Leishmaniases

Abstract

Leishmaniases are parasitic diseases, which are transmitted by the blood‐sucking sand flies as the vectors. These diseases are largely zoonotic, but considered as anthroponotic in some endemic sites. The reservoir animals include canines, rodents, edentates and other wild animals. A spectrum of clinical manifestations is associated with these diseases, ranging from self‐healing cutaneous lesions to facial mucocutaneous disfiguration to visceralization with fatal consequence. According to the World Health Organisation, there are 12 million cases of these diseases in approximately 90 countries with an annual incidence of approximately 2 million. Treatment of leishmaniases depends on very few drugs for chemotherapy, which are either expensive or toxic and have lost effectiveness due to drug‐resistance. The causative agents are the trypanosomatid protozoa Leishmania, widespread in tropical and subtropical areas. Intraphagolysosomal parasitism of macrophages by these parasites is a key feature in considering molecular mechanisms of their virulence relevant to developing effective drugs and vaccines needed.

Key Concepts:

  • Trypanosomatid protozoa in the genus of Leishmania cause Leishmaniases.

  • They have evolved mechanisms to live in macrophage endosomes/lysosomes.

  • The diseases are wide‐spread mainly in tropical and subtropical areas of the world.

  • The diseases are largely zoonotic and transmitted by blood‐sucking sand flies.

  • Reservoirs include domestic and wild animals, for example, canines, rodents & edentates.

  • Clinically, there are cutaneous, mucocutaneous and visceral Leishmaniasis.

  • The clinical spectrum results from host immunopathology to Leishmania infection.

  • Chemotherapy relies on toxic drugs and loses its effectiveness to drug‐resistance.

  • Drug development programs by targeting unique parasite enzymes are very few.

  • Control programs include the use of anti‐vector pesticide/repellents.

Keywords: Leishmania; promastigotes; amastigotes; kala azar; espundia; leishmanization

Figure 1.

Leishmania life cycle in mammalian hosts (upper) and in sandfly vectors (lower). Redrawn (not to scale) after Chang, Fong and Bray (1985). Mammalian stage: (1) delivery of infective promastigotes into mammalian skin by the bite of sandfly vector; (2) phagocytosis of promastigotes by a macrophage; (3) fusion of a promastigote‐containing phagosome with the lysosome; (4) full differentiation of promastigote into amastigote in the phagolysosome of the infected macrophage; (5) amastigote replication in a parasite‐containing or parasitophorous vacuole; (6) continuing replication of intravacuolar amastigotes in small individual or large communal parasitophorous vacuoles; (7) degeneration (symbolically shown by dotted lines) of heavily parasitized macrophage and release of amastigotes; (8) spread of infection via phagocytosis of released amastigotes or those still in the vacuoles by newly arrived macrophages or scavenging phagocytosis of degenerating cells by multiple newly arrived macrophages. Reservoirs include canines, humans, rodents and other wild animals, for example, sloth in South America. Sandfly stage: (9) ingestion of parasitized macrophages by sand flies after a bloodmeal taken from infected humans or reservoir animals; (10) rupture of the ingested macrophages and release of amastigotes in the gut of sand flies; (11) replication of amastigotes and their differentiation into promastigotes; (12) replication of promastigotes in midgut and insertion of their flagella into microvilli of the gut epithelial cells; (13) replication of those in the Viannia subgenus, for example, Leishmania brasilienisis in the pylorus and ileum of the sand fly hindgut as paramastigotes with broadened flagella attached to the chitinous gut wall via hemi‐desmosomes; (14) forward movement of promastigotes to thoracic midgut as haptomonads with broad flagella attached to the chitinous gut wall; (15) sessile paramastigotes with broad flagella attached to the chitinous wall of stomadeal valve, pharynx and buccal cavity or cibarium; (16) actively motile and infective promastigotes found in the proboscis or mouth part of female sand flies.

Figure 2.

Hypothetical model of host‐parasite interactions depicting Leishmania virulence as reflected in the clinical spectrum of the disease phenotypes seen during the progression of human leishmaniasis. (1) Parasite surface/secreted molecules, collectively referred to as invasins/evasins, allow Leishmania to evade host innate defenses for successful host/host cell invasion; (2) Leishmania pathoantigens vary with different species and thus elicit different host immunopathology, accounting for the spectrum of disease phenotypes seen; (3) Leishmania vaccine molecules, which elicit acquired cell‐mediated immunity to resolve simple cutaneous leishmaniasis of the Eurasian continent spontaneously and mucocutaneous/visceral Leishmaniasis after successful therapeutic intervention.

close

References

Akopyants NS, Kimblin N, Secundino N et al. (2009) Demonstration of genetic exchange during cyclical development of Leishmania in the sand fly vector. Science 324: 265–268.

Aphasizhev R, Aphasizheva I, Nelson RE et al. (2003) Isolation of a U‐insertion/deletion editing complex from Leishmania tarentolae mitochondria. EMBO Journal 22: 913–924.

Bente M, Harder S, Wiesgigl M et al. (2003) Developmentally induced changes of the proteome in the protozoan parasite Leishmania donovani. Proteomics 3: 1811–1829.

Berman J (2003) Current treatment approaches to leishmaniasis. Current Opinion Infectious Diseases 16: 397–401.

Beverley SM (2003) Protozomics: trypanosomatid parasite genetics comes of age. Nature Reviews Genetics 4: 11–19.

Blackwell JM, Searle S, Mohamed H et al. (2003) Divalent cation transport and susceptibility to infectious and autoimmune disease: continuation of the Ity/Lsh/Bcg/Nramp1/Slc11a1 gene story. Immunology Letters 85: 197–203.

Burns JM, Shreffler WG, Benson DR et al. (1993) Molecular characterization of a kinensin‐related antigen of Leishmania chagasi that detects specific antibody in African and American visceral leishmaniasis. Proceedings of the National Academy of Sciences of the USA 90: 775–779.

Chai Jun‐jie and Guan Liren (eds) (2006) Leishmaniasis and Phlebotomine sandflies in the Xinjiang Uygur Autonomous region, pp. 385 (in Chinese) PR China: Xinjiang People's Publication Co.

Chakravarty J, Kumar S, Trivedi S et al. (2011) A clinical trial to evaluate the safety and immunogenicity of the LEISH‐F1+MPL‐SE vaccine for use in the prevention of visceral leishmaniasis. Vaccine 29: 3531–3537.

Chang KP and Bray RS (eds) (1985) Leishmaniasis. Amsterdam: Elsevier.

Chang K‐P and McGwire BS (2002) Molecular determinants and regulation of Leishmania virulence. Kinetoplastid Biology and Disease 1: 1–7 (http://www.kinetoplastids.com/content/1/1/1).

Chang K‐P, Reed SG, McGwire BS and Soong L (2003) Leishmania model for microbial virulence: the relevance of parasite replication and pathoantigenicity. Acta Tropica 85: 375–390.

Coler RN and Reed SG (2005) Second‐generation vaccines against leishmaniasis. Trends in Parasitology 21: 244–249.

Cortez M, Huynh C, Fernandes MC et al. (2011) Leishmania promotes its own virulence by inducing expression of the host immune inhibitory ligand CD200. Cell Host Microbe 9: 463–471.

Costa CH, Peters NC, Maruyama SR – Working Group on Research Priorities for Development of Leishmaniasis Vaccines et al. (2011) Vaccines for the leishmaniases: proposals for a research agenda. PLoS Neglected Tropical Diseases 5: e943.

Croft SL and Coombs GH (2003) Leishmaniasis – current chemotherapy and recent advances in the search for novel drugs. Trends in Parasitology 19: 502–508.

Cuervo P, Domont GB and De Jesus JB (2010) Proteomics of trypanosomatids of human medical importance. Journal of Proteomics 73: 845–867.

Desjeux P (2001) The increase in risk factors for leishmaniasis worldwide. Transactions of the Royal Society of Tropical Medicine and Hygiene 95: 239–243.

Desjeux P (2004) Leishmaniasis: current situation and new perspectives. Comparative Immunology and Microbiology of Infectious Diseases 27: 305–318.

Dougall AM, Alexander B, Holt DC et al. (2011) Evidence incriminating midges (Diptera: Ceratopogonidae) as potential vectors of Leishmania in Australia. International Journal of Parasitology 41: 571–579.

Dutta S, Ongarora BG, Li H, Vicente Mda G et al. (2011) Intracellular targeting specificity of novel phthalocyanines assessed in a host‐parasite model for developing potential photodynamic medicine. PLoS One 6: e20786.

Farrell JP (ed.) (2002) Leishmania. In: Black SJ and Seed JR (eds) World Class Parasites, vol. 4, pp. 193 Boston: Kluwer Academic Publishers.

Goto Y, Bhatia A, Raman VS et al. (2011) KSAC, the first defined polyprotein vaccine candidate for visceral leishmaniasis. Clinical Vaccine and Immunology 18: 1118–1124.

Guha‐Niyogi A, Sullivan DR and Turco SJ (2001) Glycoconjugate structures of parasitic protozoa. Glycobiology 11: 45R–59R.

Haile S and Papadopoulou B (2007) Developmental regulation of gene expression in trypanosomatid parasitic protozoa. Current Opinion in Microbiology 10: 569–577.

Ilg T (2001) Lipophosphoglycan of the protozoan parasite Leishmania: stage‐ and species‐specific importance for colonization of the sandfly vector, transmission and virulence to mammals. Medical Microbiology and Immunology (Berl) 190: 13–17.

Ilg T, Stierhof YD, Craik D et al. (1996) Purification and structural characterization of a filamentous, mucin‐like proteophosphoglycan secreted by Leishmania parasites. Journal of Biological Chemistry 271: 21583–21596.

Ives A, Ronet C, Prevel F et al. (2011) Leishmania RNA virus controls the severity of mucocutaneous leishmaniasis. Science 331: 775–778.

Kaye P and Scott P (2011) Leishmaniasis: complexity at the host‐pathogen interface. Nature Review Microbiology 9: 604–615.

Kean BH, Mott KE and Russell AJ (1978) Tropical medicine and parasitology – Classic investigation, vol. 1, pp. 228–270. Ithaca & London: University Press.

Landfear SM (2011) Nutrient transport and pathogenesis in selected parasitic protozoa. Eukaryotic Cell 10: 483–493.

Laskay T, van Zandbergen G and Solbach W (2008) Neutrophil granulocytes as host cells and transport vehicles for intracellular pathogens: apoptosis as infection‐promoting factor. Immunobiology 213: 183–191.

Majumder HK, de Souza W and Chang KP (eds) (2011) Target Identification and Intervention Strategies against Kinetoplastid Protozoan Parasites. Molecular Biology International 2011.

Matlashewski G (2001) Leishmania infection and virulence. Medical Microbiology and Immunology (Berl) 190: 37–42.

Matlashewski G, Arana B, Kroeger A et al. (2011) Visceral leishmaniasis: elimination with existing interventions. Lancet Infectious Diseases 11: 322–325.

McGwire BS and Chang KP (1996) Posttranslational regulation of a Leishmania HEXXH metalloprotease (gp63). The effects of site‐specific mutagenesis of catalytic, zinc binding, N‐glycosylation, and glycosyl phosphatidylinositol addition sites on N‐terminal end cleavage, intracellular stability, and extracellular exit. Journal of Biological Chemistry 271: 7903–7909.

Myler PJ and Fasel N (2008) Leishmania after the genome. Norfolk, UK: Caister Academic Press.

Olafson RW, Thomas JR, Ferguson MA et al. (1990) Structures of the N‐linked oligosaccharides of Gp63, the major surface glycoprotein, from Leishmania mexicana amazonensis. Journal of Biological Chemistry 265: 12240–12247.

Olivier M, Gregory DJ and Forget G (2005) Subversion mechanisms by which Leishmania parasites can escape the host immune response: a signaling point of view. Clinical Microbiology Review 18: 293–305.

de Oliveira CI, Nascimento IP, Barral A et al. (2009) Challenges and perspectives in vaccination against leishmaniasis. Parasitology International 58: 319–324.

Opperdoes FR and Coombs GH (2007) Metabolism of Leishmania: proven and predicted. Trends in Parasitology 23: 149–158.

Ouellette M, Drummelsmith J and Papadopoulou B (2004) Leishmaniasis: drugs in the clinic, resistance and new developments. Drug Resistance Update 7: 257–266.

Ponte‐Sucre A (ed.) (2012) Drug Resistance in Leishmania Parasites. Berlin: Springer Verlag GmbH.

Rogers ME, Ilg T, Nikolaev AV et al. (2004) Transmission of cutaneous leishmaniasis by sand flies is enhanced by regurgitation of fPPG. Nature 430: 463.

Sacks D and Kamhawi S (2001) Molecular aspects of parasite‐vector and vector‐host interactions in leishmaniasis. Annual Review of Microbiology 55: 453–483.

Sacks D and Noben‐Trauth N (2002) The immunology of susceptibility and resistance to Leishmania major in mice. Nature Review Immunology 2: 845–858.

Van Assche T, Deschacht M, da Luz RA et al. (2011) Leishmania‐macrophage interactions: insights into the redox biology. Free Radical Biology and Medicine 51: 337–351.

Waki K, Dutta S, Ray D et al. (2007) Transmembrane molecules for phylogenetic analyses of pathogenic protists: Leishmania‐specific informative sites in hydrophilic loops of trans‐endoplasmic reticulum N‐acetylglucosamine‐1‐phosphate transferase. Eukaryotic Cell 6: 198–210.

Wang JY, Gao CH, Yang YT et al. (2010) An outbreak of the desert sub‐type of zoonotic visceral leishmaniasis in Jiashi, Xinjiang Uygur Autonomous Region, People's Republic of China. Parasitology International 59: 331–337.

World Health Organization Leishmaniasis. http://www.who.int/topics/leishmaniasis/en/.

Yao C (2010) Major surface protease of trypanosomatids: one size fits all? Infection and Immunity 78: 22–31.

Zhang K, Bangs JD and Beverley SM (2010) Sphingolipids in parasitic protozoa. Advances in Experimental Medicine and Biology 688: 238–248.

Further Reading

Bhaduri AN, Basu AK and Kumar S (eds) (1993) Current Trends in Leishmania Research. New Delhi, India: Council of Scientific and Industrial Research.

Chang KP, Chaudhuri G and Fong D (1990) Molecular determinants of Leishmania virulence. Annual Review of Microbiology 44: 499–529.

Fairlamb AH (1989) Novel biochemical pathways in parasitic protozoa. Parasitology 99: S93–S112.

Hart DT (ed.) (1989) Leishmaniasis. The Current Status and New Strategies for Control, NATO ASI Series A, 163. New York: Plenum.

Pearson RD and de Queiroz Sousa A (1996) Clinical spectrum of leishmaniasis. Clinical Infectious Diseases 22: 1–13.

Peters W and Killick‐Kendrick R (eds) (1987) Leishmaniasis. New York: Academic Press.

Reiner SL and Locksley RM (1995) The regulation of immunity to Leishmania major. Annual Review of Immunology 13: 151–177.

Schlagenhauf E, Etges R and Metcalf P (1998) The crystal structure of the Leishmania major surface proteinase leishmanolysin (gp63). Structure 6: 1035–1046.

Simpson L and Maslov DA (1994) RNA editing and the evolution of parasites. Science 264: 1870–1871.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Chang, Kwang Poo(May 2012) Leishmaniases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001954.pub3]