Evaluation of the role of IF1 on CD4+ T cell metabolism, differentiation, effector function and memory

• Grant number: 24/22337-1
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2025
• End date: March 31, 2028
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Maria Regina D'Império Lima
• Grantee: Danilo Chaves da Silva Ramos de Souza
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Malaria is an infectious disease that affects more than 250 million people annually and is one of the world's leading public health problems. During infections with Plasmodium parasites, the immune response triggered by CD4+ T cells is essential for controlling the parasite and for the development of cerebral and pulmonary pathologies associated with the infection. In secondary lymphoid organs, CD4+ T cells are activated, proliferate and differentiate into different effector profiles, including TH1 cells. TH1 cells produce large amounts of the pro-inflammatory cytokine IFN-¿, which plays both a protective role (by activating splenic macrophages and enhancing their phagocytic activity) and a pathogenic role (by promoting a response that causes tissue damage in the brain and lungs). Furthermore, CD4+ T cells can also be committed to differentiation into TFH cells that help B cells produce long-lived, high-affinity antibodies and into memory cells that promote rapid, large-scale responses in subsequent contacts with the parasite. IF1 (ATPase Inhibitory Factor 1) is a small protein that acts as an endogenous inhibitor of mitochondrial ATP synthase, promoting a decrease in oxidative phosphorylation and an increase in glycolysis, two metabolic pathways present in CD4+ T cells at various times during their response. Thus, IF1 is an important metabolic regulator whose role in CD4+ T cells is still poorly understood. We hypothesize that IF1 expression is altered during Plasmodium infection and that this influences the activation, metabolism, differentiation and effector function of CD4+ T cells, contributing to both the protective response and the development of cerebral and pulmonary malaria. We also hypothesize that IF1 is regulated by purinergic signaling components such as P2X7 and CD39. The overall objective is to investigate the role of IF1 in the CD4+ T cell response, as well as the regulation exerted by P2X7 and CD39, in models that allow evaluating the protective response against Plasmodium and the development of cerebral and pulmonary malaria. TCR-specific CD4+ T cells deficient for the gene encoding IF1 will be evaluated for their activation, metabolism, differentiation, effector function, capacity to generate immunological memory and their contribution to the development of cerebral and pulmonary pathologies in models of experimental malaria. (AU)