Chronic production of IFN-I on Sickle Cell Anemia: cellular source, mechanisms of induction and pathological outcomes

• Grant number: 24/00836-6
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: March 01, 2024
• End date: September 30, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Renata Sesti Costa
• Grantee: Izabela Felice Paes
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 19/09704-7 - Dendritic cells in Sickle Cell Anemia: molecular mechanisms involved in regulating inflammation and adaptive immune response, AP.JP
• Associated scholarship(s): 24/14626-3 - Mechanisms of plasmacytoid dendritic cells exhaustion and the impact on viral infection in sickle cell anemia mice., BE.EP.DD

Abstract

Sickle cell anemia (SCA) is one of the most common hemoglobinopathies in the world. Patients with SCA present reduced quality of life due to complications resulting from the change in the shape and physical properties of erythrocytes. These complications consist of chronic hemolytic anemia, pain crisis, organ dysfunction, susceptibility to infections, among others. SCA can be considered a chronic inflammatory disease, with the systemic release of proinflammatory cytokines such as TNF-a, IL-6 and IL-8. It is also known that genes induced by IFN-I are among the genes most expressed in PBMCs of patients with SCA, but there is no report on the role of IFN-I or plasmacytoid DCs, the main producers of these cytokines, in the pathology of the disease. In the present work, we aim to unravel the cellular source of IFN-I and the mechanisms that induce its production. Furthermore, we will breed sickle cell mice with those deficient in IFN-I receptor to investigate the consequences of chronic IFN-I production on the pathology of sickle cell disease, the predisposition to autoimmune disease, as well as the response to viral infection. We hope that the data will reveal more information about the establishment of the chronic inflammatory state and immune dysfunction presented by the patients with SCA and that they expose new therapeutic targets for specific regulation of the pathology. (AU)