Prof. Dr. Diego Luis Costa

Title: Professor Doctor
Laboratory: Immunobiology of Infectious Diseases, Room 128 (ICB-IV)
Phone: +55 (11) 3091-7382 / 2648-8260
Email: dlcosta@usp.br
Lattes CV: http://lattes.cnpq.br/3232670958870185
ResearchID: https://www.webofscience.com/wos/author/record/F-7168-2019
ORCID: https://orcid.org/0000-0002-9440-2814

Research Line:

Study of immune response regulation during tuberculosis to identify targets for host-directed therapy strategies

1 – Modulation of iron homeostasis in immune system cells and its association with host resistance to tuberculosis:

Iron can oscillate between two oxidation states: ferrous (Fe²⁺) and ferric (Fe³⁺), allowing it to act as an electron donor or acceptor in various metabolic processes. Therefore, it is an essential element for all living organisms. The regulation of intracellular iron levels in immune cells is important for maintaining cellular oxidative balance and for the activity of iron-dependent enzymes, which can mediate epigenetic changes, regulate gene transcription factors, and influence RNA translation into proteins. Thus, many effector functions of immune cells can be modulated by changes in intracellular iron levels. Similarly, the expression of iron transport or storage proteins can be regulated in response to immune cell activation by pro- or anti-inflammatory cytokines. The transporters ferroportin (exports iron extracellularly) and DMT1 (imports iron intracellularly) are expressed in immune cells, and their expression can be regulated by cytokine activation. Our group studies the role of ferroportin and DMT1 in regulating macrophage and T lymphocyte activation during the immune response to Mycobacterium tuberculosis infection and the consequences for tuberculosis pathogenesis.

2 – Involvement of hypoxia-induced transcription factors HIF1α and HIF2α in regulating the immune response to Mycobacterium tuberculosis infection:

Hypoxia-Induced Factors (HIFs), whose expression is post-translationally regulated by intracellular oxygen and iron levels, primarily control cellular energy metabolism but are also closely linked to inflammatory responses. HIF1α, in particular, has been described as a key regulator of macrophage and adaptive immune cell activation, associated with the development of pro-inflammatory responses. HIF1α signaling is essential for mounting immune responses against various infectious diseases, including tuberculosis. HIF2α, on the other hand, has been associated with anti-inflammatory processes in several studies, although its role in immune cells is less well characterized than HIF1α. Specifically in tuberculosis, the immunoregulatory functions of HIF2α remain unknown. Our group investigates the role of HIF2α-mediated intracellular signaling in macrophage activation during M. tuberculosis infection and explores the potential dichotomy between HIF1α and HIF2α pathways in regulating the immune response during tuberculosis.

3 – Role of efferocytosis receptors Axl and MerTK in modulating the immune response to Mycobacterium tuberculosis infection and tuberculosis pathogenesis:

Efferocytosis refers to the process of clearing apoptotic cells. TAM (Tyro3, Axl, and MerTK) tyrosine kinase receptors mediate the recognition of phosphatidylserine exposed on the outer membrane of apoptotic cells by macrophages, triggering their phagocytosis. In addition to promoting efferocytosis, TAM receptor activation induces intracellular signaling with anti-inflammatory effects or tissue repair responses. M. tuberculosis-infected cells that fail to control bacterial replication may undergo necrosis or apoptosis. The mode of cell death significantly influences immune modulation and disease pathogenesis: necrosis leads to tissue damage, inflammation, and bacterial spread, while apoptosis helps control bacterial replication. Axl and MerTK are the most abundantly expressed TAM receptors in macrophages, the primary cells infected by M. tuberculosis. The role of Axl and MerTK signaling in modulating the immune response to M. tuberculosis infection and tuberculosis pathogenesis remains unknown. Our group investigates the molecular mechanisms involved in host response modulation to M. tuberculosis infection, including in models of viral coinfection during tuberculosis.

4 – Inhibition of heme oxygenase-1 (HO-1) activity as a host-directed therapy strategy for treating tuberculosis and mycobacterial diseases:

Our group has previously demonstrated that inhibiting the activity of the enzyme heme oxygenase-1 (HO-1) is a promising host-directed therapy strategy for tuberculosis treatment (DOI: 10.1128/mBio.01675-16, 10.1038/s41385-020-00342-x, 10.1128/aac.01043-23), as it enhances the host’s protective response during antibiotic therapy. We are currently engaged in collaborative studies to investigate whether this strategy may also accelerate the cure of other diseases caused by mycobacterial infections.

Publications

ORCID: https://orcid.org/0000-0002-9440-2814