Study of the mechanisms of tolerance induction during infections

• Grant number: 22/15571-2
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2023
• End date: March 31, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Larissa Dias da Cunha
• Grantee: Isabella Zaidan Moreira
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 18/25559-4 - Molecular mechanisms of LC3-associated phagocytosis and its role in macrophage function, AP.JP

Abstract

Surviving an infection relies both in the capacity to detect and eliminate pathogens (resistance) and in the host adaptation to withstand the damaged caused by the virulence of the invading organism and by the host immune cells (tolerance or resilience). Tolerance induction is a multifaceted process that is still loosely defined, but that promotes maintenance of tissue barrier, downregulates proinflammatory signaling and induces anti- inflammatory cytokine secretion, initiates tissue repair and remodeling, regulates metabolic homeostasis and stimulates microbiome (re)composition. Individual genes that contribute to tolerance have already been identified in several infection models, but how these different plays converge into efficient tolerogenic responses is not well understood. Models of coinfection highlight how loss of tolerance causes susceptibility to infection is not a simple question. The interplay of the different scenarios that can lead to high morbidity and lethality suggest that different components of a general tolerance program may not have overlapping functions: tissue repair mechanisms independently of inflammatory responses may prevail locally in certain infections, whereas in other situation tolerance might be more significant systemically due to suppression of hyperinflammation. Understanding when these different mechanisms of tolerance are at play and how they are regulated in different pathologies is fundamental to direct effective therapeutic intervention approaches during life threatening occurrences. Our fundamental question that conducts this proposal is: what drives tolerance to pathogen burden during infection? While part of normal tissue homeostasis, cell death is also a hallmark of infectious diseases, either induced as a pathogen virulence strategy or as a mechanism of host defense. Our main hypothesis is that the innate immune system relies on efferocytosis as a main signal to promote tolerance during infection.