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Mechanisms and consequences of the activation of cytoplasmic receptors by intracellular pathogens

Grant number: 19/11342-6
Support type:Research Projects - Thematic Grants
Duration: March 01, 2020 - February 28, 2025
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Dario Simões Zamboni
Grantee:Dario Simões Zamboni
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Assoc. researchers:Alexandre Luiz Neves Silva ; Catarina Veltrini Horta ; Giuseppe Palmisano ; Kelly Grace Magalhaes ; Leticia de Almeida ; Luiza Antunes de Castro Jorge ; Roque Pacheco de Almeida ; Valeria de Matos Borges ; Warrison Athanásio Coelho de Andrade
Associated grant(s):20/04964-8 - Inflammasome activation by SARS-CoV-2 and the role of this platform in the pathogenesis of COVID-19: a prospective study aiming NLRP3 inhibition for COVID-19 treatment, AP.R

Abstract

Differential recognition of pathogenic versus non-pathogenic microbes is essential to ensure rapid and effective immune responses that limit the replication of pathogenic microbes in cells and tissues. This differential recognition occurs through receptors located in the cytoplasm of innate immune cells. Among these receptors is a family of cytoplasmic proteins that contain NBD and LRR domains, called NLRs. Several NLRs are able to recognize components of infecting microbes and induce activation of inflammatory caspases such as Caspases-1 and Caspase-11, leading to the formation of a multiprotein complex called inflammasomes. Once activated, inflammasomes induce inflammatory process that can lead to the restriction of pathogen replication and resistance to infection. However, uncontrolled activation of intracellular receptors and inflammasomes can promote the development of diseases such as rheumatoid arthritis, lupus, ulcerative colitis, and Crohn's disease, which affect millions of people worldwide. Thus, understanding the mechanisms related to the regulation of intracellular receptor activation is critical for our understanding the genesis of inflammatory diseases and the response against pathogenic microbes. In this project, we aim to determine the mechanisms related to the activation of intracellular receptors in response to intracellular pathogens (bacteria and protozoa) and to understand the effector mechanisms that lead to the control of pathogen replication during an infectious process. Finally, we aim to perform genetic screening using CRISPR-Cas9 to identify and validate new components involved in signaling pathways activated by intracellular receptors during infection by pathogenic microbes. The results generated may contribute directly to our knowledge about the biology of host/pathogen and generate important information for possible interference in these receptors aiming to increase or to limit the inflammatory process in patients. (AU)

Articles published in other media outlets (7 total):
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Pesquisadores investigam mecanismos que desencadeiam fase inflamatória da Covid-19 
Pesquisadores investigam mecanismos que desencadeiam fase inflamatória da Covid-19 
Pesquisadores investigam mecanismos que desencadeiam fase inflamatória da Covid-19 
Pesquisadores investigam mecanismos que desencadeiam fase inflamatória da Covid-19 
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Pesquisadores investigam mecanismos que desencadeiam fase inflamatória da Covid-19 
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