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Study on the immunomodulation of ferroportin expression and iron homeostasis in myeloid leukocytes and the related consequences to the pathogenesis of Mycobacterium tuberculosis infection

Grant number: 21/04028-3
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): June 01, 2021
Effective date (End): May 31, 2023
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Diego Luís Costa
Grantee:Marina Bonifácio Denadai
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


The absence of an effective vaccine and of a treatment able to quickly eliminate the pathogen from the host organism, contribute to making tuberculosis (TB) one of the infectious diseases that kill most people in the world. New treatment strategies being proposed in the literature suggest using host biological processes known to favor the replication of bacteria as targets for novel therapeutic approaches in order to achieve a more rapid and effective cure of the disease. Specifically, the metabolism of iron in infected cells has been shown to be a promising target for the development of host-directed therapies. Our previous results demonstrate that M. tuberculosis infection induces iron accumulation in the host cell, which impairs the effectiveness of its microbicidal mechanisms after activation with IFN-³. In particular, we observed that this accumulation coincides with an increase in the expression of heme oxygenase-1 (HO-1) and a decrease in ferroportin in these same cells. While the metabolism of heme by HO-1 results in the release of iron in the cytoplasm, ferroportin acts as a transporter of iron ions into the extracellular space. Thus, the decrease in this protein expression in the membrane of infected cells may have a direct contribution in increasing their intracellular iron concentration. Ferroportin expression is transcriptionally and post-translationally regulated in response to the activation of innate immunity receptors and by the hormone hepcidin, which is produced in response to stimulus with inflammatory cytokines. The immune mechanisms involved in the regulation of ferroportin expression during M. tuberculosis infection are poorly characterized. Likewise, the consequences of ferroportin expression modulation in the pathogenesis of TB in vivo are unknown. By using an experimental model of infection with M. tuberculosis in mice genetically deficient for the expression of ferroportin in specific myeloid leukocytes or innate immunity receptors and cytokines of innate and adaptive immunity, our objective is to characterize the immunological mechanisms that modulate the expression of ferroportin and iron homeostasis in infected cells, as well as the consequence of such modulation in the pathogenesis of M. tuberculosis infection. The comprehension of such mechanisms can identify targets for the development of host-directed therapies for the treatment of TB. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE OLIVEIRA, JOSEANA; DENADAI, MARINA B.; COSTA, DIEGO L.. Crosstalk between Heme Oxygenase-1 and Iron Metabolism in Macrophages: Implications for the Modulation of Inflammation and Immunity. ANTIOXIDANTS, v. 11, n. 5, p. 19-pg., . (20/10321-2, 21/04028-3, 19/25770-0)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
DENADAI, Marina Bonifácio. Characterization of an animal model to study the role of ferroportin in myeloid leukocytes during Mycobacterium tuberculosis infection. 2023. Master's Dissertation - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.

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