title: Genetic analysis of Leishmania donovani tropism using a naturally attenuated cutaneous strain.
abstract: A central question in Leishmania research is why most species cause cutaneous infections but others cause fatal visceral disease. Interestingly, L. donovani causes both visceral and cutaneous leishmaniasis in Sri Lanka. L. donovani clinical isolates were therefore obtained from cutaneous leishmaniasis (CL-SL) and visceral leishmaniasis (VL-SL) patients from Sri Lanka. The CL-SL isolate was severely attenuated compared to the VL-SL isolate for survival in visceral organs in BALB/c mice. Genomic and transcriptomic analysis argue that gene deletions or pseudogenes specific to CL-SL are not responsible for the difference in disease tropism and that single nucleotide polymorphisms (SNPs) and/or gene copy number variations play a major role in altered pathology. This is illustrated through the observations within showing that a decreased copy number of the A2 gene family and a mutation in the ras-like RagC GTPase enzyme in the mTOR pathway contribute to the attenuation of the CL-SL strain in visceral infection. Overall, this research provides a unique perspective on genetic differences associated with diverse pathologies caused by Leishmania infection.
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Canada.
authors.forename: Wen Wei
authors.initials: WW
authors.lastname: Zhang
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Gowthaman
authors.initials: G
authors.lastname: Ramasamy
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Canada.
authors.forename: Laura-Isobel
authors.initials: LI
authors.lastname: McCall
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Haydock
authors.affiliation: Department of Parasitology, University of Sri Jayewardenepura, Gangodawila, Sri Lanka.
authors.forename: Shalindra
authors.initials: S
authors.lastname: Ranasinghe
authors.affiliation: Teaching Hospital Anuradhapura, Anuradhapura, Sri Lanka.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Abeygunasekara
authors.affiliation: Dermatology Unit, National Hospital of Sri Lanka, Colombo, Sri Lanka.
authors.forename: Ganga
authors.initials: G
authors.lastname: Sirimanna
authors.affiliation: Department of Parasitology, University of Sri Jayewardenepura, Gangodawila, Sri Lanka.
authors.forename: Renu
authors.initials: R
authors.lastname: Wickremasinghe
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Myler
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Canada; Microbiome and Disease Tolerance Centre, McGill University, Montreal, Canada.
authors.forename: Greg
authors.initials: G
authors.lastname: Matlashewski
mesh_terms: D000818:Animals; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007893:Leishmania donovani / Q000235:genetics* / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020641:Polymorphism, Single Nucleotide; D015800:Protozoan Proteins / Q000235:genetics* / Q000276:immunology; D011544:Pseudogenes
chemical_list: D015800:Protozoan Proteins