Characterization of the role of Axl and MerTK receptors during the experimental infection with Mycobacterium tuberculosis

• Grant number: 20/10356-0
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): September 01, 2020
• Effective date (End): November 30, 2022
• 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
• 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

Tuberculosis (TB) is caused by infection with the bacterium M. tuberculosis. There is no effective vaccine for preventing disease, whereas conventional treatment with antibiotics is very long and can cause serious side effects. Therefore, new therapeutic strategies that eliminate bacteria more rapidly and efficiently are needed. In this regard, regimens that do not rely exclusively on the use of antibiotics have a special advantage because they do not promote the selection of drug-resistant microorganisms. Thus, therapy strategies that target biological processes of the host that favor the replication of bacteria, have gained attention by meeting such requirements. Treatments focused on enhancing or suppressing immune and inflammatory responses are common in several autoimmune diseases and cancer. In the case of chronic infectious diseases, such as TB, there is a need for a fine balance between the development of an immune response that is effective in eliminating microorganisms, but that does not result in exacerbated inflammation that cause damage to the tissues. Therefore, strategies that result in modulation of immune and inflammatory responses can help eliminate infection by M. tuberculosis more rapidly and effectively. The receptors Axl and MerTK play an important role in the recognition of phosphatidylserine associated with the Gas6 ligand on the surface of apoptotic cells. Intracellular signaling triggered by activation of Axl and MerTK, which occurs after their binding to Gas6-phosphatidylserine, results in decreased production of pro-inflammatory cytokines and suppresses the activation of antigen presenting cells, thereby reducing the magnitude of adaptive immune response activation. We observed that infection with M. tuberculosis induces an increase in the expression of Axl and MerTK in myeloid leukocytes present in the infectious site, as well as in the expression of Gas6 ligand in the lung tissue. The role played by Axl and MerTK receptors and their ligand Gas6 in the immunomodulation that occurs during M. tuberculosis infection is completely unknown. By using genetically deficient mice for Axl, MerTK and Gas6, or innate immunity receptors and innate and adaptive immunity cytokines, our objective is to characterize the role played by signaling via these receptors in modulating the immune response during Experimental TB, as well as the immunological mechanisms that regulate Axl, MerTK and Gas6 expression in cells infected with M. tuberculosis. The comprehension of such mechanisms can identify targets for the development of host-directed therapies for the treatment of TB. (AU)