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Role of STING signaling pathway in recognizing and controling Leishmania spp infection

Grant number: 19/21978-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2020
Effective date (End): January 31, 2023
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal researcher:Dario Simões Zamboni
Grantee:Tamara Silva Rodrigues
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:14/04684-4 - The inflammasome in the host response against intracellular pathogens and the microbial mechanisms for its evasion, AP.TEM

Abstract

Leishmaniasis is a disease that represents a serious public health problem in developing countries. The disease is caused by the protozoan Leishmania spp. and although there are treatments available at the clinic, it still affects about 12 million people worldwide. About 350 million people are at risk of infection, and the absence of vaccines and the long treatment along with high-toxicity are still challenges to be overcome. In order to develop new therapeutic options, it is necessary to investigate the pathogenesis of the disease and the cellular mechanisms involved in controlling infection. The innate immune system is essential for early recognition of the pathogen. In addition to Toll-like receptors, NLRs, and CLRs, cytosolic sensors, such as cGAS, also play an important role in this initial pathogen recognition process. cGAS recognizes double stranded DNA in the cytoplasm and catalyzes the formation of cyclic GMP-AMP or cGAMP by joining one GTP molecule and another ATP molecule. cGAMP is released and binds to the STING (Stimulator of Interferon Genes) adaptor protein, which leads to type I interferon (IFN-I) transcription and autophagy. In addition, cGAS-STING signaling induces activation of NF-kB and inflammatory cytokines such as IL-6 and TNF. The function of cGAS-STING has been studied mainly in autoimmune diseases and cancer. In the context of Leishmania infection, there is only one study that observed that Leishmania donovani DNA mediates IFN-beta induction in a manner dependent on TBK1 and IRF3. Interestingly, this mechanism of L. donovani DNA recognition via cGAS occurs mainly with strains resistant to antimonial therapy, which induce higher production of INF-beta and IL-10. Recently, our group demonstrated that the presence of RNA virus in different Leishmania species inhibits NLRP3 inflammasome activation and IL-1beta production dependent on TLR3, IFN-beta and autophagy, increasing the likelihood of mucocutaneous development of the disease. The same work suggested that extracellular vesicles released by Leishmania would be the possible form of virus release, enabling its recognition by TLR3 in infected macrophages. Given these findings, we hypothesized in the present project that vesicles released by Leishmania could contain double strand DNA (dsDNA) from the parasite, which could directly modulate the cGAS-STING pathway, which could directly influence the control of parasite replication and severity of infection. Our preliminary data using Sting -/- and Ifnar -/- animals support this hypothesis and indicate that this signaling pathway is detrimental during both in vitro and in vivo infections. Additionally, this pathway negatively regulated inflammasome activation, suggesting that the recognition by cGAS/STING/IFN-beta axis plays a central role during Leishmaniasis. (AU)

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