Abstract
Leishmaniasis is a neglected tropical disease with diverse outcomes ranging from self-healing lesions, to progressive non-healing lesions, to metastatic spread and destruction of mucous membranes. Although resolution of cutaneous leishmaniasis is a classic example of type-1 immunity leading to self-healing lesions, an excess of type-1 related inflammation can contribute to immunopathology and metastatic spread. Leishmania genetic diversity can contribute to variation in polarization and robustness of the immune response through differences in both pathogen sensing by the host and immune evasion by the parasite. In this study, we observed a difference in parasite chemokine suppression between the Leishmania (L.) subgenus and the Viannia (V.) subgenus, which is associated with severe immune-mediated pathology such as mucocutaneous leishmaniasis. While Leishmania (L.) subgenus parasites utilize the virulence factor and metalloprotease glycoprotein-63 (gp63) to suppress the type-1 associated host chemokine CXCL10, L. (V.) panamensis did not suppress CXCL10. To understand the molecular basis for the inter-species variation in chemokine suppression, we used in silico modeling to identify a putative CXCL10-binding site on GP63. The putative CXCL10 binding site is in a region of gp63 under significant positive selection, and it varies from the L. major wild-type sequence in all gp63 alleles identified in the L. (V.) panamensis reference genome. Mutating wild-type L. (L.) major gp63 to the L. (V.) panamensis sequence at the putative binding site impaired cleavage of CXCL10 but not a non-specific protease substrate. Notably, Viannia clinical isolates confirmed that L. (V.) panamensis primarily encodes non-CXCL10-cleaving gp63 alleles. In contrast, L. (V.) braziliensis has an intermediate level of activity, consistent with this species having more equal proportions of both alleles. Our results demonstrate how parasite genetic diversity can contribute to variation in immune responses to Leishmania spp. infection that may play critical roles in the outcome of infection.
Highlights
Parasites in the genus Leishmania infect over 1.6 million people annually causing a diverse collection of diseases ranging from visceral systemic illness to simple self-resolving cutaneous lesions to diffuse non-healing lesions with metastatic spread [1,2]
Our results demonstrate how diversity among Leishmania parasite species can contribute to variation in immune responses that may play critical roles in the outcome of infection
As Viannia parasites induce high cxcl10 expression [12,13,15] and have a large copy number expansion [28,30] of the CXCL10-cleaving protease GP63 [23], we asked whether Leishmania Viannia panamensis infection results in a net increase or decrease of CXCL10 protein
Summary
Parasites in the genus Leishmania infect over 1.6 million people annually causing a diverse collection of diseases ranging from visceral systemic illness to simple self-resolving cutaneous lesions to diffuse non-healing lesions with metastatic spread [1,2]. This diverse spectrum of disease outcomes is in part mediated by parasite genetic diversity influencing the host-immune response. These exceptions to the rule of protective type-1 immunity raise the question: what determines if a type-1 immune response protects the patient or exacerbates disease?
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