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

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)