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

• Grant number: 19/11342-6
• Support Opportunities: Research Projects - Thematic Grants
• Start date: March 01, 2020
• End date: September 30, 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
• City of the host institution: Ribeirão Preto
• 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 research grant(s): 24/19002-8 - Multi-user equipment approved in grant 2019/11342-6: iD3 plate reader for fluorescence and luminescence, AP.EMU; 23/01560-1 - Analysis of role signaling pathways and effector molecules related to inflammasomes in the control of infection by Leishmania amazonensis, AP.R; 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): 25/18949-4 - Intracellular dynamics of Gasdermin-D during inflammasome activation., BP.IC; 25/06480-1 - Evaluation of the Role of Legionella longbeachae Capsule in Immunological Modulation and Pathophysiology of Lethal Infection in Murine Models, BP.DD; 25/02106-8 - Screening of compounds as NLRP3 inflammasome inhibitors, BP.TT; + associated scholarships 25/04555-4 - Evaluation of the role of Gasdermin-D in Visceral Leishmaniasis., BP.TT; 24/15217-0 - Mechanisms and consequences of the activation of cytoplasmic receptors by intracellular pathogens., BP.TT; 24/16161-8 - Mechanisms and consequences of the activation of cytoplasmic receptors by intracellular pathogens., BP.TT; 24/22157-3 - Investigation of the role of glucose concentration and hypoxia condition on inflammasome activation on macrophages, BP.IC; 24/13944-1 - Evaluation of the role of neutrophil extracellular traps in the pathogenesis and control of pulmonary replication of Legionella spp., BP.DR; 24/12851-0 - Evaluation of the Role of Ninj1 in Neutrophil Cell Death and the Development of Inflammatory Diseases, BP.PD; 24/07282-6 - Importance of the Aim2 Inflammasome in the Response to Betacoronavirus Infection, BP.DR; 24/15218-6 - Mechanisms and consequences of cytoplasmic receptor activation by intracellular pathogens., BP.TT; 24/05233-8 - Evaluating the role of interleukin-11 in the pathogenesis of cutaneous leishmaniasis and its implications in bacterial co-infections., BP.PD; 24/06657-6 - The role of NLRC4 in the activation of Caspase-11 in response to Leishmania spp. infection, BP.TT; 24/07303-3 - Mechanisms and consequences of the activation of cytoplasmic receptors by intracellular pathogens., BP.TT; 23/12861-2 - The participation of the inflammasome in the response against SARS-CoV-2 and Influenza infections in an experimental murine model, BP.DR; 23/16442-4 - Mechanisms and consequences of the activation of cytoplasmic receptors by intracellular pathogens, BP.IC; 23/09371-3 - Identification of Caspase-7 substrates operating in the inflammasome pathway for the control of Legionella pneumophila infection, BP.DR; 23/15539-4 - Mechanisms and consequences of the activation of cytoplasmic receptors for intracellular pathogens (Leticia TT1), BP.TT; 23/06903-4 - Mechanisms and consequences of activation of cytoplasmic receptors by intracellular pathogens., BP.TT; 23/07075-8 - Mechanisms and consequences of activation of cytoplasmic receptors by intracellular pathogens (TT5), BP.TT; 22/14157-8 - Evaluation of the role of the transcription factor HIF1alpha in the inflammasome activation and progression of Leishmania infection, BP.PD; 23/05508-4 - Mechanisms and consequences of activation of cytoplasmic receptors by intracellular pathogens, BP.TT; 22/16844-2 - Evaluation of the capsule role in the pathogenesis of Legionella longbeachae infections in mice, BP.IC; 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; 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

(17)

(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)

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)

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)

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.; ZAMBONI, DARIO S.. Inflammasome activation by SARS-CoV-2 and its participation in COVID-19 exacerbation. CURRENT OPINION IN IMMUNOLOGY, v. 84, p. 6-pg., 2023-10-01. (13/08216-2, 20/04964-8, 19/11342-6)

DE SA, KEYLA S. G.; AMARAL, LUANA A.; RODRIGUES, TAMARA S.; ISHIMOTO, ADRIENE Y.; DE ANDRADE, WARRISON A. C.; DE ALMEIDA, LETICIA; FREITAS-CASTRO, FELIPE; BATAH, SABRINA S.; OLIVEIRA, SERGIO C.; PASTORELLO, MONICA T.; et al. Gasdermin-D activation promotes NLRP3 activation and host resistance to Leishmania infection. NATURE COMMUNICATIONS, v. 14, n. 1, p. 19-pg., 2023-02-24. (13/08216-2, 18/14398-0, 19/11342-6)

DE SA, KEYLA S. G.; AMARAL, LUANA A.; RODRIGUES, TAMARA S.; CAETANO, CAMILA C. S.; BECERRA, AMANDA; BATAH, SABRINA S.; LOPES, FELIPE T.; DE OLIVEIRA, ISADORA M.; LOPES, LETICIA S.; ALMEIDA, LETICIA; et al. Pulmonary inflammation and viral replication define distinct clinical outcomes in fatal cases of COVID-19. PLOS PATHOGENS, v. 20, n. 6, p. 24-pg., 2024-06-01. (19/11342-6, 13/08216-2, 20/04964-8)

RODRIGUES, TAMARA S.; CAETANO, CAMILA C. S.; DE SA, KEYLA S. G.; ALMEIDA, LETICIA; BECERRA, AMANDA; GONCALVES, AUGUSTO, V; LOPES, LETICIA DE SOUSA; OLIVEIRA, SAMUEL; MASCARENHAS, DANIELLE P. A.; BATAH, SABRINA S.; et al. CASP4/11 Contributes to NLRP3 Activation and COVID-19 Exacerbation. Journal of Infectious Diseases, v. 227, n. 12, p. 12-pg., 2023-02-10. (13/08216-2, 20/04964-8, 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)

DE ALMEIDA, LETICIA; DA SILVA, ALEXANDRE L. N.; RODRIGUES, TAMARA S.; OLIVEIRA, SAMUEL; ISHIMOTO, ADRIENE Y.; SERIBELLI, AMANDA A.; BECERRA, AMANDA; ANDRADE, WARRISON A.; ATAIDE, MARCO A.; CAETANO, CAMILA C. S.; et al. Identification of immunomodulatory drugs that inhibit multiple inflammasomes and impair SARS-CoV-2 infection. SCIENCE ADVANCES, v. 8, n. 37, p. 15-pg., 2022-09-16. (20/04964-8, 13/08216-2, 19/11342-6)

SCHMIDT, SILKE; MONDINO, SONIA; GOMEZ-VALERO, LAURA; ESCOLL, PEDRO; MASCARENHAS, DANIELLE P. A.; GONCALVES, AUGUSTO; CAMARA, PEDRO H. M.; RODRIGUEZ, FRANCISCO J. GARCIA; RUSNIOK, CHRISTOPHE; SACHSE, MARTIN; et al. The unique Legionella longbeachae capsule favors intracellular replication and immune evasion. PLOS PATHOGENS, v. 20, n. 9, p. 34-pg., 2024-09-01. (19/11342-6)

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)

ANDRADE, WARRISON A.; ZAMBONI, DARIO S.. NLRC4 biology in immunity and inflammation. Journal of Leukocyte Biology, v. 108, n. 4, p. 11-pg., 2020-06-12. (19/11342-6, 14/04684-4, 13/08216-2, 18/14398-0)

RODRIGUES, TAMARA S.; ZAMBONI, DARIO S.. Inflammasome Activation by RNA Respiratory Viruses: Mechanisms, Viral Manipulation, and Therapeutic Insights. IMMUNOLOGICAL REVIEWS, v. 330, n. 1, p. 21-pg., 2025-03-01. (22/14157-8, 19/11342-6, 13/08216-2)

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, p. 6-pg., 2020-10-01. (13/08216-2, 18/14398-0, 19/11342-6)

MASCARENHAS, DANIELLE P. A.; ZAMBONI, DARIO S.. Innate immune responses and monocyte-derived phagocyte recruitment in protective immunity to pathogenic bacteria: insights from Legionella pneumophila. Current Opinion in Microbiology, v. 80, p. 8-pg., 2024-06-21. (23/07075-8, 13/08216-2, 19/11342-6)

FERNANDES, JULIANE C. R.; ZAMBONI, DARIO S.. Mechanisms regulating host cell death during Leishmania infection. MBIO, v. 15, n. 11, p. 11-pg., 2024-10-11. (18/14398-0, 19/11342-6, 13/08216-2, 22/14157-8)

LOTERIO, ROBSON K.; THOMAS, DAVID R.; ANDRADE, WARRISON; LEE, YI WEI; SANTOS, LEONARDO L.; MASCARENHAS, DANIELLE P. A.; STEINER, THIAGO M.; CHIARATTO, JESSICA; FIELDEN, LAURA F.; LOPES, LETICIA; et al. Coxiella co-opts the Glutathione Peroxidase 4 to protect the host cell from oxidative stress-induced cell death. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 120, n. 36, p. 11-pg., 2023-09-05. (19/11342-6, 13/08216-2, 14/04684-4, 16/07870-9, 16/24275-7)