Toll-like Receptors; Inflammation; Leishmania; Metastasis; Macrophages; Leishmania RNA virus; LCMV
Dias-Teixeira Karina Luiza, Calegari-Silva Teresa C., Medina Jorge M., Vivarini Áislan C., Cavalcanti Átila, Teteo Nataly, Santana Alynne Karen M., Real Fernando, Gomes Ciro M., Pereira Renata Meirelles Santos, Fasel Nicolas, Silva João S., Aktas Bertal H., Lopes Ulisses G. (2017), Emerging Role for the PERK/eIF2α/ATF4 in Human Cutaneous Leishmaniasis, in Scientific Reports
, 7(1), 17074-17074.
Klompmaker Sandra H., Kohl Kid, Fasel Nicolas, Mayer Andreas (2017), Magnesium uptake by connecting fluid-phase endocytosis to an intracellular inorganic cation filter, in Nature Communications
, 8(1), 1879-1879.
Vivarini Áislan de Carvalho, Calegari-Silva Teresa Cristina, Saliba Alessandra Mattos, Boaventura Viviane Sampaio, França-Costa Jaqueline, Khouri Ricardo, Dierckx Tim, Dias-Teixeira Karina Luiza, Fasel Nicolas, Barral Aldina Maria Prado, Borges Valéria Matos, Van Weyenbergh Johan, Lopes Ulisses Gazos (2017), Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis, in Frontiers in Immunology
, 8, 1127.
The endosymbiosis of viruses in microbes is a well-described and prevalent environmental partnership, where viruses offer their microbial host incentives of fitness in exchange for the use of their metabolic machinery and of virulence, when the microbial host is a pathogen. In the last few years, our group has described this last notion as a fundamental factor in exacerbated and metastatic lesions of mucocutaneous leishmaniasis (MCL), a pathological form often difficult to treat and subject to relapses after a first-line drug treatment. We reported that the dsRNA of the Leishmania RNA virus (LRV), a viral endosymbiont residing inside the Leishmania human protozoan parasites, is recognized by the host cell Toll-like Receptor 3 (TLR-3) causing a destructive inflammatory response, exacerbating the disease and causing metastasis of the infection. In this context, we reported the detrimental role of LRV-dependent type-1 IFNs as promoting inflammatory cytokines and chemokines; the impact of LRV on the enhanced survival of infected macrophages via expression of miR-155 and phosphorylation of the Akt pro-survival kinase; on the relevance of IL-17 in the dissemination of the infection using a mouse metastatic model and on favoring relapses in patients after a first-line drug treatment. These pathological outcomes are driven by subverting the innate immune response to the advantage of the parasite and its viral passenger. Although we described essential mediators of this TLR-3-driven subversion of the host response, there is still no information on how primary and secondary lesions are formed, on the types of infected cells (the cargo cells) and the mechanism(s) implicated in the metastasis of the infection. In addition, other co-infecting viruses could play the same role as the endosymbiotic LRV. The aims of the experiments included in this research proposal are to determine: 1) which are the cell types and the mechanisms underlying the LRV-dependent dissemination of the infection to secondary sites and lesion formation; 2) the impact of other viruses on exacerbation, relapses and metastasis of Leishmania infection and the underlying mechanisms; 3) the molecular mechanisms relevant to relapses of the infection in patients previously exposed to a first-line drug treatment. To achieve these goals, we will use two mouse metastatic leishmaniasis models we developed in order to characterize the exacerbation of the primary lesion, to identify which cargo cells are implicated in the metastatic process and to determine the mechanisms of dissemination and secondary lesion formation firstly in LRV-dependent pathology and secondly in viral co-infection. Considering that LRV-dependent TLR-3 activation has an impact on relapses in drug-treated patients, we will investigate the signaling pathways important in this form of resistance and determine how LRV subverts the anti-oxidant response of the mammalian to the advantage of its parasite host.In conclusion, our research on LRV and co-infecting viruses will provide seminal information on the exacerbation and dissemination in MCL and on how parasites and other co-infecting viruses can subvert the innate immune response to escape anti-Leishmania drugs. These results will bring new concepts relevant not only to the Leishmania field but also to several other pathologies, including new emerging infectious diseases and the relevance of the innate immune response on resistance to drugs.