Integrative analysis of immunoregulatory mechanisms in patients with Long COVID-19

• Grant number: 22/06371-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: November 01, 2022
• End date: October 31, 2023
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Otávio Cabral Marques
• Grantee: Gabriela Crispim Baiocchi
• Supervisor: Akiko Iwasaki
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Yale School of Medicine (YSM), United States
• Associated to the scholarship: 20/07972-1 - Systemic and integrative analysis of T lymphocyte exhaustion mechanisms in patients with COVID-19, BP.DD

Abstract

The immune system plays an important role in the homeostatic control of the body. For this fundamental function, the system is activated in response to external or internal injuries. Therefore, the activation mechanisms of the immune system are important and desirable but must be finely controlled to avoid immunopathology. Several evolutionary conserved immunoregulatory mechanisms such as immune exhaustion and the production of autoantibodies have been detected in healthy individuals at physiological levels, playing a myriad of homeostatic roles. The activation of immunoregulatory mechanisms depends on where and how the immune system is activated. On the other hand, several inhibitory pathways can be activated, preventing excessive immune activation and tissue damage (immunopathology). Among these inhibitory mechanisms, immune exhaustion leads to the loss of cell effector function, sustained expression of inhibitory receptors (e.g.: PD-1, TIM-3, CTLA-4, TIGIT), changes in the transcriptional and epigenetic profiles, and metabolic reprogramming. In this context, it is poorly understood why the coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have been associated with immune dysregulation and abnormal levels of autoantibodies targeting immunological proteins such as cytokines and chemokines. Several studies have highlighted functional impairment, reduced numbers, and increased expression of exhaustion markers by T cells from patients with COVID-19, indicating an attempt of the immune system to control the hyperactivation induced by the SARS-CoV-2 infection. Even so, the landscape of autoantibodies, their association with immune exhaustion, and the role of those immunoregulatory mechanisms in the immunopathology of COVID-19 remains uncharted territory. We hypothesized that there is an intersection between the immune regulatory mechanisms such as immune exhaustion and autoantibody production that could be driving altered and hyperinflammatory immune states and different COVID-19 outcomes. The overarching goal of this proposal is to characterize immunoregulation mechanisms in the context of SARS-CoV-2 infection, particularly the contribution of autoantibodies and immune exhaustion to post-acute sequelae of SARS-CoV-2 infection. To reach this goal, we will perform an integrative analysis of immunoregulatory mechanisms of patients with Long COVID-19 to understanding how the intersection between autoimmunity and immune exhaustion could be driving altered and hyperinflammatory immune states and different COVID-19 outcomes. We expect that our findings will provide new insights about the immunopathology of acute and post-acute (Long) COVID-19, opening avenues to develop new treatment strategies. (AU)