Evidence that interspeciesLeishmaniahybrids contribute to changes in disease pathology
Authors: Lypaczewski Patrick , Matlashewski Greg 
Published: June 2020

AbstractBackgroundLeishmaniasis is a widespread neglected tropical disease present in over 90 countries with diverse pathologies associated with different species ofLeishmaniaparasites transmitted by infected sand flies.Leishmania donovanicauses visceral leishmaniasis, a highly virulent fatal infection of the visceral organs.Leishmania majorandLeishmania tropicacause less virulent cutaneous leishmaniasis where the infection remains in the skin at the site of the sandfly bite. A major molecular epidemiological question is why some variants ofL. donovaniin Sri Lanka cause cutaneous disease rather than the typical visceral disease.MethodsWhole genome sequencing data for 684L. donovanisamples was used to perform sequence alignments and worldwide phylogenetic analyses to determine the source of the atypicalL. donovanistrains from Sri Lanka.L. donovanigenome sequences originating from Sri Lanka were further analyzed for evidence of hybridization with otherLeishmaniaspecies by determining the density of heterozygous alleles. Polymorphisms from potentialLeishmaniahybrids were used to reconstruct the parental genetic sequences to identify the potential parental species and quantify their genetic contribution through sequence comparison of the reconstructed parental sequences with all Old WorldLeishmaniagenomes.FindingsHere we show thatL. donovaniin Sri Lanka contains genes with widespread gene polymorphisms derived from AfricanL. majorandL. tropicagenomes that were likely obtained as a result of diploid genome hybridization and recombination resulting in progeny with mosaic genomes. Furthermore, evidence is presented that multipleL. donovanihybrid parasites originating from visceral leishmaniasis endemic Africa have entered Sri Lanka yet visceral leishmaniasis remains non-existent raising the possibility that environmental factors favour the establishment of atypicalL. donovanistrains in Sri Lanka.InterpretationThe discovery ofL. majorandL. tropicagenome sequences inL. donovaniprovides a compelling rationale how someL. donovanistrains in Sri Lanka may be able to cause cutaneous rather than visceral leishmaniasis. The identification ofL. donovanihybrid parasites in cutaneous leishmaniasis lesions provides a unique opportunity to investigate environmental and parasite genetic factors controlling disease epidemiology and pathogenesis.FundingCanadian Institutes of Health Research and Fonds de recherche du Québec – SantéResearch in contextEvidence before this studyDifferentLeishmaniaspecies parasites cause either benign cutaneous leishmaniasis or fatal visceral leishmaniasis. It is unknown why some variants ofLeishmania donovanithat typically causes visceral leishmaniasis in Asia and Africa can cause cutaneous leishmaniasis in specific geographic locations including Sri Lanka.Leishmaniahas a diploid genome and hybrid parasites have been identified in nature and generated experimentally. In the context of this study, hybrids are considered to be progeny derived from a single outcross event between two diverse parents. Uncertainty remains whether interspecies hybrids with visceral and cutaneous leishmaniasis causing species in nature are associated with different disease outcomes.Added value of this studyEvidence for genetic hybridization between visceral and cutaneous disease causingLeishmaniaspecies is described from Sri Lanka where cutaneous leishmaniasis is highly endemic yet there is no ongoing visceral leishmaniasis transmission. This provides a potential explanation howL. donovanican become attenuated for visceral disease and could help to identify geographic environmental factors associated with selection for parasite attenuation.Implications of all the available evidenceHybridLeishmaniaparasites may be one source of atypical cutaneous leishmaniasis. Epidemiological studies are needed to determine why diverseL. donovanihybrid parasites have become ubiquitous in specific geographic locations where the incidence of cutaneous leishmaniasis is increasing. This has implications for understanding the genetic control of disease pathogenesis and for the prevention of cutaneous or visceral leishmaniasis locally and in neighboring countries.