYP3A4 enzyme [79, 80, 81, 82]. The in vitro findings were confirmed by clinical observations that blood concentrations of ciclosporin/tacrolimus or sirolimus/everolimus increased as a consequences of concomitant treatment with erythromycin or clarithromycin [73, 83, 84, 85, 86]. Page et al. [87] and Mori et al. [88] have reported some potential of azithromycin for drug interaction with ciclosporin and tacrolimus; however, in vitro experiments demonstrated that azithromycin poorly interfere with CYP3A4 [89]. When concomitant therapy with these macrolides is necessary, blood concentrations of calcineurin inhibitors or mTOR inhibitors should be carefully monitored, and the immunosuppressant doses should be adjusted. In contrast, the macrolide rifampicin is a potent CYP3A4 inducer and can activate PXR, resulting in a substantial increase in CYP3A4 expression [90]. The increased CYP3A4 activity consequently enhances the metabolism and elimination of calcineurin inhibitors, mTOR inhibitors, and corticosteroids [91, 92, 93]. However, blood concentration–guided dose-adjustment of immunosuppressants should be applied carefully because increased metabolism can evoke elevation of toxic metabolite formation (e.g., ciclosporin).
A significant cause of graft failure still remains viral infections, which are acquired as new infection or reactivation of latent viruses. After transplantation, cytomegalovirus (CMV) is the most common viral infection in recipients, primarily in those CMV-seronegative patients who were transplanted with graft from CMV-seropositive donors, resulting in viral reactivation. For prophylaxis and treatment of CMV infection, aciclovir, ganciclovir, and valganciclovir (the prodrug of ganciclovir) are generally applied. None of these antiviral drugs influences the function of drug-metabolizing CYPs or UDP-glucuronyl transferases, and consequently, they do not modify the pharmacokinetic properties of immunosuppressants. Aciclovir and ganciclovir are eliminated primarily in the urine as unchanged compounds. Increased risk of nephrotoxicity and leukopenia has been reported in patients who were co-medicated with a drug that can reduce renal clearance of aciclovir or ganciclovir. During co-administration with mycophenolate or mycophenolate-mofetil, mycophenolate-glucuronide and aciclovir or ganciclovir can significantly compete for renal tubular secretion, resulting in an increase in aciclovir/ganciclovir and mycophenolate-glucuronide exposure, as well as the risk of nephrotoxicity or leukopenia [94, 95, 96]. Management of potent metabolic drug interactions between antiviral protease inhibitors and immunosuppressants is a major challenge because most of the protease inhibitors are clinically significant CYP3A4 inhibitors. Ritonavir-boosted therapies require substantial reduction of immunosuppressant doses (to 5–20% for ciclosporin; to 1–3.5% for tacrolimus) with continuous monitoring of blood concentrations [97, 98, 99, 100, 101].
Dyslipidemia is often developed as an adverse impact of immunosuppressive therapy [102]. Ciclosporin, mTOR inhibitors, and prednisone are mainly implicated in lipid alterations. For treatment of hypercholesterolemia, the basic guidelines for dyslipidemia recommend diet and HMG-CoA reductase (hydroxymethyl-glutaryl-CoA reductase) inhibitor statins with special considerations for transplant patients. Although both ciclosporin and most statins (atorvastatin, fluvastatin, simvastatin, lovastatin) are primarily metabolized by CYP3A4 and metabolic drug interactions are likely occur, statins do not evoke increased ciclosporin exposure [103, 104, 105, 106]. In contrast, ciclosporin induces significant elevation of statin blood concentrations which can be explained by the ten-fold higher molar concentrations of ciclosporin than statins. In combination with ciclosporin, the blood levels are increased in a statin-dependent manner, e.g., lovastatin is increased to a much greater extent than atorvastatin [104, 107]. Dose reduction of lipid-lowering agents is recommended to avoid myopathy or rhabdomyolysis. The blood concentrations of macrolide immunosuppressants (tacrolimus, sirolimus, and everolimus) are similar to that of statins [108, 109]; therefore, the lack of clinically relevant interactions between macrolides and statins is not unexpected.
Organ transplantation and immunosuppressive therapy (e.g., ciclosporin, prednisone) frequently trigger hypertension or worsen the preexisting disease in patients. While most of the antihypertensive agents (β-adrenoceptor blockers, α1-adrenergic receptor antagonists, central α2-adrenergic receptor agonists, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers) are not expected to influence the pharmacokinetics of immunosuppressants, medication with diltiazem, verapamil, or amlodipine requires special consideration and frequent monitoring of immunosuppressant blood concentrations. The metabolism of all three Ca-channel blockers is primarily catalyzed by CYP3A4, anticipating potential drug interactions with immunosuppressants. Furthermore, significant inhibition of CYP3A4 by diltiazem, verapamil, and amlodipine has been demonstrated with an additional inhibitory property of metabolite intermediate complex formation that catalytically inactivates CYP3A4 and CYP3A5 enzymes [79, 80, 82, 110, 111, 112, 113, 114]. The inactivation of CYP3A enzymes by comedication with these antihypertensive drugs consequently leads to a permanent increase in blood concentrations of calcineurin inhibitors or mTOR inhibitors [115, 116, 117, 118, 119, 120, 121, 122]. In transplant recipients comedicated with sirolimus and verapamil, an increase of blood concentrations of both sirolimus and verapamil was observed [123]. Furthermore, in patients carrying wild-type CYP3A5*1 allele, concomitant treatment with amlodipine significantly decreased tacrolimus clearance, and along with the changes in tacrolimus pharmacokinetics, an increase in amlodipine blood concentrations was also observed [124]. The metabolism of the Ca-channel blocker nifedipine is catalyzed almost exclusively by CYP3A enzymes, and competition for the active site of CYP3As may be expected if nifedipine and CYP3A substrate calcineurine inhibitors or mTOR inhibitors are concomitantly applied. In contrast, no evidence for pharmacokinetic drug interactions has been provided in transplant recipients treated with nifedipine and ciclosporin/tacrolimus or sirolimus/everolimus. Carvedilol is often used for treatment of hypertension in transplant patients, and pharmacokinetic drug interaction between carvedilol and ciclosporin has been observed that required 10–20% reduction of ciclosporin doses to maintain the blood concentrations within the therapeutic range [125, 126]. The major metabolic pathways of carvedilol are catalyzed by CYP2D6 and CYP1A2 rather than by CYP3A4 [127]; however, inhibition of CYP3A enzymes by carvedilol does not account for pharmacokinetic drug interaction with ciclosporin. Carvedilol has been demonstrated to block the function of the ABCB1 transporter protein (ATP-binding cassette B1; previously called as Pgp) [128]. In the intestinal wall, ABCB1 transporter pumps pharmacons or other xenobiotics passed into the enterocytes back into the gut lumen. The inhibition of ABCB1-mediated transcellular transport in the intestine by carvedilol is responsible for the increased absorption of ciclosporin. Under careful monitoring of ciclosporin blood concentration, the ABCB1 inhibition by carvedilol can be beneficial in ciclosporin-sparing therapy for transplant patients. Since the absorption of tacrolimus and mTOR inhibitors is also mediated by ABCB1, similar pharmacokinetic drug interactions between these immunosuppressants and carvedilol are presumably developed as with ciclosporin.
Hyperglycemia developing posttransplant diabetes mellitus is generally medication related. Corticosteroids can evoke reduction of glucose tolerance, whereas ciclosporin and tacrolimus directly block insulin-release by islet cells. The metabolism of the sulfonylurea type antidiabetic agents (e.g., tolbutamide, glipizide, glibenclamide, and glimepiride) is mediated by CYP2C9; therefore, metabolic drug interactions with immunosuppressants are not expected in patients treated with any of these oral hypoglycemic drugs. Although the thiazolidinedione type troglitazone and rosiglitazone are not CYP3A substrates, they can induce the expression of CYP3A enzymes by activation of the nuclear receptors, PXR and CAR [129, 130, 131, 132]. Enhanced transcription results in an increase in CYP3A activities and the metabolism of calcineurin inhibitors, mTOR inhibitors and corticosteroids, increasing the risk of rejection [133]. Immunosuppressant dose adjustment is required to avoid subtherapeutic blood concentrations, and careful monitoring of immunosuppressant blood concentrations is recommended during withdrawal of troglitazone or rosiglitazone and during switching to other antihyperglycemic agent.
The most common psychiatric disorders encountered in transplant patients are anxiety, depression, mood disorders, behavior problems, and insomnia that are reversible in most cases; however, they often require psychotherapy with antidepressants, mood stabilizers, anxiolytic agents, or even with antipsychotics. Many of these pharmacons are metabolized by enzymes other than CYP3A4 and do not influence the drug-metabolizing activities of CYP3A4; consequently, metabolic drug interactions with immunosuppressants cannot be expected. Nevertheless, the CYP3A4 inducing or inhibitory properties of some of these psychopharmacons should be considered. The mood stabilizer carbamazepine and valproic acid have been clearly evidenced to be able to activate CAR and PXR. The nuclear receptor activation leads to an increase in transcription of CYP3A4 gene and CYP3A4 metabolic activity [134, 135], anticipating decrease of immunosuppressant blood concentrations [136]. To reduce the risk of organ rejection, adjustment (increase) of immunosuppressant doses is required with continuous monitoring of immunosuppressant blood levels. Furthermore, the CYP3A4 deinduction process can last for about 2 weeks after cessation of carbamazepine or valproic acid [137]; thus, careful monitoring of immunosuppressant blood concentrations during withdrawal is essential. The comedication with the antidepressant fluvoxamine is contraindicated because of its strong inhibitory properties for CYP3A4 substrates and potential drug interactions with ciclosporin/tacrolimus or with sirolimus/everolimus [80, 138, 139]. For psychotherapeutic agents that are CYP3A substrates (haloperidol, quetiapine, clonazepam, midazolam, alprazolam), continuous monitoring of immunosuppressant blood levels is highly recommended to avoid metabolic drug interactions.
The metabolic drug interactions with ciclosporin/tacrolimus, sirolimus/everolimus, and corticosteroids are generally associated with reversible or irreversible inhibition of CYP3A activities, as well as with transcriptional induction of CYP3A4 and CYP3A5 expression. Clinically significant drug interaction occurs during simultaneous therapy with azathioprine (or 6-mercaptopurine) and allopurinol, the antihyperuricemic agent [140, 141]; however, it involves enzyme other than CYP3As. The metabolism of both 6-mercaptopurine and allopurinol is catalyzed by xantine oxidase, anticipating metabolic drug interactions and developing serious adverse reactions. As a consequence of inhibition of xantine oxidase by allopurinol, myelotoxicity is evoked by the accumulation of 6-thioguanine-nucleotide metabolites of azathioprine. The risk of bone marrow depletion is increased in patients with low thiopurine methyl-transferase activity. To avoid the serious myelosuppression during treatment of hyperuricemia and gout, substantial reduction of azathioprine dose (by at least 50%) is required when allopurinol is given concomitantly, or alternative agents other than allopurinol should be considered [142, 143, 144].
Pharmacokinetic herb-drug interactions can also significantly influence the outcome of immunosuppressive therapy and long-term graft survival [145]. St John’s wort (Hypericum perforatum) extract and grapefruit juice are well described as modifiers of pharmacokinetic properties of ciclosporin and tacrolimus [146, 147, 148]. St John’s wort extract is a herbal product for treatment of symptoms of mild or moderate depression, including anxiety, fatigue, and sleeping problems. The extract contains a number of biologically active components, e.g., hyperforin of high interest. Hyperforin has a strong affinity for PXR and significantly increases the expression and activities of CYP3A4 enzyme, which is involved in metabolism of many drugs [149, 150]. Consequently, chronic consumption of St John’s wort extract can decrease the blood concentrations of CYP3A substrates, such as calcineurin inhibitors, mTOR inhibitors, and corticosteroids [151, 152, 153, 154]. In addition, St John’s wort extract has been reported to induce the expression of ABCB1 transporter that reduces the absorption of ABCB1-ligand drugs from the gut. The hyperforin contents of commercially available St John’s wort preparations are variables that appear to significantly affect the extent of pharmacokinetic interactions [150, 155]. Coadministration of ciclosporin with St John’s wort extract has been reported to lead a 40–60% decrease of ciclosporin blood concentrations, increasing the risk of rejection; therefore, substantial dose adjustment is required [151, 152, 155, 156, 157, 158, 159]. Since clinicians are often unaware of concomitant consumption of herbal supplements, transplant patients should be informed about the drug interaction potential of St John’s wort that can endanger the success of organ transplantation.
Concomitant intake of grapefruit (Citrus paradisii) or pomelo (Citrus grandis) has been demonstrated to increase the bioavailability of immunosuppressants [147, 160, 161]. Some components of these citrus fruits, bergamottin and naringenin responsible for the bitter taste, can inhibit the activities of CYP3A4 and CYP3A5 enzymes both in the intestinal wall and in the liver, resulting in significant reduction of first-pass metabolism of CYP3A substrates, including ciclosporin and tacrolimus [162, 163, 164]. Significant reduction of ciclosporin/tacrolimus doses is necessary to avoid the risk of nephrotoxicity or other adverse events associated with immunosuppressive therapy. The furanocoumarin bergamottin is a “suicide substrate,” namely it is metabolized by CYP3A4 to an epoxid metabolite that covalently binds to and inactivates the enzyme [165]. The flavonoid naringenin was found to be a less-potent CYP3A4 inhibitor than bergamottin [166]; however, during consumption of grapefruit, the inhibitory effects of naringenin and bergamottin are added together. Since clear evidence of bergamottin content and CYP3A4 inhibitory potential of citruses other than grapefruit and pomelo was provided [167], the transplantation centers do not recommend citrus consumption for transplant patients during immunosuppressive therapy.
Although success of organ transplantation is continuously improving, several short- and long-term complications can adversely affect the outcome. One of the most significant factors influencing the long-term graft and patient survival is the appropriate immunosuppressive therapy. Subtherapeutic blood concentrations of immunosuppressive drugs can evoke acute or chronic graft injury mediated by immunological mechanisms, whereas overdosing leads to over-suppression of the immune system that consequently develops serious infections, as well as adverse and even life-threatening side effects. Because of the narrow therapeutic indexes, dosing of most of the immunosuppressive agents is applied under careful monitoring of their blood concentrations. The knowledge of the potential factors that can modify immunosuppressive therapy, as well as pharmacokinetic and metabolic drug interactions, can decrease the fluctuation of immunosuppressant blood concentrations, can facilitate to avoid the serious adverse events, can improve the therapeutic outcome for transplant patients, and can reduce the medical costs.
The appropriate and tailored immunosuppressive medication is a great challenge and requires careful and continuous attention, because unrecognized simple interactions can induce serious complications. As such during administratrion of clarithromycin or antifungal agents without dose reduction of calcineurin inhibitors or mTOR inhibitors, blood concentrations of immunosuppressants can substantially exceed the therapeutic range within some days. Without dose modification, a reverse outcome is expected during comedication with anticonvulsants (valproic acid and carbamazepine) or with rifampicin resulting in subtherapeutic blood concentrations of immunosuppressants and increasing the risk of organ rejection. The lack of mycophenolate dose reduction during cessation of ciclosporin or replacement of ciclosporin to another immunosuppressant can also evolve development of serious adverse reactions. It is anticipated that the special attention and the knowledge of potential drug interactions can prevent the majority of misdosing-induced adverse events.
This work was supported by MedInProt Synergy VIII program of the Hungarian Academy of Sciences and by the Society of Hungarian Toxicologists.
The author declares that there is no conflict of interest.
Extremophile organisms capable of growing in extreme conditions draw considerable attention since they show that life is robust and adaptable and help us understand its limits. In addition, they show a high biotechnological potential [1, 2]. Most of the best-characterized extreme environments on Earth are geophysical constraints (temperature, pressure, ionic strength, radiation, etc.) in which opportunistic microorganisms have developed various adaptation strategies. Deep-sea environments, hot springs and geysers, extreme acid waters, hypersaline environments, deserts, and permafrost or ice are some or the most recurrent examples of extreme environments [3]. However, the atmosphere is rarely thought of as an extreme habitat. In the atmosphere, the dynamics of chemical and biological interactions are very complex, and the organisms that survive in this environment must tolerate high levels of UV radiation, desiccation (wind drying), temperature (extremely low and high temperatures), and atmospheric chemistry (humidity, oxygen radicals, etc.) [4]. These factors turn the atmosphere (especially its higher layers) into one of the most extreme environments described to date and the airborne microorganisms into extremophiles or, at least, multiresistant ones [5].
\nIt is known that airborne cells can maintain viability during their atmospheric residence and can exist in the air as spores or as vegetative cells thanks to diverse molecular mechanisms of resistance and adaptation [2, 6]. The big question is whether some of them can be metabolically active and divide. Bacterial residence times can be several days, which facilitate transport over long distances. This fact, together with the extreme conditions of the atmosphere, has led researchers to think for years that they do not remain active during their dispersion. However, recent studies strongly suggest that atmospheric microbes are metabolically active and were aerosolized organic matter and water in clouds would provide the right environment for metabolic activity to take place. Thus, the role played by microorganisms in the air would not only be passive but could also influence the chemistry of the atmosphere. In any case, only a certain fraction of bacteria in the atmosphere would be metabolically active [2, 7].
\nDespite recognizing its ecological importance, the diversity of airborne microorganisms remains largely unknown as well as the factors influencing diversity levels. Recent studies on airborne microbial biodiversity have reported a diverse assemblage of bacteria and fungi [4, 8, 9, 10, 11, 12], including taxa also commonly found on leaf surfaces [13, 14] and in soil habitats [15]. The abundance and composition of airborne microbial communities are variable across time and space [11, 16, 17, 18, 19]. However, the atmospheric conditions responsible for driving the observed changes in microbial abundances have not been thoroughly established. One reason for these limitations in the knowledge of aerobiology is that until recently, microbiological methods based on culture have been the standard, and it is known that such methods capture only a small portion of the total microbial diversity [20]. In addition, because pure cultures of microorganisms contain a unique type of microbes, culture-based approaches miss the opportunity to study the interactions between different microbes and their environment.
\nAnother limitation for the study of aerial microbial ecology at higher altitudes or in open ocean areas is the difficulty of repeated and dedicated use of airborne platforms (i.e., aircraft or balloons) to sample the air. Most studies to date on the atmospheric microbiome are restricted to samples collected near the Earth’s surface (e.g., top of mountains or buildings). Aircraft, unmanned aerial systems (UASs), balloons or even rockets, and satellites could represent the future in aerobiology knowledge [5, 21, 22]. These platforms could open the door to conducting microbial studies in the stratosphere and troposphere at high altitudes and in open-air masses, where long-range atmospheric transport is more efficient, something that is still poorly characterized today. The main challenge in conducting these kinds of studies stems from the fact that microbial collection systems are not sufficiently developed. There is a need for improvement and implementation of suitable sampling systems for platforms capable of sampling large volumes of air for subsequent analyses using multiple techniques, as this would provide a wide range of applications in the atmospheric, environmental, and health sciences.
\nIn aerobiology, dust storms deserve special mention. Most of them originate in the world’s deserts and semideserts and play an integral role in the Earth system [23, 24]. They are the result of turbulent winds, including convective haboobs [25]. This dust reaches concentrations in excess of 6000 μg m−3 in severe events [26]. Dust and dust-associated bacteria, fungal spores, and pollen can be transported thousands of kilometers in the presence of dust [9].
\nIn this chapter, we approach the atmosphere as an extreme environment and make use of some advanced data from an example of an in situ study of the atmosphere: the analysis of bacterial diversity of the low troposphere of the Iberian Peninsula during an intrusion of Saharan dust using a C-212 aircraft adequately improved for aerobiological sampling.
\nIt is well known that there is a biota in the atmospheric air. The first study dates back to the nineteenth century, which speak about the presence and dispersion of microorganisms and spores in the atmosphere [27, 28]. Although the atmosphere represents a large part of the biosphere, the density of airborne microorganisms is very low. Estimates suggest that from the ground surface up to about 18 km above sea level (troposphere), there is less than a billionth of the number of cells found in the oceans, soils, and subsurface. Between approximately 18 and 50 km above sea level (stratosphere), temperature, oxygen, and humidity decrease and with them the number of cells. Above the ozone layer (between 18 and 35 km into stratosphere), ultraviolet (UV) and cosmic radiation become lethal factors. Once in the mesosphere (above 50 km), life is difficult to imagine; however microorganisms of terrestrial origin could arrive to the stratosphere from lower layers via different phenomena (human activity, thunderstorms, dust storms, or volcanic activity), and bacteria have been found isolated up to 41 km or in dust samples from the International Space Station (\nFigure 1\n) [6, 29]. Therefore, airborne microbes are always present in the atmosphere [11, 30, 31], and their permanence is dynamic, resulting in an environment with enormous variability. Estimates calculate that over 1021 cells are lifted into the atmosphere every year, leading to considerable transport and dispersal around the atmosphere, with a large portion of these cells returning to the surface due to different atmospheric events as part of a feedback cycle. Undoubtedly, airborne microbes play an important role in meteorological processes. They have been linked to the nucleation phenomena that lead to the formation of clouds, rain, and snow and to the alteration of precipitation events [32, 33, 34]. Their presence is essential to understand long-range dispersal of plant and potential pathogens [7, 35, 36] and maintain diversity in ground systems and could interfere with the productivity of natural ecosystems [17, 18]. On the other hand, airborne bacteria can have important effects on human health, being responsible for different phenomena such as seasonal allergies and respiratory diseases. Based on data from terrestrial environments, the global abundance of airborne bacteria has been estimated to range between 104 and 106 m−3 [37]. However, more recent studies incorporating direct counting by microscopy or quantitative PCR have provided more accurate estimates of the number of airborne microbes, which apparently point to a higher number of cells present in the atmosphere [38, 39, 40, 41].
\nDiagram displaying atmosphere layers, temperature and airborne emission sources. Yellow line marks atmospheric temperature. Bottom of the figures shows the common sources of aerosolized bacteria, with special attention to dust storms.
There is a great variety of airborne microorganism sampling systems, allowing us to select the most suitable one depending on our objectives [42]. On the other hand, no standardized protocols exist, which is a major pitfall when developing our objectives. This fact has led some authors to propose the creation of consortiums of interested parties for establishing standardized protocol reproducibility [20], as well as the need to establish global networks of aerobiological studies [11]. Two approaches are proposed: particles or cells can be collected passively or directly from the atmosphere. Passive media usually involves decanting [43] and collecting particles over snow [44] or through the collection of atmospheric water [45]. On the other hand, active methodologies entail three major approaches: filtration, impaction, and liquid impingement. All three approaches are very efficient when developing culture-dependent techniques. In contrast, culture-independent approaches produce some serious problems that make the work difficult: the high variability of the system and the low biomass mean that sampling campaigns are, in many cases, extremely inefficient [20]. Lastly, the use of airborne platforms is not very extended, but they represent a good opportunity to conduct a more direct study of the atmosphere [5, 19, 31].
\nFiltration is a simple and cheap method that is often efficient. It involves pumping air through a filter where the mineral and biological particles are trapped. Filters of different materials and porosity are available made of cellulose, nylon, polycarbonate or fiberglass, or quartz. Sizes used range from 0.2 to 8 μm, depending on the size of the particles to be captured and the capacity of the pump. In many cases, a PM10 filter can give better results when collecting smaller bacteria, as it allows greater airflow. Airflow filtration rates generally range between 300 and 1000 L/minute [4, 46]. Microorganisms trapped in the filter can be cultured, or the filters can be directly used for DNA extraction. In addition, filters are a very suitable support for microscopy, and countless holders for filters are available (an example is shown in \nFigure 2A\n).
\nThree different samplers of airborne microorganisms. (A) Filter holder and a filter (PALL Corporation). (B) Impinger sampling of bioaerosols (BioSampler, SKC, Inc.). (C) Six-stages Andersen Cascade Impactor (Thermo Fisher Scientific).
In impingement, particles are collected in a liquid matrix [20]. Normally a buffer is used such as phosphate buffer saline (PBS) that helps maintain the viability of the cells. One of the more widely used liquid impingers is BioSampler SKC (\nFigure 2B\n). In this case, the tangential movement of the particles inside the flow impinger retains the particles in the collecting liquid. The suspension obtained could be used for culturing or for molecular ecology assays [20]. One of the advantages of impingement collection is that it facilitates quantitative techniques such as flow cytometry or in situ hybridization [47].
\nIn this system, the particles generally impact into a petri dish with an enrichment medium. It is, possibly, the most efficient and most used method to conduct studies based on culture. Airflow impacting onto the plates is controlled by slots that allow the homogeneous distribution of the air. The system can be single stage or several stages in cascade, causing the particles to be distributed by size in the different petri dishes [20]. Some variants replace petri dishes with agarose filters or Vaseline strips, in order to carry out independent culture methodologies, but efficiency is very low. The original and more popular impactor is the Andersen cascade impactor (\nFigure 2C\n) [48].
\nSeveral studies explain and compare sampling methodologies in aerobiology, but most of them focus on the surface of the Earth (e.g., on top of mountains or buildings) or indoors [42, 49, 50, 51, 52, 53, 54]. However, small studies have been conducted at higher altitudes or in open sea areas. The use of airborne platforms (balloons, aircraft, rockets, etc.) for aerobiology sampling would allow conducting a direct study of the microbial ecology of the atmosphere. Another advantage of airborne platforms is the possibility of studying the vertical distribution of airborne microbial communities. In addition, some aircraft allow us to develop studies in the upper troposphere or in the stratosphere. Unfortunately, atmospheric microbial collection instruments have not been developed enough for airborne platforms.
\nAmong the different airborne platforms, aircraft, due to their versatility and access, are particularly interesting. Some studies have been conducted, but not enough samples have been developed yet, and efficiency is still very low. As already mentioned, the efficiency of samplers in soil-level aerobiology faces a series of problems (low biomass, high variability of populations, lack of standardized protocols). In the case of airplanes, in addition to these intrinsic problems associated with atmospheric microbial ecology, other additional ones exist: (1) the high velocity of the aircraft in relation to the relative quiescent air mass. This makes it difficult to obtain an isokinetic sampler and, therefore, one that is sufficiently efficient that would allow us to obtain a correct quantification of the incoming air [55]; (2) the sampler must be in a location on the airplane that avoids chemical contamination from the operation of the device. Previous studies have used wing-mounted air samplers or the roof of the aircraft to reduce the possibility of in-flight contamination [21, 22, 56, 57, 58]. Similarly, it should allow the aseptic collection of samples, avoiding microbiological contamination during the process. This operation, which can be very simple in the laboratory or at ground level, becomes tremendously complicated on an airplane, since air intakes that are part of the fuselage of the aircraft are often difficult to sterilize. It is therefore necessary to develop robust sterilization protocols. The spectacular work of DeLeon-Rodríguez of 2013 has been criticized in this aspect [40, 59]; (3) sampling time. A possible solution to the low biomass of the atmosphere is to increase sampling time, but in the case of flights, we are limited to the flight autonomy of the aircraft. Although scarce, some studies from airplanes have been conducted. The first studies that were conducted in airplanes were carried out by impaction on a petri plate with enrichment means, which allowed isolating microorganisms from the upper troposphere and even from the stratosphere [21, 57, 60]. However, advances in molecular ecology have caused the most recent studies to favor filtration [40, 58].
\nThe European Facility for Airborne Research (EUFAR) program brings together infrastructure operators of both instrumented research aircraft and remote sensing instruments with the scientific user community. However, it lacked aircraft prepared for microbiological sampling. The National Institute for Aerospace Technology (INTA) belonging to the Spanish Ministry of Defence has two CASA C-212-200 aircraft that were suitably modified to be used as flying research platforms. Now, these two aircraft are a unique tool for the study of atmospheric microbial diversity and the different environments of the EUFAR program. Our research group has a CASA-212 aircraft with an air intake located on the roof of the aircraft. A metal tube fits the entrance and is fitted inside the aircraft to a filter holder, a flowmeter, and a pump (\nFigure 3\n). This simple system is easy to sterilize, and both the metal tube and the filter holder can be replaced in flight by other sterile ones if we want to take different samples. Using PM10 fiberglass filters, we can obtain isokinetic conditions and pass 1800 L of air per hour through the filter, as indicated by the flowmeter.
\nAirborne microorganisms sampler installed in INTA’s CASA C-212-200 aircraft.
In a series of recent experiments, we tried to install a multi-sampler system in our aircraft, where we had five systems in parallel and connected to the same intake of the plane: one filter holder, two impingement systems, and two impactors (\nFigure 4\n). The results clearly showed that in the case of our aircraft, filtration was more efficient (data not shown).
\nMulti-sampler system tested in INTA’s CASA C-212-200 aircraft. (A) Impinger sampler, design and manufacture own. (B) Impactor sampler (Impaktor FH6, Markus Klotz GmbH). (C) Coriolis μ (Bertin Technologies SAS) a impinger biological air sampler. (D) Filter holder (PALL Corporation). (E) Six-stages Andersen Cascade Impactor (Thermo Fisher Scientific).
Aerobiology studies have traditionally focused on the collection of bacterial cells and the analysis of samples by total counting and culture-based techniques. It is known that such methods capture only a small portion of the total microbial diversity [61]. The almost exclusive use, for years, of these methodologies is one of the reasons for these limitations in the knowledge of aerobiology. In addition, culture-dependent methods do not allow us to study the interactions between different species of microorganisms. Culture-independent methods have been used to assess microbial diversity, increasing the specificity of microbial identification and the sensitivity of environmental studies, especially in extreme environments. These methods have recently been applied to various areas of airborne microbiology [62, 63, 64, 65] revealing a greater diversity of airborne microorganisms when compared to culture-dependent methods. Some good studies approach the challenges and opportunities of using molecular methodologies to address airborne microbiology [20, 66]. Although molecular ecology methods allow the rapid characterization of the diversity of complex ecosystems, the isolation of the different components is essential for the study of their phenotypic properties in order to evaluate their role in the system and their biotechnological potential. A combination of culture-dependent and culture-independent methods is ideal to address the complete study of the system.
\nModern culture-independent approaches to community analysis, for example, metagenomics and individual cell genomics, have the potential to provide a much deeper understanding of the atmospheric microbiome. However, molecular ecology techniques face several particular challenges in the case of the atmospheric microbiome: (1) very low biomass [20]; (2) inefficient sampling methods [20]; (3) lack of standard protocols [9, 20]; (4) the composition of airborne microbes continuously changes due to meteorological, spatial, and temporal patterns [7, 62, 67, 68, 69, 70]; and (5) avoidance of the presence of foreign DNA in the system [59]. Because these issues are not yet resolved, most of the non-culturing approaches focus on microbial diversity, where they are highly efficient.
\nThe most recurrent techniques are those based on DNA extraction, gene amplification of 16S/18S rRNA, and next-generation sequencing (NGS) technologies. Often, this approach is more efficient due to the greater efficiency and sensitivity of this process, as opposed to gene cloning and Sanger sequencing; thus some authors are inclined toward metagenomics instead of amplification. This provides more information and avoids an intermediate step, but bioinformatic processing is tedious and often only provides data in relation to diversity, making the annotation of the rest of the information very complicated [20]. These approaches can be complemented with quantitative methods such as qPCR, flow cytometry, or fluorescence in situ hybridization (FISH) [41, 47, 66, 71]. FISH is surely the best and most specific cell quantification methodology that exists. However, in the case of aerobiology, it cannot always be used. A minimum number of cells must exist so that we can observe and count them under a fluorescence microscope. Due to the variability of microbial populations in the air, this is not always achieved. In our research group, we have obtained very good results in this regard, optimizing cell concentration. \nFigure 5\n shows epifluorescence micrographs of bacteria from an air sample. On this occasion, sampling was performed using a biological air sampler (Coriolis μ, Bertin Technologies SAS), where biological particles are collected and concentrated in a liquid (PBS). Sampling was conducted for 2 hours at ground level, pumping a total of 36,000 L of air. After this time, the sample was paraformaldehyde fixed and filtered through a 0.2 μm pore size, hydrophilic polycarbonate membrane, 13 mm diameter (GTTP, Millipore). A half sample was hybridized with the universal Bacteria domain probe, EUB338I-III [72], following a conventional protocol [73]. The second half was hybridized with the probe NON338 [74] as negative control. In this case, an average of 140 cells per liter of air was counted. Occasionally, FISH also allows to observe bacteria attached to mineral particles (\nFigure 5C\n–\nD\n).
\nEpifluorescence micrographs of bacteria from an air sample. (A and C) DAPI-stained cells; (B and D) same fields a A, and C, respectively, showing cells hybridized with probes EUB338I-III (Cy3 labeled), specific for Bacteria domain. All micrographs correspond to the same hybridization process, performed with a sample obtained after 4 hours sampling at ground. C and D show microorganisms attaches to a mineral particles (arrow sign). Bars, 5 μm.
DNA gives us much information about the diversity of the system, but if we wish to obtain information about the metabolic activity that is taking place in the ecosystem, metabolomic and metatranscriptomic approaches are needed [50, 66]. In the case of the atmosphere, this is crucial, since we are not fully certain if the cells present are active. Some studies indicate that a part of the microorganisms in the atmosphere are developing an activity [6], but until we conduct RNA-based and metabolite-based studies, we will not have the certainty that this is the case. The big problem is that it is very difficult to carry out these studies using the current microbial capture systems.
\nScanning electron microscopy (SEM) also provides much information of the aerobiology [7]. Specifically, it allows the characterization of eukaryotic cells (e.g., diatoms) and, above all, pollens and fungal spores, from which we can obtain great information with good images alone. \nFigure 6A\n shows pine tree pollen observed via SEM in a sample obtained after a 30 minutes flight of the C-212 aircraft.
\nSEM images of different airborne samples. (A) Pinus pollen. Ground sample after 2 hours sampling. (B) Air sample collected from C-212-200 aircraft during a Saharan dust intrusion (February 24, 2017). Filter appear completely cover of mineral particles. (B and C) Biological particles sampled using C-212-200 aircraft. (E) Diatomea sampled by C-212-200 aircraft in a fligth along the northern coast of Spain (9 March 2017). (F) Cell attached to mineral particles and organic matter.
As mentioned above, factors, such as the shortage of nutrients and substrates, high UV radiation, drying, changes in temperature and pH, or the presence of reactive oxygen species, make the atmosphere an extreme environment. However, it is possible that the high variability of its conditions is the one characteristic that makes this environment more extreme [1, 20]. Among the cells present in the atmosphere, a considerable portion appears in the resistance forms capable of withstanding low-temperature and high-radiation conditions. This is what probably happens with fungi and gram-positive bacteria. Bacillus strains recurrently isolated from the atmosphere have characteristics and a capacity to sporulate very similar to strains isolated from the soil. Undoubtedly, another part of the cells will be in the form of latency and may even suffer modifications of the cell wall and slow down or stop their metabolic activity [75, 76]. These transformations can improve resistance to physical stresses, such as UV radiation [58]. On the other hand, some of the bacteria present in the atmosphere, such as Geodermatophilus, show pigmentation that undoubtedly protects it from excessive radiation. The microorganisms that are usually detected in the atmosphere originate mainly from the soil, which means they will share similar mechanisms of resistance. In some strains, metabolic adaptations have been observed to lack nutrients such as cytochrome bd biosynthesis to survive iron deprivation [77]. Deinococcus is also a recurrent genus in the atmosphere, which, like those in soil, has multiresistance mechanisms based on high DNA-repair efficiency. Bacteria that do not form spores and certain archaea, in contrast, often have genomes rich in G + C, which may increase tolerance to UV rays and overall survival [78].
\nAnother strategy of resistance could be cell clustering and adhesion to particles. Several studies have confirmed the loss of viability and shielding or the reflective properties of the mineral particles as an important role for the protection of UV radiation [19, 31]. In that sense, it is very possible that many cells have mechanisms that promote aggregation. In our samples, we often find the cells adhered to each other or to minerals, which undoubtedly makes them more resistant (\nFigure 6\n).
\nGlobal and regional models have been used to explain bioaerosol emission, transport, and atmospheric impact [17, 18, 79, 80, 81, 82, 83, 84]. Even so, it is not an easy phenomenon to explain, since it depends on a large number of factors. On the one hand, there are numerous sources of tropospheric aerosols, which include sea salt, volcanic dust, cosmic dust, industrial pollutants, and desert and semidesert areas [6, 85]. We must also consider the factors that make the transfer of particles possible, for example, meteorological phenomena, solar radiation, temperature, tides, erosion, etc. [85]. On the other hand, anthropogenic activities can also affect dust emissions indirectly, by changing the climate and the hydrological cycle. In these aerosols, microorganisms will be included in a greater or lesser number. The degree of richness in cells of tropospheric aerosols will depend largely on the source of emission. Thus, the large wooded masses or fields of crops provide the atmosphere with a good number of microorganisms due to the effect of air or the aerosols produced by rain. Similarly, anthropogenic activity contributes large amounts of bacteria to the environment, treatment plants, and composting areas being sources of airborne microorganisms [85].
\nDesert dust storms play a major role in particle emissions and with them that of microorganisms. In this way, most of the material reaching the atmosphere from the surface comes from desert and semidesert areas, which is known as desert dust. The Sahara-Sahel desert, the Middle East, central and eastern Asia, and Australia are the major sources of desert dust, although all the arid zones of the world are emission sources [9, 86]. Dust storms are atmospheric events typically associated with dry lands due to the preponderance of dried and unconsolidated substrates with little vegetation cover. The strong and turbulent winds that blow on these surfaces raise fine-grained material, a large part of which consists of particles the size of silt (4–62.5 μm) and clay (<4 μm), reducing visibility to less than 1 km. The atmospheric concentrations of PM10 dust exceed 15,000 μg/m3 in severe events [87], although the concentrations naturally decrease with the distance from the areas of origin, extending hundreds of kilometers. The dust particles and cells associated with them are transported in this manner and will be deposited finally, by the effect of rain, snow, or other meteorological phenomena. Therefore, there is a continuous transfer of mineral and biological matter through the atmosphere that moves from the air to the terrestrial environment and changes its geographical area [7, 24].
\nThe Sahara-Sahel desert located in northwestern Africa is one of the major sources of windblown dust in the world [9]. This phenomenon has an impact on the Mediterranean coastline, but Saharan dust has been transported toward the north of Europe and has been found on numerous occasions in the Alps [88, 89] or blown toward the Atlantic and Caribbean [8, 90]. It has been estimated that 80–120 tons of dust are transported annually through the Mediterranean toward Europe [23, 91, 92]. In particular, dust transported by the winds can reach an elevation of up to 8 km in the atmosphere over the Mediterranean basin [93]. Because of its geographic position, the Iberian Peninsula is often affected by these dust events. Specifically, the Sahara-Bodele depression, located at the southern edge of the Sahara desert, has been described as the richest dust source reaching the Iberian Peninsula. Southern Spain is the main area affected, but dust can reach the Pyrenees and even France [43]. Different researchers have studied the mineralogical and chemical composition of Saharan dust, which has been observed to contain calcite, dolomite, quartz, different clay minerals, and feldspars as the main mineral components [94]. The intrusion of big amounts of these components is an important influence on nutrient dynamics and biogeochemical cycling in the atmosphere of the Iberian Peninsula.
\nDespite the large number of studies on dispersion, geochemistry, and mineralogy of African dust, few are focused on microbiology. All these studies conclude that there are microbes associated with dust because there are higher concentrations of aerosolized microorganisms during dust events [43, 90, 93, 94, 95, 96]. However, the magnitude of the concentrations and the specific microbes associated with dust events remain the subject of debate. On the other hand, the viability of these microorganisms is another big question. The United States Geological Survey (USGS) develops the Global Dust Program to investigate the viability of microorganisms transported in dust masses. USGS authors using DNA sequencing of the ribosomal gene were able to isolate and identify more than 200 viable bacteria and fungi in St. John’s samples in the USA [8, 36, 90]. Fungi and bacteria associated with atmospheric dust can be recovered and cultivated, but they must be gram-positive bacteria and many spore formers, which makes them resistant to the extreme conditions of the atmosphere.
\nTherefore, fungi and bacteria associated with dust may have been isolated from dust intrusions, but a percentage of the viable ones already remains an unanswered question. Another big question is the activity of these cells in the atmosphere. It is clear that they are resistant to extremophile conditions, but the question is whether they are developing their life cycle in this particular environment. This question could be answered by molecular ecology methodologies based on the isolation and sequencing of mRNA, but low atmospheric biomass and high variability are, once again, the great problem when developing this type of RNA-based methodologies. On the other hand, clinical records point to many of the viable microorganisms identified in the Saharan dust as the cause of respiratory diseases (asthma and lung infections or allergic reactions), cardiovascular diseases, and skin infections [7, 90, 97, 98]. It is known that other microbes associated with dust in the air are pathogenic to humans, including those that cause anthrax and tuberculosis, or to livestock (such as foot and mouth disease) or plants [7, 90, 97, 98]. Characterization, quantification, and feasibility studies are vital to address these problems.
\nIt is common to find fungal spores belonging to the genus Aspergillus, Nigrospora, Arthrinium, and Curvularia associated with Saharan dust. Bacterial taxa comprised a wide range of phyla, including Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetes. Generators of genus spores such as Clostridium and Bacillus are very common, along with other gram-positive ones such as Geodermatophilus or Streptococcus. Also, Alphaproteobacteria, a very common bacterium class in soils (e.g., the family Sphingomonadaceae), are associated with dust [4, 9]. As regards Archaea, there are few studies of the atmosphere, in general, and of dust, in particular, that focus on this domain. Surely, reduced cases of pathogenic archaea have been studied to a lesser extent. Aeropyrum is the most detected genus of airborne archaea, but it is related to marine aerosols [11]. On the other hand, studies of pollen associated with dust are widespread. An interesting study investigated pollen transported from North Africa to Spain through Saharan dust and found that pollen from five non-native plant species was detected exclusively during dust events [99]. Lastly, viruses and virus-like particles have a great interest in the emission of dust. One study mentions virus-like particles associated with a transoceanic dust event. This report is based on epifluorescent microscopy of filters stained with a specific nucleic acid stain. An increase in the order of magnitude of virus-like particles was observed, from 104 to 2105 m−3 between the baseline condition and dust conditions in the Caribbean [41]. It is speculated that free airborne viruses show worse resistance to high ultraviolet radiation and dry air associated with long-distance transport in dust events resist worse than others [9].
\nFour aerobiology sampling flights took place during February and March 2017 using the CASA C-212-200 aircraft from INTA. The study focused on microbial diversity in the atmosphere of the Iberian Peninsula during and after a Saharan dust intrusion. Flights took place under four different conditions: (1) during a strong Sahara dust storm that reached the north of the Iberian Peninsula, from February 22 to 24, 2017 (February 23, 2017) (\nFigure 7\n); (2) following precipitation (February 28, 2017); (3) following a dry period (March 8, 2017); and (4) along the northern coast of Spain (March 9, 2017). In each flight, samples were collected at different altitudes, and air samples were obtained simultaneously at ground level. A total of 20 samples were collected and are being analyzed. Cell presence was observed by scanning electron microscopy (SEM), and bacterial diversity is being studied by DNA extraction, 16S rRNA gene amplification, and Illumina MiSeq sequencing. Results are being analyzed via bioinformatics and biostatistical software (MOTHUR, SPSS, STAMP, CANOCO, and PAST) which will allow us to compare the results between the different flows and scenarios.
\nSaharan dust intrusion. Dust pours off the northweat Afrincan coast and blankets the Iberian Peninsula, 23 February, 2016. NASA satelital imagen via MODIS.
Although this study is not yet finished, some data can be advanced in this chapter. \nFigure 6\n shows SEM microphotographs obtained from samples in different scenarios. In general, the samples obtained during the days of dust intrusion (flight of February 23) appear completely covered with mineral particles. In these cases, more biological cells were detected than in the rest of the days. In the particular case of samples from the marine coast flight, more diatoms were observed (\nFigure 6E\n).
\nThe analysis of diversity using the Shannon index showed that, in all cases, diversity was greater on days of Saharan dust intrusion, both in the samples taken from the ground and those taken at higher altitudes with the aircraft. This indicates that Saharan dust contributes microorganisms that are not present in the atmosphere on a daily basis. Diversity analysis showed phylum characteristics of soils, being Alpha- and Betaproteobacteria the most abundant classes. All of the analyses performed showed that bacterial diversity detected at ground level and in-flight samples during the dust intrusion event were similar among one another. The genus taxonomic levels of Sphingomonas, Geodermatophilus, Methylobacter, Rhizobiales, Bacillus, or Clostridium were present in every sample, but their sequences were more abundant in the case of ground samples and dust intrusion samples collected during the day flight. However, sequences of the genus Flavobacterium, Streptococcus, or Cupriavidus were most abundant in the case of samples collected during flight.
\nPreliminary conclusions show that bacterial diversity of airborne bacteria during days of dust intrusion is higher and similar to bacterial diversity commonly detected in soil samples. Further analyses are being conducted with these samples to obtain a complete description of the evolution of bacterial diversity during those days.
\nIntense UV radiation, low pressure, lack of water and nutrients, and freezing temperatures turn the atmosphere into an extreme environment, especially its upper layers. However, it is widely known that airborne bacteria, fungal spores, pollen, and other bioparticles exist. Numerous bacteria and fungi have been isolated and can survive even at stratospheric altitudes. Microbial survival in the atmosphere requires extremophilic characteristics, and therefore airborne microbiota is potentially useful for biotechnological applications. The role of airborne microbial communities is vital in the Earth, including interactions among the atmosphere, biosphere, climate, and public health. Airborne microorganisms are involved in meteorological processes and can serve as nuclei for cloud drops and ice crystals that precede precipitation, which influences the hydrological cycle and climate. Furthermore, their knowledge is essential in understanding the reproduction and propagation of organisms through various ecosystems. Furthermore, they can cause or improve human, animal, and plant diseases.
\nAirborne platforms that allow conducting a direct study of microorganisms in the atmosphere and molecular methodologies (e.g., “omics”) could represent a major opportunity for approaching this question. Nevertheless, some challenges must yet be solved, such as low biomass, efficiency of sampling methods, the absence of standard protocols, or the high variability of the atmospheric environment.
\nDeserts and arid lands are one of the most important sources of aerosol emissions. Clouds of dust generated by storms mobilize tons of mineral particles, and it is known that microorganisms remain attached to the particles being transported over long distances. The large number of mineral particles and microorganisms thus placed into the atmosphere has global implications for climate, biochemical cycling, and health. North African soils, primarily the Sahara Desert, are one of the major sources of airborne dust on Earth. Saharan dust is often transported to southern Europe and could even reach high altitudes over the Atlantic Ocean and the European continent. Again, airborne platforms could be a perfect opportunity for conducting a direct study of the microbiology of this kind of events.
\nThis work has been supported by grants from the Spanish government (
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