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

• Grant number: 19/11342-6
• Support Opportunities: Research Projects - Thematic Grants
• Duration: March 01, 2020 - February 28, 2025
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Dario Simões Zamboni
• Grantee: Dario Simões Zamboni
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated 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 at NLRP3 inhibition for COVID-19 treatment, AP.R
• Associated scholarship(s): 21/14752-0 - Mechanisms and consequences of the activation of cytoplasmic receptors by intracellular pathogens, BP.TT; 22/00274-2 - Mechanisms and consequences of the activation of cytoplasmic receptors by intracellular pathogens, BP.TT; 21/07384-5 - Evaluation of the role of Ninj1 in the modulation of cell death in Leishmania-infected macrophages and its participation in inducing the immune response in vivo, BP.PD; + associated scholarships 21/11579-6 - Mechanisms and consequences of activation of cytoplasmic receptors by intracellular pathogens, BP.TT; 21/02431-5 - Mechanisms and consequences of the activation of cytoplasmic receptors for intracellular pathogens (Lucas TT1), BP.TT; 20/06177-3 - Optimization of a CRISPR/Cas9 genetic deletion system in macrophages to evaluate proteins important for the activation of NLRC4 inflammasome in macrophages, BP.MS - associated scholarships

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)

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

OLIVIER, MARTIN; ZAMBONI, DARIO S.. Leishmania Viannia guyanensis, LRV1 virus and extracellular vesicles: a dangerous trio influencing the faith of immune response during muco-cutaneous leishmaniasis. CURRENT OPINION IN IMMUNOLOGY, v. 66, n. SI, p. 108-113, OCT 2020. (13/08216-2, 18/14398-0, 19/11342-6)

LOTERIO, ROBSON KRIIGER; ZAMBONI, DARIO S.; NEWTON, HAYLEY J.. eeping the host alive - lessons from obligate intracellular bacterial pathogen. PATHOGENS AND DISEASE, v. 79, n. 9, DEC 2021. (16/24275-7, 14/04684-4, 19/11342-6)

RODRIGUES, TAMARA S.; DE SA, KEYLA S. G.; ISHIMOTO, ADRIENE Y.; BECERRA, AMANDA; OLIVEIRA, SAMUEL; ALMEIDA, LETICIA; GONCALVES, V, AUGUSTO; PERUCELLO, DEBORA B.; ANDRADE, WARRISON A.; CASTRO, RICARDO; et al. Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients. JOURNAL OF EXPERIMENTAL MEDICINE, v. 218, n. 3, MAR 1 2021. (20/04964-8, 13/08216-2, 19/11342-6)

DE CARVALHO, RENAN V. H.; LIMA-JUNIOR, DJALMA S.; DE OLIVEIRA, V, CAROLINE; ZAMBONI, DARIO S.. Endosymbiotic RNA virus inhibits Leishmania-induced caspase-11 activation. ISCIENCE, v. 24, n. 1, JAN 22 2021. (19/11342-6, 13/08216-2, 18/14398-0)

ANDRADE, WARRISON A.; ZAMBONI, DARIO S.. NLRC4 biology in immunity and inflammation. Journal of Leukocyte Biology, JUN 2020. (13/08216-2, 18/14398-0, 19/11342-6, 14/04684-4)