The effect of TNF and TNF70–80 on
Abstract
Body clearance of fungi such as Candida albicans involves phagocytosis by fixed tissue macrophages as well as infiltrating monocytes and neutrophils. Through phagocytosis, the fungi are confined and killed by the oxidative and non-oxidative anti-microbial systems. These include oxygen derived reactive species, generated from the activation of the NADPH oxidase complex and granule constituents. These same mechanisms are responsible for the damage to hyphal forms of C. albicans. Complement promotes phagocytosis, through their interaction with a series of complement receptors including the recently described complement receptor immunoglobulin. However, it is also evident that under other conditions, the killing of yeast and hyphal forms can occur in a complement-independent manner. Phagocytosis and killing of Candida is enhanced by the cytokine network, such as tumour necrosis factor and interferon gamma. Patients with primary immunodeficiency diseases who have phagocytic deficiencies, such as those with defects in the NADPH oxidase complex are predisposed to fungal infections, providing evidence for the critical role of phagocytes in anti-fungal immunity. Secondary immunodeficiencies can arise as a result of treatment with anti-cancer or other immunosuppressive drugs. These agents may also predispose patients to fungal infections due to their ability to compromise the anti-microbial activity of phagocytes.
Keywords
- Candida albicans
- macrophages
- neutrophils
- complement
- innate immunity
- phagocytosis
- fungal killing mechanisms
- cytokines
- trained immunity
- immunodeficiency
- immunopharmacology
1. Introduction
In neutrophils, the major response associated with phagocytosis of microbial pathogens is the oxygen-dependent respiratory burst and the generation of reactive oxygen species (ROS). Several decades ago it became evident that neutrophils displayed a unique respiratory burst in the absence of mitochondria, where the generation of ATP comes mainly from glycolysis (reviewed in [2]). It also became apparent that the majority of the oxygen consumed was converted to superoxide (O·2–) which is then converted to further oxygen intermediates, including singlet oxygen and H2O2. The enzyme which catalyses the conversion of O2 to O·2– is assembled in the phagocytic vacuole membrane, facilitating its release into the bacteria or fungus-containing vacuole. In neutrophils, the release of the azurophilic granule content simultaneously into the phagocytic vacuole leads to the generation of HOCl, a highly potent anti-microbial agent, as a result of the action of myeloperoxidase on H2O2 in the presence of chloride ions. In addition, ingestion of microbial pathogens and their confinement to the vacuolar environment may restrict the supply of essential nutrients necessary for growth.
The NADPH oxidase complex is responsible for the respiratory burst and consists of a number of different proteins which assemble in the neutrophil vacuole membrane following cell stimulation. This is typically initiated during phagocytosis of bacteria and fungi [3]. The complex consists of the oxidase-specific phox proteins gp91phox, p22phox, p40phox, p47phox, p67phox and the small GTPases, Rac1 and Rac2. Cell activation leads to the assembly of these components in the membrane and the initiation of enzymatic activity.
The non-oxidative microbicidal system complements the respiratory burst. Components of the azurophilic granules in neutrophils have been shown to have anti-microbial activity. These include defensins, serprocidins and bactericidal/permeability increasing protein (BPI). Defensins are cationic peptides with broad spectrum antimicrobial activity [2]. The seroprodins, elastase, azurocidin and cathepsin G have antimicrobial activity independent of their enzymatic activity [2].
As with neutrophils, most bacteria and fungi are confined and killed within phagosomes by macrophages [4], involving a variety of agents such as toxic metabolites, peptides and enzymes. These may act either alone or synergistically. In addition, macrophages can produce ROS which have anti-microbial action but unlike monocytes, macrophages lack MPO. Most striking is the marked heterogeneity of macrophages enabling these leukocytes to perform functions relevant to specific tissues in which they are located.
The extrusion of neutrophil extracellular traps (NETs) is also considered to be a defence mechanism against microbial pathogens. NETs are structures composed of DNA as well as anti-microbial substances, elastase, calprotectin and MPO [5]. NETs not only trap the microbial pathogens, but also kill them. Interestingly, it has been reported that the formation of NETs requires the presence of ROS [6].
Effective recognition of microbial pathogens by neutrophils and macrophages requires receptors which bind peptides deposited on bacterial and fungal surfaces which have been generated through the activation of complement, namely C3b and iC3b. Receptors recognising iC3b include CR3 (CD18/CD11b) and CR4 (CD18/CD11c), which are present on both neutrophils and macrophages. Recently, another complement receptor type, complement immunoglobulin receptor (CRIg), expressed only by a subpopulation of macrophages has been described, which binds both iC3b and C3b (reviewed in [7]). It has been shown that this receptor plays an important role in clearance of bacteria from the circulation by liver Kupffer cells [8] and may also be a pattern recognition receptor, facilitating clearance of bacteria in the absence of complement [9].
Antibody bound to microbial pathogens also promotes phagocytosis through the Fcγ receptors, FcγRI (CD64), FcγRIIA (CD32) and FcγRIIIB (CD16), all of which engage the Fc domain of Immunoglobulin G (IgG). The FcαRI which binds the Fc domain of Immunoglobulin A (IgA) also promotes microbial phagocytosis and killing [2].
Apart from the integrins and FcγRs, neutrophils and macrophages express a range of pattern recognition receptors (PPR) which recognise conserved microbial pathogen structures, such as lipoteichoic acid, β-glucans and lipopolysaccharide. Families of PPRs include those found in serum (pentraxins, collectins, complement), those which are membrane bound (classic C-type lectins, non-classic C-type lectin leucine-rich proteins, scavenger receptors) and those which are located intracellularly (NODs, interferon induced proteins).
2. Complement dependent and independent phagocytosis of C. albicans
Despite the importance of complement-independent mechanisms for host anti-candidal immunity, it is evident that complement is required for optimal resistance to fungal infection [10, 11, 12]. It was also evident in these studies that complement could be activated by
Zymosan A is a yeast cell wall glucan and, like
The classical complement pathway is likely to be activated by mannan-specific antibodies found in human serum [19] whereas the lectin pathway is activated by the binding of mannose-binding lectin to mannan on the cell wall of the fungus [20]. However, it has also been shown that
The unique complement receptor CRIg is a member of the transmembrane protein of the type 1 immunoglobulin superfamily, encoded by
While CR3 and FcRγ mediate phagocytosis of complement and antibody opsonised
Cells of the phagocytic system are able to recognise
Neutrophils recognise
3. Trained macrophage immunity in anti-fungal immunity
Trained immunity (TI) refers to the ability of innate immune cells to exhibit ‘memory’ and prevent reinfection of previously encountered invading pathogens [41]. Termed by Netea and colleagues [42], TI induces a state of enhanced antimicrobial action in cells of the innate immune system, particularly monocytes and macrophages, which is distinct from both typical innate immunity and the memory of the adaptive immune system. Alternatively, TI refers to the enhanced response to reinfection against the initial invading microorganisms and cross-protection against different pathogens. Although the concept of TI is relatively new, the phenomenon of protection afforded by previous infection in a manner distinct from adaptive immunity has long been known, particularly in plant and insect systems [43, 44].
TI has been shown to have a role in infection and immunity against
While other molecules such as fungal chitin have also been shown to induce TI [48], β-glucan remains the most well-studied molecule with respect to
4. Killing of C. albicans by neutrophils and macrophages
Ferrante [52] demonstrated that killing of yeast forms of
Two distinct mechanisms for human neutrophil-mediated killing have been documented, depending on the state of fungal opsonisation. Using
5. Intracellular signalling required for killing of C. albicans
Approximately two decades ago it was demonstrated that human neutrophil-mediated killing of
In comparison, Gazendam et al. [61] demonstrated that neutrophils display two different mechanisms in the killing of
6. Neutrophil extracellular traps in immunity to C. albicans
7. Cytokine priming in phagocyte-mediated killing of C. albicans
Over three decades ago it became evident that neutrophil responses to microbial pathogens could be significantly increased if the cells were pre-sensitised with products released by activated lymphocytes and macrophages [69], a process dependent on the presence of TNF [70, 71]. The importance of cytokine priming in killing of
The use of TNF to enhance immunity against various microbial infections has not been considered appropriate because of the highly toxic and tissue damaging effects of TNF. In an effort to harness the anti-infective properties of TNF and exclude some of its tissue damaging properties, we synthesised short peptides representative of the TNF sequence [77]. One of these elevenmer peptides, TNF70–80, was found to activate neutrophils and macrophages to increase microbial killing both
Our studies with
Treatment | No. mice/group | Log CFU/g kidney (M ± SD) |
---|---|---|
PBS | 23 | 7.3 ± 0.6 |
Amphotericin B | 15 | 2.7 ± 2.4*** |
TNF (0.1 mg/kg) | 29 | 5.6 ± 1.2*** |
TNF70–90 (4 mg/kg) | 9 | 5.75 ± 1.7** |
Treatment | Route | Dose (mg/kg) | Survivors 10 days post-infection |
---|---|---|---|
Vehicle control | IP | — | 8 |
Cyclophosphamide | PO | 30 | 2* |
TNF70–80 + cyclophosphamide | IP | 100 | 7ns |
TNF70–80 + cyclophosphamide | IP | 10 | 4ns |
TNF70–80 + cyclophosphamide | IP | 1 | 4ns |
TNF70–90 + cyclophosphamide | IP | 0.1 | 2* |
Azimexone + cyclophosphamide | IP | 100 | 6ns |
Cytokines also influence the ability of macrophages to phagocytose and kill fungi. Human monocyte-derived macrophages (MDMs) treated with interferon gamma showed increased ability to phagocytose and kill yeast forms of
From the described studies, it is evident that when considering killing of microbial pathogens including
8. Primary immunodeficiency diseases associated with susceptibility to fungal infection
Primary immunodeficiency diseases (PID) are a heterogeneous group of inborn errors of immunity. Affected individuals develop severe, unusual or recurrent infections, and may also develop features of immune dysregulation with autoimmune manifestations. There are currently over 320 described molecular genetic causes of PID, which can be categorised according to presenting phenotypic features [86]. The International Union of Immunological Sciences (IUIS) classify PID into the following disease categories: immunodeficiencies affecting cellular and humoral immunity, combined immunodeficiencies (CID) with associated or syndromic features, predominantly antibody deficiencies, diseases of immune dysregulation, congenital defects of phagocyte number, function or both, defects in intrinsic and innate immunity, auto-inflammatory disorders, complement deficiencies and phenocopies of PID [86].
Intact immunological processes and pathways are required to mount an effective immune response against fungi, incorporating both innate and adaptive components [87]. Several immune cells and immunological mediators such as cytokines are of critical importance to maintenance of anti-fungal immunity. These include phagocytes, dendritic cells, T cells (particularly T helper 1 (TH1) and T helper 17 (TH17) cells) [87]. The importance of these effectors is evidenced by patients with PID affecting cellular or phagocytic immunity developing severe, invasive or recurrent fungal infections [1].
Primary phagocytic disorders result from mutations in genes encoding key proteins that are essential for normal phagocytic development and function. These disorders may be classified according to whether phagocyte number, function or both are affected, and by the presence or absence of associated syndromic features [86]. These disorders and their underlying, causative genetic abnormality are summarised in Table 3.
Congenital defects of phagocytic number, function or both | |||
---|---|---|---|
Associated with syndromic features | Not associated with syndromic features | ||
Disorder | Gene(s) | Disorder | Gene(s) |
Shwachman-Diamond syndrome | Elastase deficiency (SCN1) | ||
G6PC3 deficiency (SCN4) | Kostmann disease (HAX1 deficiency; SCN3) | ||
Glycogen storage disease type 1b | GFI1 deficiency (SCN2) | ||
Cohen syndrome | X-linked neutropaenia/myelodysplasia WAS GOF | ||
Barth syndrome (3-methylglutaconic aciduria type II) | G-CSF receptor deficiency | ||
Clericuzio syndrome (poikiloderma with neutropaenia) | Neutropaenia with combined immune deficiency | ||
VPS45 deficiency (SCN5) | |||
P14/LAMTOR2 deficiency | |||
JAGN1 deficiency | |||
3-methylglutaconic aciduria | |||
SMARCD2 deficiency | |||
WDR1 deficiency | |||
HYOU1 deficiency | |||
Cystic fibrosis | Chronic granulomatous disease | ||
Papillon-Lefevre syndrome | Rac2 deficiency | ||
Localised juvenile periodontitis | G6PD deficiency Class 1 | ||
Leukocyte adhesion deficiency (LAD) 1 | GATA2 deficiency (MonoMac syndrome) | ||
Leukocyte adhesion deficiency (LAD) 2 | Specific granule deficiency | ||
Leukocyte adhesion deficiency (LAD) 3 | Pulmonary alveolar proteinosis |
Of the described primary immunodeficiency diseases of phagocytic number or function, recurrent or invasive candidal disease has been reported in cases of chronic granulomatous disease and myeloperoxidase deficiency [1] and GATA2 deficiency [88]. Candidosis is reported but tends to be less common in leukocyte adhesion deficiency and congenital neutropaenic syndromes [1].
Chronic granulomatous disease (CGD) occurs as a result of defects in components of the NADPH oxidase system, resulting in defective neutrophil oxidative burst and susceptibility to a narrow range of organisms, particularly those which are catalase-producing. As well as the predisposition to infection, patients with CGD develop a hyperinflammatory response and granuloma formation [89]. X-linked CGD occurs due to mutations in the
Candidosis is well described in CGD patients, with candidal species implicated in episodes of meningitis, fungaemia, suppurative adenitis, pneumonia, subcutaneous abscesses and liver abscess reported in a cohort of 368 patients with CGD [90]. Although the majority of these infections were expected to be due to underlying, impaired phagocytic function, additional factors such as steroid use likely increase the risk of invasive candidiasis. Candidal oesophagitis, keratitis and disseminated infection (particularly affecting young infants) have also been described, however mucocutaneous candidiasis is uncommon in CGD patients [1].
Patients with gp40phox mutations have been noted to have a distinct clinical phenotype as compared with those with other forms of CGD, with a milder clinical course and lower frequency of invasive fungal infection [91]. There is no impairment in the ability of the neutrophils of affected patients to kill candida, suggesting residual NADPH oxidase activity and a potential gp40phox-independent process for reactive oxygen species production. Furthermore, monocyte and monocyte-derived macrophage NADPH oxidase generation appears to occur independently of gp40phox [91]. In patients with CGD, a correlation has been shown between residual production of reactive oxygen intermediates (ROI) and improved long-term survival [92]. The specific mutation in NADPH oxidase predicts the amount of residual production of ROI [92].
CGD may be conservatively managed with antibiotic and antifungal prophylaxis, along with adjunctive therapies including subcutaneous interferon therapy. CGD is curable by haematopoietic stem cell transplantation (HSCT), and trials are underway to evaluate the role of gene therapy as an alternative definitive management strategy [93].
MPO deficiency is autosomal recessive with variable penetrance, may be complete or partial, and has an estimated incidence of between 1:2000 and 1:4000 individuals [94]. Most individuals are clinically asymptomatic, although severe infections are reported in around 5% of those affected. MPO-deficient phagocytes have an impaired capacity to kill
In addition to the critical role of phagocytes in anti-fungal immunity, defects in other immune cells and immunologic pathways also give rise to susceptibility to infection with candida and other fungi. A range of single-gene inborn errors of immunity resulting in severe or recurrent superficial or invasive candidiasis have been described [86, 98]. Cell-mediated immunity is essential for anti-fungal immunity. This is evidenced by the predisposition to severe fungal infection in infants with severe combined immunodeficiency (SCID), a life-threatening condition manifested by low, absent or severely dysfunctional T cells [86]. Other forms of combined immunodeficiency, for example, those due to deficiencies in CD25, NEMO/IKBG, DOCK8, TCR-α, ORAI1, MST1/STK4, MHC Class II, along with
9. Secondary immunodeficiency diseases associated with disorders of phagocyte number or function
Immunosuppression is a well-described risk factor for infection with candida and other fungal species [98]. Corticosteroids are commonly used in the management of a range of inflammatory and malignant conditions, and use of these agents is a known risk factor for fungal infection [104]. The precise mechanisms by which corticosteroids lead to impaired anti-candidal immunity remain unclear, and this is likely multifactorial [105]. In terms of phagocytic cell function, corticosteroids appear to alter leukocyte differentiation programs. They induce monocytes and macrophages to adopt an anti-inflammatory phenotype. This is modulated by the cytokine environment (including increased IL-10 expression on macrophages), increased apoptotic activity and induction of transcription of anti-inflammatory genes which impact upon chemotaxis, phagocytosis and resistance to oxidative stress [105]. However, despite these observations it has been recently shown that dexamethasone increases the expression of CRIg on human MDMs but not CR3 or CR4, and that this increase was associated with an increase in phagocytosis of complement opsonised
Cancer patients are at an increased risk of systemic candidiasis, and
Patients with liver disease are at an increased risk of fungal infection. Those with cirrhosis have been found to have reduced complement levels and impaired monocyte activation and neutrophil mobilisation [106]. Patients with liver disease are at risk for infectious peritonitis, and
Finally, it is also evident that anti-fungal drugs
Acknowledgments
We are grateful to Christ Stewart for technical assistance with the mouse work. We are also indebted to our colleagues who have contributed to the listed publications. Our research has been supported by grants obtained from the NHMRC of Australia and the Women’s and Children’s Hospital Network, South Australia.
Authors AGS and JRK declare no conflicts of interest. Authors DAR and AF declare that they are inventors on patent relating to TNF70–80 technology.
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