scholarly journals Evidence that interspecies Leishmania hybrids contribute to changes in disease pathology

2020 ◽  
Author(s):  
Patrick Lypaczewski ◽  
Greg Matlashewski
Keyword(s):  
Sri Lanka ◽  
Visceral Leishmaniasis ◽  
Environmental Factors ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Donovani ◽  
Genome Sequences ◽  
Geographic Locations ◽  
Diploid Genome ◽  
Cutaneous Disease ◽  
Visceral Disease

AbstractBackgroundLeishmaniasis is a widespread neglected tropical disease present in over 90 countries with diverse pathologies associated with different species of Leishmania parasites transmitted by infected sand flies. Leishmania donovani causes visceral leishmaniasis, a highly virulent fatal infection of the visceral organs. Leishmania major and Leishmania tropica cause 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 of L. donovani in Sri Lanka cause cutaneous disease rather than the typical visceral disease.MethodsWhole genome sequencing data for 684 L. donovani samples was used to perform sequence alignments and worldwide phylogenetic analyses to determine the source of the atypical L. donovani strains from Sri Lanka. L. donovani genome sequences originating from Sri Lanka were further analyzed for evidence of hybridization with other Leishmania species by determining the density of heterozygous alleles. Polymorphisms from potential Leishmania hybrids 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 World Leishmania genomes.FindingsHere we show that L. donovani in Sri Lanka contains genes with widespread gene polymorphisms derived from African L. major and L. tropica genomes that were likely obtained as a result of diploid genome hybridization and recombination resulting in progeny with mosaic genomes. Furthermore, evidence is presented that multiple L. donovani hybrid 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 atypical L. donovani strains in Sri Lanka.InterpretationThe discovery of L. major and L. tropica genome sequences in L. donovani provides a compelling rationale how some L. donovani strains in Sri Lanka may be able to cause cutaneous rather than visceral leishmaniasis. The identification of L. donovani hybrid 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 studyDifferent Leishmania species parasites cause either benign cutaneous leishmaniasis or fatal visceral leishmaniasis. It is unknown why some variants of Leishmania donovani that typically causes visceral leishmaniasis in Asia and Africa can cause cutaneous leishmaniasis in specific geographic locations including Sri Lanka. Leishmania has 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 causing Leishmania species is described from Sri Lanka where cutaneous leishmaniasis is highly endemic yet there is no ongoing visceral leishmaniasis transmission. This provides a potential explanation how L. donovani can become attenuated for visceral disease and could help to identify geographic environmental factors associated with selection for parasite attenuation.Implications of all the available evidenceHybrid Leishmania parasites may be one source of atypical cutaneous leishmaniasis. Epidemiological studies are needed to determine why diverse L. donovani hybrid 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.

scholarly journals Leishmania donovani Induced Cutaneous Leishmaniasis: An Insight into Atypical Clinical Variants in Sri Lanka

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Yamuna Siriwardana ◽  
Bhagya Deepachandi ◽  
Chalukya Gunasekara ◽  
Wipula Warnasooriya ◽  
Nadira D. Karunaweera
Keyword(s):  
Sri Lanka ◽  
Head And Neck ◽  
Cutaneous Leishmaniasis ◽  
Disease Transmission ◽  
Leishmania Donovani ◽  
Developmental Stages ◽  
Clinical Entity ◽  
Delayed Treatment ◽  
Separate Clinical Entity ◽  
Study Laboratory

Sri Lanka is a recent focus having Leishmania donovani induced cutaneous leishmaniasis (CL) as the main clinical entity. A separate clinical entity within profile of CL was described in this study. Laboratory confirmed cases of CL (n= 950, 2002-2014) were analysed. Most lesions showed known classical developmental stages of CL (CCL) observed in other CL endemic settings while few cases (13%, 122/950) showed atypical skin manifestations (ACL). Clinical, geographical, and treatment response patterns of ACL were different from those of CCL. ACL was mainly found among males (68.0%), in 21-40 year age group (51.6%), and reported delayed treatment seeking (23.5% vs 16.3% in CCL), more nonclassical onset (lesions other than acne form <1cm sized papules), (12.1 vs 2.7%, P<0.05.), more head and neck lesions (41.5%. vs 27.2%), more large lesions (>4cm), (18.6 vs 9.9%), and poor laboratory positivity rates (65.6% vs 88.2%) when compared to CCL. When compared to lesions reporting a typical onset, lesions reporting nonclassical onset were more likely to develop ACL later on (50.1% vs 10.7%). As compared to lesions on limbs, those on head and neck and trunk were more likely to be ACL (7.0%, 16.3%, and 22.8%, respectively, P<0.05). ACL features were not age or gender dependent. Highest proportion within ACL category (32.8%) and small proportion of CCL (10.1%) originated from less leishmaniasis prevalent areas (other regions) (P<0.05). North reported more ACL than South (15.9% vs 7.4%). A total of 95 CL cases with a significant travel history were further analyzed. Residents of other regions when acquired infection from North or South developed more ACL than residents in North or South (60.9% vs 15.9% and 42.9% vs 7.4% respectively). Patients in other regions when travelled to North developed more ACL than when they travelled to South (60.9%, 42.9%). ACL and CCL required an average of 18 doses over 16.7 months and 10 doses over 12 weeks, respectively, to achieve a complete clinical cure. Underlying host immunological factors, parasite strain variations and regional variations of both could be underlying etiologies. Established independent transmission within less leishmaniasis prevalent regions combined with an unusual clinical picture leading to poor clinical suspicion and low laboratory confirmation rate will pose potential difficulties in early case detection in these highly populated and commercialized areas. This in turn will further facilitate silent and high disease transmission.

scholarly journals Histopathology of Cutaneous Leishmaniasis Caused by Leishmania donovani in Sri Lanka

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Harshima Wijesinghe ◽  
Nayana Gunathilaka ◽  
Saveen Semege ◽  
Nishantha Pathirana ◽  
Nuwani Manamperi ◽  
...  
Keyword(s):  
Sri Lanka ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Donovani ◽  
Clinical Presentation ◽  
Cross Sectional Study ◽  
Causative Organism ◽  
Variable Intensity ◽  
Cross Sectional ◽  
The North ◽  
Parasitic Load

Cutaneous leishmaniasis (CL) is a neglected tropical disease that is gaining importance in Sri Lanka and internationally. The clinical presentation, pathology, and method of parasite elimination in CL vary according to the species. Leishmania donovani is the causative organism for leishmaniasis in Sri Lanka. This collaborative cross-sectional study describes the clinicopathological features of cutaneous leishmaniasis among personnel of the tri-forces serving in the North and East of the country. The histology of fifty cases of CL confirmed by at least two methods (slit skin smear, lesion aspirate, tissue impression, and histology) was reviewed. The parasitic load was assessed semiquantitatively. The histological features were correlated with the clinical presentation and organism load. The majority (89.8%; n=44) presented with a single lesion mostly located in the upper limb (69.4%). The lesion types included papule (34.7%), nodule (32.7%), and an ulcer (30.6%). The evolution time of lesions averaged 31.55 weeks. Epidermal changes were observed in 49 of the biopsies and included hyperkeratosis (90.0%; n=45), acanthosis (44.0%; n=22), atrophy (34.0%; n=17), and interface change (66%; n=33). Dermal changes were seen in all cases and were characterized by a lymphohistioplasmacytic inflammatory infiltrate of variable intensity with ill-formed granuloma in 19 cases (38%) and well-formed epithelioid granulomas in 22 cases (44%). Focal necrosis was present in 20% (n=10). Leishmania amastigote forms were observed in 88% (n=44). Transepidermal elimination (P=0.025), granuloma (P=0.027) formation, and type of lesion (P=0.034) were significantly associated with the organism load. Granuloma formation was associated with a reduction in organism load, indicating that the macrophage activation played an important role in the control of the organism.

scholarly journals Evidence for Seroprevalence in Human Localized Cutaneous Leishmaniasis Caused byLeishmania donovaniin Sri Lanka

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Yamuna Deepani Siriwardana ◽  
Bhagya Deepachandi ◽  
Samantha Ranasinghe ◽  
Preethi Soysa ◽  
Nadira Karunaweera
Keyword(s):  
Sri Lanka ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Igg Antibodies ◽  
Major Health ◽  
Systemic Involvement ◽  
Number Of Patients ◽  
Nodular Lesions

Visceral leishmaniasis (VL) is considered as a major health threat in the Indian subcontinent.Leishmania donovani, a usually visceralizing species, causes cutaneous leishmaniasis (CL) in Sri Lanka. However, visceralizing potential of the localL. donovaniis not yet fully understood. This project studied the seroprevalence of local CL by using an in-house ELISA. An IgG-based ELISA using crudeLeishmaniaantigen (Ag) was developed and validated. A total of 50 laboratory confirmed cases of locally acquired CL were examined using the newly developed ELISA. According to the optimized ELISA, seroprevalence of anti-LeishmaniaIgG antibodies in the study group was 34.0% (n=17/50). Majority of seropositive individuals were males (n=13/17), representing 76%. Nearly half of the seropositive individuals were young adults (20–40 years,n=9/17, 53%). Higher proportions of single lesions, large lesions, and nodular lesions were associated with a seroconversion. A proportion of localL. donovaniinfections leading to CL have the ability to raise an antibody response in the host. This may indicate early systemic involvement as one possibility. Study of a large number of patients with adequate follow-up would be useful.

scholarly journals Genetic diversity of Leishmania donovani that causes cutaneous leishmaniasis in Sri Lanka: a cross sectional study with regional comparisons

2017 ◽  
Vol 17 (1) ◽  
Author(s):  
Udeshika Lakmini Kariyawasam ◽  
Angamuthu Selvapandiyan ◽  
Keshav Rai ◽  
Tasaduq Hussain Wani ◽  
Kavita Ahuja ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Sri Lanka ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Donovani ◽  
Cross Sectional Study ◽  
Sectional Study ◽  
Cross Sectional ◽  
Regional Comparisons

scholarly journals Evidence that a naturally occurring single nucleotide polymorphism in the RagC gene of Leishmania donovani contributes to reduced virulence

2021 ◽  
Vol 15 (2) ◽  
pp. e0009079
Author(s):  
Patrick Lypaczewski ◽  
Wen-Wei Zhang ◽  
Greg Matlashewski
Keyword(s):  
Sri Lanka ◽  
Leishmania Donovani ◽  
Gene Knockout ◽  
Bioinformatic Analysis ◽  
Culture Conditions ◽  
Single Nucleotide ◽  
Tor Pathway ◽  
Naturally Occurring ◽  
Visceral Disease ◽  
Principal Species

Leishmaniasis is a widespread neglected tropical disease transmitted by infected sand flies resulting in either benign cutaneous infection or fatal visceral disease. Leishmania donovani is the principal species responsible for visceral leishmaniasis, yet an atypical L. donovani has become attenuated in several countries including Sri Lanka and causes cutaneous leishmaniasis. Previous studies have identified 91 genes altered in the atypical cutaneous L. donovani compared to typical visceral disease associated L. donovani including mutations in the RagC and Raptor genes that are part of the eukaryotic conserved TOR pathway and its upstream sensing pathway. In the present study, we investigate whether the RagC R231C mutation present in atypical cutaneous L. donovani introduced into the virulent L. donovani 1S2D chromosome by CRISPR gene editing could affect virulence for survival in visceral organs. Through bioinformatic analysis, we further investigated the presence of sensing pathway components upstream of TOR in L. donovani including RagC complexing proteins, RagA and Raptor. L. donovani 1S2D edited to express mutant RagC R231C were viable in promastigote but had reduced visceral parasitemia in infected BALB/c mice. The RagC R231C mutant retained the ability to interact with RagA and gene knockout experiments revealed that although the RagA gene was essential, the RagC gene was not essential under promastigote culture conditions but was essential for survival in the liver of experimentally infected mice. These results provide evidence that the TOR associated sensing pathway plays a prominent role in L. donovani visceral disease and the RagC R231C mutation contributed to the atypical pathology of cutaneous L. donovani in Sri Lanka.

Leishmanization revisited: Immunization with a naturally attenuated cutaneous Leishmania donovani isolate from Sri Lanka protects against visceral leishmaniasis

Vaccine ◽  
2013 ◽  
Vol 31 (10) ◽  
pp. 1420-1425 ◽  
Author(s):  
Laura-Isobel McCall ◽  
Wen-Wei Zhang ◽  
Shanlindra Ranasinghe ◽  
Greg Matlashewski
Keyword(s):  
Sri Lanka ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani

scholarly journals Assessment of intralesional cytokine profile of cutaneous leishmaniasis caused by Leishmania donovani in Sri Lanka

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Lahiru Sandaruwan Galgamuwa ◽  
Buthsiri Sumanasena ◽  
Devika Iddawela ◽  
Susiji Wickramasinghe ◽  
Lalani Yatawara
Keyword(s):  
Sri Lanka ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Donovani ◽  
Cytokine Profile

scholarly journals Polymerase chain reaction detection of LeishmaniaDNA in skin biopsy samples in Sri Lanka where the causative agent of cutaneous leishmaniasis is Leishmania donovani

2015 ◽  
Vol 110 (8) ◽  
pp. 1017-1023 ◽  
Author(s):  
Shalindra Ranasinghe ◽  
Renu Wickremasinghe ◽  
Sanjeeva Hulangamuwa ◽  
Ganga Sirimanna ◽  
Nandimithra Opathella ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Sri Lanka ◽  
Skin Biopsy ◽  
Cutaneous Leishmaniasis ◽  
Causative Agent ◽  
Leishmania Donovani ◽  
Polymerase Chain Reaction Detection ◽  
Chain Reaction ◽  
Polymerase Chain

Leishmania donovani causing cutaneous leishmaniasis in Sri Lanka: a wolf in sheep's clothing?

2009 ◽  
Vol 25 (10) ◽  
pp. 458-463 ◽  
Author(s):  
Nadira D. Karunaweera
Keyword(s):  
Sri Lanka ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Donovani

scholarly journals Evolutionary genomics of epidemic visceral leishmaniasis in the Indian subcontinent

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Hideo Imamura ◽  
Tim Downing ◽  
Frederik Van den Broeck ◽  
Mandy J Sanders ◽  
Suman Rijal ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Evolutionary Genomics ◽  
Whole Genome ◽  
Parasitic Disease ◽  
Distinct Population ◽  
Genome Sequences ◽  
Vector Borne ◽  
Base Pair Insertion

Leishmania donovani causes visceral leishmaniasis (VL), the second most deadly vector-borne parasitic disease. A recent epidemic in the Indian subcontinent (ISC) caused up to 80% of global VL and over 30,000 deaths per year. Resistance against antimonial drugs has probably been a contributing factor in the persistence of this epidemic. Here we use whole genome sequences from 204 clinical isolates to track the evolution and epidemiology of L. donovani from the ISC. We identify independent radiations that have emerged since a bottleneck coincident with 1960s DDT spraying campaigns. A genetically distinct population frequently resistant to antimonials has a two base-pair insertion in the aquaglyceroporin gene LdAQP1 that prevents the transport of trivalent antimonials. We find evidence of genetic exchange between ISC populations, and show that the mutation in LdAQP1 has spread by recombination. Our results reveal the complexity of L. donovani evolution in the ISC in response to drug treatment.

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