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

• Grant number: 19/08445-8
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: January 01, 2020
• End date: June 30, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Diego Luís Costa
• Grantee: Diego Luís Costa
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Vânia Luiza Deperon Bonato
• Associated scholarship(s): 25/11525-4 - Training in laboratory techniques, animal facility management, breeding and genotyping of transgenic mouse strains with conditional genetic deficiency, BP.TT; 24/08040-6 - Training in laboratory techniques, animal husbandry, breeding and genotyping of transgenic mouse lines with conditional genetic deficiency, BP.TT; 24/03695-4 - Protective mechanisms played by ferroportin against cellular necrosis during Mycobacterium tuberculosis infection, BP.TT; + associated scholarships 23/00767-1 - Training in laboratory techniques, animal facility procedures, breeding and genotyping of transgenic mice with conditional genetic deficiency, BP.TT; 22/11059-5 - Assessment of the role of DMT-1 and ferroportin transporters in iron homeostasis regulation and activation of T lymphocytes during Mycobacterium tuberculosis infection., BP.PD; 21/13946-6 - Characterization of the role of HIF2a in myeloid leukocytes during infection with Mycobacterium tuberculosis, BP.DR; 22/05259-1 - Training in laboratory techniques, animal facility procedures, breeding and genotyping of transgenic mice with conditional genetic deficiency, BP.TT; 21/04028-3 - Study on the immunomodulation of ferroportin expression and iron homeostasis in myeloid leukocytes and the related consequences to the pathogenesis of Mycobacterium tuberculosis infection, BP.MS; 20/10321-2 - Training in laboratory techniques, animal facility procedures, breeding and genotyping of transgenic mice with conditional genetic deficiency, BP.TT; 20/10356-0 - Characterization of the role of Axl and MerTK receptors during the experimental infection with Mycobacterium tuberculosis, BP.MS; 19/25770-0 - 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, BP.JP - associated scholarships

Abstract

Tuberculosis (TB) is the leading cause of death due to an infectious disease in the world. There is no effective vaccine to prevent infection and its conventional antibiotic therapy is too long and causes diverse side effects. Therefore, more effective treatments that rapidly eliminate the pathogen are needed. Approaches directed to host biological processes are promising strategies to achieve this goal. Blocking the host enzyme heme oxygenase-1 activity during TB results in reduction of bacterial loads and accelerates pathogen clearance by antibiotic therapy. Our results suggest that this effect occurs because of enhancement in infected macrophages' microbicidal activity due to the reduction of intracellular iron levels. Iron cellular homeostasis is modulated by mediators and transporters whose expression are regulated in response to inflammatory stimuli. On the other hand, alterations in intracellular iron levels can interfere with the expression of transcription factors that play a role in the modulation of inflammatory responses. The first goal of this proposal is to characterize the mechanisms through which immune responses developed against M. tuberculosis interfere in the regulation of intracellular iron levels in infected phagocytes, and how theses alterations modulate the activation of these cells. In parallel, we identified that during TB there is an increase in the expression of the receptors Axl and MerTK in myeloid cells and of their ligand Gas6 in the lungs. These receptors induce suppression of the inflammatory response, however, their function during TB is unknown. Therefore, the second goal of this proposal is to characterize the role of these receptors in the modulation of the inflammatory response and T lymphocyte activation during M. tuberculosis infection. Ultimately, after identifying mediators from the mentioned pathways that play important roles in the modulation of the infection pathogenesis, our aim is to utilize them as targets for immunopharmacological intervention and development of host-directed therapies for TB treatment. (AU)

Scientific publications

(The scientific publications listed on this page originate from the Web of Science or SciELO databases. Their authors have cited FAPESP grant or fellowship project numbers awarded to Principal Investigators or Fellowship Recipients, whether or not they are among the authors. This information is collected automatically and retrieved directly from those bibliometric databases.)

MATTEUCCI, KELY C.; CORREA, ANDRE A. S.; COSTA, DIEGO L.. Recent Advances in Host-Directed Therapies for Tuberculosis and Malaria. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 12, p. 23-pg., 2022-05-20. (20/01043-9, 19/08445-8, 19/25770-0, 20/10356-0)

TENORIO DE MENEZES, YONNE KAROLINE; ETO, CAROLINA; DE OLIVEIRA, JOSEANA; LARSON, ERICA C.; MENDES, DANIEL A. G. B.; MALAQUIAS DIAS, GREICY BRISA; DELGOBO, MURILO; GUBERNAT, ABIGAIL K.; GLEIM, JANELLE L.; MUNARI, EDUARDA LAIS; et al. The Endogenous Retinoic Acid Receptor Pathway Is Exploited by Mycobacterium tuberculosis during Infection, Both In Vitro and In Vivo. JOURNAL OF IMMUNOLOGY, v. 211, n. 4, p. 11-pg., 2023-08-15. (21/13946-6, 19/08445-8, 19/25770-0)

COSTA, DIEGO L.; AMARAL, EDUARDO P.; ANDRADE, BRUNO B.; SHER, ALAN. Modulation of Inflammation and Immune Responses by Heme Oxygenase-1: Implications for Infection with Intracellular Pathogens. ANTIOXIDANTS, v. 9, n. 12, DEC 2020. (19/08445-8)