1. Introduction
Leishmaniasis comprises a broad-spectrum of neglected vector-borne diseases ranging in severity from the self-healing but disfiguring and stigmatizing cutaneous lesions to mucocutaneous and fatal visceral manifestations, depending on the species and host characteristics. This syndrome primarily afflicts the impoverished population of low-income countries falling in the tropics and subtropics. Globally, 0.7–1.2 million new cases of cutaneous leishmaniasis (CL) occur every year while for visceral leishmaniasis (VL), 200,000–400,000 new cases and 20,000–40,000 deaths are reported each year, with 95% of fatal cases occurring in only six countries, namely, India, Bangladesh, Sudan, South Sudan, Ethiopia and Brazil [1]. The disease is transmitted by the bite of female
This chapter gives a brief glimpse of the recent advances in immunopathogenesis and immune evasion strategies employed by the
2. Immunopathogenesis and immune evasion strategies
Invasion of host macrophages by
3. Current vaccination and immunotherapeutic approach
A major challenge to mitigation of this endemic disease is to achieve safe, efficacious and low-cost prophylactic or therapeutic vaccines with long-lasting protection. These vaccines should be effective against both stages of the parasite curbing its progression and accompanying pathology that stems from an imbalance between the pathogen and the host immune system. The plethora of candidate vaccines range from the live non-pathogenic vectors to the recombinant subunit vaccines, alone or together with adjuvants and/or delivery systems for induction of cell-mediated immunity. Some of these include
Immunotherapy on the other hand has been found to promote sterilizing cure. However, immunotherapeutic intervention with
An emerging therapeutic modality for CL is photodynamic therapy of zinc porphyrin that results in loss of plasma membrane integrity and hyperpolarization of the mitochondrial membrane potential [24].
4. Therapeutic targets and inhibitors
Identification of new drug targets can contribute towards designing inhibitors and strengthen the pipeline for disease elimination. DNA topoisomerases that control the over- or under-winding of DNA have been reported as deadly targets for topoisomerase inhibitors that may act as potential antileishmanial drugs [25]. Computational tools using
5. Natural products as source of antileishmanial drugs
In view of looming chemotherapeutic drug resistance, natural products and scaffolds from medicinal plants are being emphasized as leads for drug discovery. Plant-based bioactive compounds have merit over synthetic compounds, considering their unique structural variety, providing an unlimited source of molecules and biological activities [35]. A host of plant extracts or oils and their phytoconstituents (alkaloids, terpenoids, quinones, flavonoids, saponins, phenylpropanoids, flavonoids, lignoids, naphthoquinones, iridoids, and more) have shown promise
Antimicrobial peptides have been reported to improve the therapeutic outcome of antileishmanial drugs [45]. Synergistic drug-natural product combinations have also been explored [46, 47].
6. Nanomedicines
In recent years, numerous advances in drug discovery have been made for treating leishmaniasis, exploiting nanotechnological approaches to target the immune cell phagolysosomes that harbors the
Green nanoparticles, that is, plant-based synthesis of nanoparticles have an upper edge over the synthetic nanoparticles owing to their biosynthesis being rapid, eco-friendly, non-pathogenic and economical. An array of biogenic nanoparticles from plant extracts has been reported to have antileishmanial activity with boosting of anti-oxidant activity [52, 53].
Miltefosine- and ketoconazole-loaded nanoniosomes with improved antileishmanial activity have also been reported [54]. AmBisome-miltefosine combination therapy for VL-HIV co-infected patients has been reported in Ethiopia with 83.8% cure rate [55].
7. Diagnosis of leishmaniasis
A definitive diagnosis of leishmaniasis is crucial to guide timely and appropriate therapy. The disease is often confused with other co-endemic diseases and HIV co-infections may result in atypical clinical presentation [4]. Differential diagnosis of VL should be considered in patients of endemic areas after organ transplantation [56]. This underscores the need for highly sensitive and specific diagnostic modalities. In this regard, molecular techniques such as real-time polymerase chain reaction (qPCR)-based methods are gaining ground for detection and quantification of
8. Conclusions and future perspectives
To strengthen the leishmaniasis elimination drive, particular emphasis has to be laid on the diagnosis, chemotherapeutics and new targets identification and vaccination strategies for control of this endemic disease. This underscores renewed efforts to combat upcoming challenges in the quest for new drug targets in achieving definitive cure and/or safe, cost-effective prophylactic vaccines with long-lasting immunity against leishmaniasis. An effective therapeutic vaccine may further boost the immunosuppressed state and thus control the visceralizing form of leishmaniasis that is mainly harbored in the South Asian region.
References
- 1.
Alvar J, Velez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS One. 2012; 7 (5):e35671 - 2.
Karunaweera ND, Ferreira MU. Leishmaniasis: Current challenges and prospects for elimination with special focus on the South Asian region. Parasitology. 2018; 145 (4):425-429 - 3.
Dumetz F, Cuypers B, Imamura H, Zander D, D’Haenens E, Maes I, et al. Molecular preadaptation to antimony resistance in Leishmania donovani on the Indian subcontinent. mSphere. 2018; 3 (2):e00548-e00517 - 4.
de Lima Henn GA, Júnior ANR, Colares JKB, Mendes LP, Silveira JGC, Lima AAF, et al. Is visceral Leishmaniasis the same in HIV-coinfected adults? The Brazilian Journal of Infectious Diseases. 2018; 22 (2):92-98 - 5.
Pandey K, Goyal V, Das V, Verma N, Rijal S. PKDL development after combination treatment with miltefosine and paromomycin in a case of visceral leishmaniasis: First ever case report. Journal of Medical Microbiology and Immunology Research. 2018; 2 (1) - 6.
do Lago AS, Nascimento M, Carvalho AM, Lago N, Silva J, Queiroz JR, et al. The Elderly Respond to Antimony Therapy for Cutaneous Leishmaniasis Similarly to Young Patients but Have Severe Adverse Reactions. The American Journal of Tropical Medicine and Hygiene. 2018; 98 (5):1317-1324 - 7.
Siriwardana YD, Deepachandi B, Ranasinghe S, Soysa P, Karunaweera N. Evidence for Seroprevalence in human localized cutaneous leishmaniasis caused by Leishmania donovani in Sri Lanka. BioMed Research International. 2018;2018 :9320367 - 8.
Calegari-Silva TC, Vivarini ÁC, Pereira RM, Dias-Teixeira KL, Rath CT, Pacheco AS, et al. Leishmania amazonensis downregulates macrophage iNOS expression via histone: Deacetylase 1 (HDAC1): A novel parasite evasion mechanism. European Journal of Immunology. 2018;48 (7):1188-1198 - 9.
Kumar V, Kumar A, Das S, Kumar A, Abhishek K, Verma S, et al. Leishmania donovani activates hypoxia inducible factor-1α and miR-210 for survival in macrophages by downregulation of NF-κB mediated pro-inflammatory immune response. Frontiers in Microbiology. 2018;9 :385 - 10.
Borges AF, Gomes RS, Ribeiro-Dias F. Leishmania (Viannia) guyanensis in tegumentary leishmaniasis. Pathogens and Disease. 2018; 76 (4):fty025 - 11.
Dey R, Joshi AB, Oliveira F, Pereira L, Guimarães-Costa AB, Serafim TD, et al. Gut Microbiota Egested during Bites of Infected Sand Flies Augments Severity of Leishmaniasis Via Inflammasome-Derived IL-1β. 2018 - 12.
Fernández L, Carrillo E, Sánchez-Sampedro L, Sánchez C, Ibarra-Meneses AV, Jimenez MA, et al. Antigenicity of leishmania-activated C-kinase antigen (LACK) in human peripheral blood mononuclear cells, and protective effect of prime-boost vaccination with pCI-neo-LACK plus attenuated LACK-expressing Vaccinia viruses in hamsters. Frontiers in Immunology. 2018; 9 - 13.
Noormehr H, Hosseini AZ, Soudi S, Beyzay F. Enhancement of Th1 immune response against Leishmania cysteine peptidase A, B by PLGA nanoparticle. International Immunopharmacology. 2018; 59 :97-105 - 14.
Emami T, Rezayat SM, Khamesipour A, Madani R, Habibi G, Hojatizade M, et al. The role of MPL and imiquimod adjuvants in enhancement of immune response and protection in BALB/c mice immunized with soluble Leishmania antigen (SLA) encapsulated in nanoliposome. Artificial Cells, Nanomedicine, and Biotechnology. 2018:1-10 - 15.
Kumar A, Dikhit MR, Amit A, Zaidi A, Pandey RK, kumar Singh A, et al. Immunomodulation induced through ornithine decarboxylase DNA immunization in Balb/c mice infected with Leishmania donovani . Molecular Immunology. 2018;97 :33-44 - 16.
Martin-Martin I, Chagas AC, Guimaraes-Costa AB, Amo L, Oliveira F, Moore IN, et al. Immunity to LuloHya and Lundep, the salivary spreading factors from Lutzomyia longipalpis, protects against Leishmania major infection. PLoS Pathogens. 2018;14 (5):e1007006 - 17.
Banerjee A, Bhattacharya P, Dagur PK, Karmakar S, Ismail N, Joshi AB, et al. Live attenuated Leishmania donovani centrin gene–deleted parasites induce IL-23–dependent IL-17–protective immune response against visceral leishmaniasis in a murine model. The Journal of Immunology. 2018;200 (1):163-176 - 18.
Almeida APM, Machado LF, Doro D, Nascimento FC, Damasceno L, Gazzinelli RT, et al. New vaccine formulations containing a modified version of the amastigote 2 antigen and the non-virulent Trypanosoma cruzi CL-14 strain are highly antigenic and protective againstLeishmania infantum challenge. Frontiers in Immunology. 2018;9 :465 - 19.
Oliveira MP, Martins VT, Santos TT, Lage DP, Ramos FF, Salles B, et al. Small myristoylated protein-3, identified as a potential virulence factor in Leishmania amazonensis , proves to be a protective antigen against visceral leishmaniasis. International Journal of Molecular Sciences. 2018;19 (1):129 - 20.
Bezerra IPS, Abib MA, Rossi-Bergmann B. Intranasal but not subcutaneous vaccination with LaAg allows rapid expansion of protective immunity against cutaneous leishmaniasis. Vaccine. 2018; 36 (18):2480-2486 - 21.
Viana KF, Lacerda G, Teixeira NS, Cangussu ASR, Aguiar RWS, Giunchetti RC. Therapeutic vaccine of killed Leishmania amazonensis plus saponin reduced parasite burden in dogs naturally infected withLeishmania infantum . Veterinary Parasitology. 2018;254 :98-104 - 22.
Habib S, El Andaloussi A, Elmasry K, Handoussa A, Azab M, Elsawey A, et al. PDL-1 blockade prevents T cell exhaustion, inhibits autophagy, and promotes clearance of Leishmania donovani . Infection and Immunity. 2018;86 (6):e00019-e00018 - 23.
Yadav NK, Joshi S, Ratnapriya S, Sahasrabuddhe AA, Dube A. Immunotherapeutic potential of Leishmania (Leishmania) donovani Th1 stimulatory proteins against experimental visceral leishmaniasis. Vaccine. 2018; 36 (17):2293-2299 - 24.
Andrade C, Figueiredo R, Ribeiro K, Souza L, Sarmento-Neto J, Rebouças J, et al. Photodynamic effect of zinc porphyrin on the promastigote and amastigote forms of Leishmania braziliensis . Photochemical & Photobiological Sciences. 2018;17 (4):482-490 - 25.
Elmahallaw E, Garcia-Estrada C, Carbajo-Andres R, Balana-Fouce R. DNA topoisomerases of Leishmania parasites; druggable targets for drug discovery. Current Medicinal Chemistry. 2018 - 26.
Shokri A, Abastabar M, Keighobadi M, Emami S, Fakhar M, Teshnizi SH, et al. Promising antileishmanial activity of novel imidazole antifungal drug Luliconazole against Leishmania major : In vitro and in silico studies. Journal of Global Antimicrobial Resistance. 2018. pii: S2213-7165(18)30091-2 - 27.
Vadloori B, Sharath A, Prabhu NP, Maurya R. Homology modelling, molecular docking, and molecular dynamics simulations reveal the inhibition of Leishmania donovani dihydrofolate reductase-thymidylate synthase enzyme by Withaferin-A. BMC Research Notes. 2018;11 (1):246 - 28.
Chávez-Fumagalli MA, Schneider MS, Lage DP, Tavares GSV, Mendonça DVC, Santos TTO, et al. A computational approach using bioinformatics to screening drug targets for Leishmania infantum species. Evidence-Based Complementary and Alternative Medicine. 2018;2018 - 29.
Ortalli M, Ilari A, Colotti G, De Ionna I, Battista T, Bisi A, et al. Identification of chalcone-based antileishmanial agents targeting trypanothione reductase. European Journal of Medicinal Chemistry. 2018; 2018 :6813467 - 30.
da Silva Cardoso V, Vermelho AB, Ricci Junior E, Almeida Rodrigues I, Mazotto AM, Supuran CT. Antileishmanial activity of sulphonamide nanoemulsions targeting the β-carbonic anhydrase from Leishmania species. Journal of Enzyme Inhibition and Medicinal Chemistry. 2018; 33 (1):850-857 - 31.
Dorsey BM, McLauchlan CC, Jones MA. Evidence that speciation of oxovanadium complexes does not solely account for inhibition of Leishmania acid phosphatases. Frontiers in Chemistry. 2018; 6 :109 - 32.
Mishra A, Khan M, Jha PK, Kumar A, Das S, Das P, et al. Oxidative stress-mediated overexpression of uracil DNA glycosylase in Leishmania donovani confers tolerance against antileishmanial drugs. Oxidative Medicine and Cellular Longevity. 2018;2018 :4074357 - 33.
Stevanović S, Perdih A, Senćanski M, Glišić S, Duarte M, Tomás AM, et al. In silico discovery of a substituted 6-methoxy-quinalidine with Leishmanicidal activity in Leishmania infantum . Molecules. 2018;23 (4):772 - 34.
Jawed JJ, Saini P, Majumdar S. Exploring the role of immune-modulators in pathogen recognition receptor NOD2 mediated protection against visceral leishmaniasis. World Academy of Science, Engineering and Technology. International Journal of Medical and Health Sciences. 2018; 5 (3) - 35.
Varela M, Fernandes J. Natural products: Key prototypes to drug discovery against neglected diseases caused by Trypanosomatids. Current Medicinal Chemistry. 2018 - 36.
Simoben CV, Ntie-Kang F, Akone SH, Sippl W. Compounds from African medicinal plants with activities against selected parasitic diseases: Schistosomiasis, trypanosomiasis and leishmaniasis. Natural Products and Bioprospecting. 2018:1-19 - 37.
de Lima Moreira F, Riul TB, de Lima Moreira M, Pilon AC, Dias-Baruffi M, Araújo MS, et al. Leishmanicidal effects of piperlongumine (Piplartine) and its putative metabolites. Planta Medica. 2018 - 38.
dos Santos Sales V, Monteiro ÁB, de Araújo Delmondes G, do Nascimento EP. Antiparasitic activity and essential oil chemical analysis of the piper Tuberculatum Jacq fruit. Iranian Journal of Pharmaceutical Research. 2018; 17 (1):268-275 - 39.
Zafar S, Ur-Rehman F, Shah ZA, Rauf A, Khan A, Humayun Khan M, et al. Potent leishmanicidal and antibacterial metabolites from Olea ferruginea. Journal of Asian Natural Products Research. 2018:1-9 - 40.
Krstin S, Sobeh M, Braun MS, Wink M. Anti-parasitic activities of Allium sativum andAllium cepa againstTrypanosoma b. brucei andLeishmania tarentolae . Medicine. 2018;5 (2):37 - 41.
Monzote L, Geroldinger G, Tonner M, Scull R, De Sarkar S, Bergmann S, et al. Interaction of ascaridole, carvacrol, and caryophyllene oxide from essential oil of Chenopodium ambrosioides L. with mitochondria in Leishmania and other eukaryotes. Phytotherapy Research. 2018 - 42.
Domeneghetti L, Demarchi I, Caitano J, Pedroso R, Silveira T, Lonardoni M. Calophyllum brasiliense modulates the immune response and promotes Leishmania amazonensis intracellular death. Mediators of Inflammation. 2018;2018 :6148351 - 43.
Peretz A, Zabari L, Pastukh N, Avital N, Masaphy S. In vitro antileishmanial activity of a black Morel, Morchella importuna (ascomycetes). International Journal of Medicinal Mushrooms. 2018;20 (1):71-80 - 44.
Souza GS, de Carvalho LP, de Melo EJT, Gomes VM, AdO C. The toxic effect of Vu-Defr, a defensin from Vigna unguiculata seeds, on Leishmania amazonensis is associated with reactive oxygen species production, mitochondrial dysfunction, and plasma membrane perturbation. Canadian Journal of Microbiology. 2018;64 (999):1-10 - 45.
Fragiadaki I, Katogiritis A, Calogeropoulou T, Brückner H, Scoulica E. Synergistic combination of alkylphosphocholines with peptaibols in targeting Leishmania infantum in vitro. International Journal for Parasitology: Drugs and Drug Resistance. 2018;8 (2):194-202 - 46.
Khanra S, Kumar YP, Dash J, Banerjee R. In vitro screening of known drugs identified by scaffold hopping techniques shows promising leishmanicidal activity for suramin and netilmicin. BMC Research Notes. 2018; 11 (1):319 - 47.
Vieira-Araújo FM, Rondon FCM, Vieira ÍGP, Mendes FNP, de Freitas JCC, de Morais SM. Sinergism between alkaloids piperine and capsaicin with meglumine antimoniate against Leishmania infantum . Experimental parasitology. 2018;188 :79-82 - 48.
Halder A, Shukla D, Das S, Roy P, Mukherjee A, Saha B. Lactoferrin-modified Betulinic acid-loaded PLGA nanoparticles are strong anti-leishmanials. Cytokine. 2018. pii: S1043-4666(18)30208-4 - 49.
Jabir MS, Taha AA, Sahib UI. Linalool loaded on glutathione-modified gold nanoparticles: A drug delivery system for a successful antimicrobial therapy. Artificial Cells, Nanomedicine, and Biotechnology. 2018; Apr 4 :1-11 - 50.
den Boer M, Das AK, Akhter F, Burza S, Ramesh V, Ahmed B-N, et al. Safety and effectiveness of short-course AmBisome in the treatment of post-kala-azar dermal leishmaniasis (PKDL): A prospective cohort study in Bangladesh. Clinical Infectious Diseases. 2018 - 51.
de Jesus Sousa-Batista A, Pacienza-Lima W, Arruda-Costa N, CAB F, Ré MI, Rossi-Bergmann B. Depot subcutaneous injection with chalcone CH8-loaded poly (lactic-co-glycolic acid) microspheres as a single-dose treatment of cutaneous leishmaniasis. Antimicrobial Agents and Chemotherapy. 2018; 62 (3):e01822-e01817 - 52.
El-khadragy M, Alolayan EM, Metwally DM, El-Din MFS, Alobud SS, Alsultan NI, et al. Clinical efficacy associated with enhanced antioxidant enzyme activities of silver nanoparticles biosynthesized using Moringa oleifera leaf extract, against cutaneous leishmaniasis in a murine model of Leishmania major . International Journal of Environmental Research and Public Health. 2018;15 (5):1037 - 53.
Ovais M, Khalil AT, Raza A, Islam NU, Ayaz M, Saravanan M, et al. Multifunctional theranostic applications of biocompatible green-synthesized colloidal nanoparticles. Applied Microbiology and Biotechnology. 2018; 102 (10):4393-4408 - 54.
Nazari-Vanani R, Vais RD, Sharifi F, Sattarahmady N, Karimian K, Motazedian M, et al. Investigation of anti-leishmanial efficacy of miltefosine and ketoconazole loaded on nanoniosomes. Acta Tropica. 2018; 185 :69-76 - 55.
Abongomera C, Diro E, de Lima Pereira A, Buyze J, Stille K, Ahmed F, et al. The initial effectiveness of liposomal amphotericin B (AmBisome) and miltefosine combination for treatment of visceral leishmaniasis in HIV co-infected patients in Ethiopia: A retrospective cohort study. PLoS Neglected Tropical Diseases. 2018; 12 (5):e0006527 - 56.
Sánchez FC, Sánchez TV, Díaz MC, Moyano VS, Gallego CJ, Marrero DH, editors. Visceral leishmaniasis in renal transplant recipients: Report of 2 cases. Transplantation Proceedings. 2018; 50 (2):581-582 - 57.
Galluzzi L, Ceccarelli M, Diotallevi A, Menotta M, Magnani M. Real-time PCR applications for diagnosis of leishmaniasis. Parasites & Vectors. 2018; 11 (1):273 - 58.
Merino-Espinosa G, Rodríguez-Granger J, Morillas-Márquez F, Tercedor J, Corpas-López V, Chiheb S, et al. Comparison of PCR-based methods for the diagnosis of cutaneous leishmaniasis in two different epidemiological scenarios: Spain and Morocco. Journal of the European Academy of Dermatology and Venereology. 2018 - 59.
Bangert M, Flores-Chávez MD, Llanes-Acevedo IP, Arcones C, Chicharro C, García E, et al. Validation of rK39 immunochromatographic test and direct agglutination test for the diagnosis of Mediterranean visceral leishmaniasis in Spain. PLoS Neglected Tropical Diseases. 2018; 12 (3):e0006277 - 60.
Shrestha M, Pandey BD, Maharjan J, Dumre SP, Tiwari PN, Manandhar KD, et al. Visceral leishmaniasis from a non-endemic Himalayan region of Nepal. Parasitology Research. 2018; 117 (7):2323-2326 - 61.
Adams ER, Schoone G, Versteeg I, Gomez MA, Diro E, Mori Y, et al. Development and evaluation of a novel LAMP assay for the diagnosis of cutaneous and visceral leishmaniasis. Journal of Clinical Microbiology. 2018; 56 (7). pii: e00386-18 - 62.
Van Griensven J, Mengesha B, Mekonnen T, Fikre H, Takele Y, Adem E, et al. Leishmania antigenuria to predict initial treatment failure and relapse in visceral leishmaniasis/HIV coinfected patients: An exploratory study nested within a clinical trial in Ethiopia. Frontiers in Cellular and Infection Microbiology. 2018; 8 :94