Characterization of the role of HIF2a in myeloid leukocytes during infection with Mycobacterium tuberculosis

• Grant number: 21/13946-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date until: August 01, 2022
• End date until: December 31, 2025
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Diego Luís Costa
• Grantee: Joseana de Oliveira
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/08445-8 - Immunomodulation of iron homeostasis and regulation of tyrosine kinase TAM receptor signaling pathway during Mycobacterium tuberculosis infection: targets for the development of host-directed immunopharmacological therapies, AP.JP

Abstract

The human Tuberculosis (TB), caused by Mycobacterium tuberculosis bacillus, is one of the infection diseases that kill the most in the world. There is no effective vaccine to TB, moreover their treatment is long and cause many adverse effects. To combat the disease in an efficiency way, there are necessary news therapies that eliminate the infection readily. Approaches targeted to host biologic process involved on disease pathogenesis has been proposed as new treatment. Our group identify that the intracellular iron accumulates impair the microbial activity of the M. tuberculosis cells infected and favor the bacterial replication. Iron participates of various cells metabolic reactions and is involved on modulation of expression of hypoxic-induced transcription factors ("Hypoxia Induced Factors" - HIF). The HIF1a factor, abundantly expressed in pro-inflammatory macrophages M1, are involved on development of immune response protection against M. tuberculosis. However, the HIF2a factor, expressed in anti- inflammatory macrophages M2, has the unknown role on M. tuberculosis infection. The levels alteration of intracellular iron exerts opposite effects on HIF1a and HIF2a expression, being those high levels of iron result in HIF2a increasing and HIF1a decreasing. Our hypothesis is that intracellular iron accumulates observed on M. tuberculosis infection favor HIF2a expression in detriment of HIF1a, promoting bacterial replication in infection cells. Therefore, the intent of the project is characterized the role of HIF2a during M. tuberculosis infection and the molecular mechanisms involved on modulation of their expression.