metastatic leishmaniasis; Leishmania RNA virus; immune response; Leishmania; oxidative stress; antimony response
Castiglioni Patrik, Hartley Mary-Anne, Rossi Matteo, Prevel Florence, Desponds Chantal, Utzschneider Daniel T., Eren Remzi-Onur, Zangger Haroun, Brunner Livia, Collin Nicolas, Zehn Dietmar, Kuhlmann F. Matthew, Beverley Stephen M., Fasel Nicolas, Ronet Catherine (2017), Exacerbated Leishmaniasis Caused by a Viral Endosymbiont can be Prevented by Immunization with Its Viral Capsid, in PLOS Neglected Tropical Diseases
, 11(1), e0005240-e0005240.
Rossi Matteo, Castiglioni Patrik, Hartley Mary-Anne, Eren Remzi Onur, Prével Florence, Desponds Chantal, Utzschneider Daniel T., Zehn Dietmar, Cusi Maria G., Kuhlmann F. Matthew, Beverley Stephen M., Ronet Catherine, Fasel Nicolas (2017), Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis, in Proceedings of the National Academy of Sciences
Fasel Nicolas (2016), Leishmaniavirus-Dependent Metastatic Leishmaniasis Is Prevented by Blocking IL-17A., in Plos Pathogens
, pp. e10058.
Eren R.O (2016), Mammalian Innate Immune Response to a Leishmania-Resident RNA Virus Increases Macrophage Survival to Promote Parasite Persistence., in Cell Host and Microbe
Hartley M. A., Drexler S., Ronet C., Beverley S. M., Fasel N. (2014), The immunological, environmental, and phylogenetic perpetrators of metastatic leishmaniasis, in Trends in Parasitology
, 30(8), 412-422.
Protozoan Leishmania parasites have been plaguing humans for centuries. They reside within host macrophages in a phagolysosome-like organelle, impacting on host metabolism and immune response. Different types of pathologies are induced by Leishmania parasites depending on the infectious species, ranging from cutaneous lesions developing at the site of a female sand fly bite to visceralized or metastatic leishmaniases. In metastatic leishmaniases, parasites disseminate to secondary cutaneous and/or mucosal sites. These clinical presentations are mainly found in Leishmania (L.) braziliensis, L. panamensis and L. guyanensis infected patients. Parameters implicated in this dissemination are poorly described. Inflammation and relapses after the first line of treatment (antimony) are the main hallmarks of metastatic leishmaniases.We have demonstrated that the presence of an endosymbiotic dsRNA virus (LRV) inside L. guyanensis parasites impacts on the immune and cellular response of the host, aggravating Leishmania pathologies. LRV dsRNA binds to the endosomal Toll-like receptor 3 (TLR3) and exacerbates the disease in our animal models, causing larger lesions and increasing parasite survival and consequently parasite burden. This exacerbation is a consequence of a very early induction of interferon-ß, which is responsible for the production of inflammatory cytokines and chemokines such as interleukin-6 and tumor necrosis factor-a, markers known to be relevant in chronic inflammation in mucosal leishmaniasis patients. Paradoxically, while LRV helps in maintenance and survival of parasites, it also up-regulates inducible nitric oxide synthase, responsible for the production and release of higher levels of nitric oxide and peroxinitrite, which participates in the killing of most Leishmania parasites. The mechanisms behind the LRV-dependent parasite survival, the oxidative stress environment and the TLR3 activation and their impact on relapses after antimony treatment are not known. Our recent data strongly suggest that there is a link between TLR3, microRNA-155 and heme-oxygenase-1 as well as between parasite entry, reactive oxygen species and the detoxification machinery. The timing of these responses is critical and the events taking part in the first hours of infection are essential for an increased LRV-dependent parasite survival and to determine the outcome of disease. Thus, in the context of this complex situation, an intracellular parasite and its endosymbiotic virus, and based on our previous data, we will focus on how LRV impacts on parasite survival by studying two macrophage pathways involved in detoxification: the NF-E2-related factor 2/microRNA-155/heme oxygenase-1 pathway (AIM 1), the peroxiredoxins/sulfiredoxin pathway (AIM 2) and also by investigating the impact of antimony in the context of this nested co-infection and detoxification machineries (AIM 3). Our results should not only facilitate the introduction of new clinical strategies to fight metastatic leishmaniases, but also improve our understanding of the cross-talk between the immune response and the host metabolism in the context of this host-pathogen interaction and in other co-infections.