Research Article: Genetic Analysis of Leishmania donovani Tropism Using a Naturally Attenuated Cutaneous Strain

Date Published: July 3, 2014

Publisher: Public Library of Science

Author(s): Wen Wei Zhang, Gowthaman Ramasamy, Laura-Isobel McCall, Andrew Haydock, Shalindra Ranasinghe, Priyanka Abeygunasekara, Ganga Sirimanna, Renu Wickremasinghe, Peter Myler, Greg Matlashewski, Robert McMaster.


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.

Partial Text

Leishmaniasis is a neglected tropical disease present in 98 countries, with over 350 million people at risk of infection and is caused by Leishmania protozoan parasites transmitted by infected sand flies [1], [2]. Visceral leishmaniasis is the most serious form of this disease and it is among the most lethal parasitic infections after malaria. Cutaneous leishmaniasis in comparison causes skin lesions which usually self-heal. Over 20 Leishmania species can infect humans; however only the Leishmania donovani complex including L. infantum cause the vast majority of visceral leishmaniasis cases worldwide [2], [3].

A major question concerning leishmaniasis in Sri Lanka is whether one or different L. donovani strains are responsible for cutaneous and visceral leishmaniasis. We provide compelling evidence here including fulfilment of Koch’s postulates that different strains of L. donovani MON-37 are responsible for visceral and cutaneous disease in Sri Lanka. Most strikingly, the CL-SL clinical isolate was severely attenuated for survival in visceral organs in experimentally infected BALB/c mice, yet acquired the ability to cause cutaneous leishmaniasis in humans. Atypical cutaneous leishmaniasis in Sri Lanka caused by L. donovani is therefore most likely due to parasite-specific rather than host-specific determinants.




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