Abstract
Cutaneous leishmaniasis has various outcomes, ranging from self-healing reddened papules to extensive open ulcerations that metastasise to secondary sites and are often resistant to standard therapies. In the case of L. guyanensis (L.g), about 5–10% of all infections result in metastatic complications. We recently showed that a cytoplasmic virus within L.g parasites (LRV1) is able to act as a potent innate immunogen, worsening disease outcome in a murine model. In this study, we investigated the immunophenotype of human patients infected by L.g and found a significant association between the inflammatory cytokine IL-17A, the presence of LRV1 and disease chronicity. Further, IL-17A was inversely correlated to the protective cytokine IFN-γ. These findings were experimentally corroborated in our murine model, where IL-17A produced in LRV1+ L.g infection contributed to parasite virulence and dissemination in the absence of IFN-γ. Additionally, IL-17A inhibition in mice using digoxin or SR1001, showed therapeutic promise in limiting parasite virulence. Thus, this murine model of LRV1-dependent infectious metastasis validated markers of disease chronicity in humans and elucidated the immunologic mechanism for the dissemination of Leishmania parasites to secondary sites. Moreover, it confirms the prognostic value of LRV1 and IL-17A detection to prevent metastatic leishmaniasis in human patients.
Highlights
5% of humanity lives at risk of Leishmania infection across 98 countries worldwide [1]
Cutaneous leishmaniasis is a neglected parasitic disease problematic in the South American tropics, where the parasites have an ability to migrate from the initial inoculation site in a process called “infectious metastasis”
In this paper we show that the expression of the pro-inflammatory cytokine IL-17A is correlated with disease chronicity in patients infected by LRV+ Leishmania parasites
Summary
5% of humanity lives at risk of Leishmania infection across 98 countries worldwide [1]. While most infections remain localized at this site, several of the 20+ Leishmania species have a particular risk of infectious metastasis, where parasites migrate to unrelated cutaneous locations, causing secondary lesions that are often severely inflamed, deforming surrounding tissues into debilitating ulcerations, nodular granulomas or maculopapular rashes [5]. This may occur several years after resolution of the initial lesion where the extreme symptomatic diversity and poor predictability of the outcome poses major challenges to the diagnosis, treatment and control of metastatic leishmaniasis in the resource-scarce environments in which it is endemic [6, 7]. Metastatic CL due to L. guyanensis is not documented in mice, and there is no simple model or information on the immunological determinants of leishmanial metastasis with which we could design immunotherapeutic interventions to prevent and treat this disfiguring clinical complication
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