Leishmaniavirus-Dependent Metastatic Leishmaniasis Is Prevented by Blocking IL-17A

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.

Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis

“…The importance of IFN-γ was further demonstrated as a critical component of our murine model for metastatic leishmaniasis, where IFN-γ −/− mice failed to control Lgy infection, causing multiple metastatic lesions, usually located on the tail (17). In this model, metastases were accelerated in the presence of the endogenous LRV1 within Lgy parasites.…”

“…These findings may explain why the tight correlation between disease severity and metastasis with LgyLRV1 + in animal models (5) may be more variable in humans (13,17,47,48). Potentially, coinfection with viruses or other pathogens inducing a sufficient amount of type I IFNs could increase the severity of Lgy infection, contributing to the development of more severe disease manifestations.…”

“…Matched LgyLRV1 + and LgyLRV1 − parasites expressing luciferase obtained following limited treatment with anti-LRV1 inhibitors were used in all studies (20). In vivo parasites were quantified by luciferase bioluminescence imaging as described previously (17).…”

“…We recently showed that LRV1-dependent IL-17 promotes the dissemination of the parasite and the consequent formation of metastatic lesions (17). Moreover, we demonstrated that LRV1 increases the life span of Lgy-infected macrophages through a Toll-like receptor 3 (TLR3) and Akt-dependent pathway (18).…”

Tilting the balance between RNA interference and replication eradicatesLeishmaniaRNA virus 1 and mitigates the inflammatory response

“…The assignment of the LRV1 specificity of these phenotypes benefited greatly from the availability of a single isogenic LRV1-free line of Lgy (12). Importantly, recent studies have shown that disease severity is increased in patients infected with LRV1 + Lgy, relative to LRV1-negative parasites (13).…”