Role of the interaction between signaling via IFNAR/STAT1 and Axl and MerTK receptors in modulating pulmonary pathogenesis during infection with Mycobecterium tuberculosis and viral co-infections

• Grant number: 23/18297-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2024
• End date: December 31, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Diego Luís Costa
• Grantee: André Aparecido dos Santos Correa
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is one of the most lethal diseases in the world, and BrazilIt is among the countries with the highest incidence. The adaptive immune response mediated by CD4+ Th1 T cells plays a rolecrucial in resistance to Mtb infection. The TAM receptors Axl and MerTK, whose expression is induced in response to infection byMtb, promote the phagocytosis of apoptotic cells and trigger anti-inflammatory and immunoregulatory signaling, which cansuppress the Th1 response. However, our previous results indicate that genetic deficiency of Axl and MerTK does not interferein resistance to infection by the Mtb H37Rv strain. However, recent results demonstrated that MerTK deficiencyincreases susceptibility to infection with the hypervirulent strain HN878. Type I interferon (IFN) production and signalingvia its receptor (IFNAR) is associated with susceptibility to TB, and it is known that one of the factors involved in the greater severity of TBdisease caused by strain HN878 is the greater induction of type I IFNs production in response to this strain compared toothers. The detrimental role of type I IFNs during Mtb infection was evidenced in viral co-infection models, whereit was observed that the robust production of type I IFNs induced by viruses impairs the Th1 innate and adaptive immune response,exacerbating the pathogenesis of TB. Interestingly, the anti-inflammatory and immunoregulatory effects of TAM receptorsdepend on their interaction with type I IFN signaling via IFNAR, and it is not known whether the participation of TAM receptorstogether with IFNAR signaling may have a role in immunoregulation that impairs resistance to Mtb infection when there isexcess production of type I IFNs. We imagine that the difference in type I IFN production in response to infection byH37Rv or HN878 strains are involved in the difference in susceptibility of animals deficient in TAM receptors to infectionfor the same ones. More specifically, our hypothesis is that different immunoregulatory effects occur through signaling viaAxl/IFNAR/STAT1 and/or MerTK/IFNAR/STAT1. Additionally, we believe that the participation of Axl and/orMerTK play an important role in modulating IFNAR signaling, which compromises the protective immune responseagainst Mtb in viral co-infection scenarios. Therefore, the objectives of this project include evaluating the role of Axl and MerTKduring infection by hypervirulent Mtb (HN878) and in a viral co-infection model, as well as understanding the interaction betweenTAM receptors and signaling via IFNAR during infection.