Mycobacterium tuberculosis is the etiology agent responsible for the infection and development of tuberculosis (TB). According to the World Health Organization (WHO), in 2020, an estimated 10 million people fell ill, of whom 1.3 million died from the disease. It is well established that host and pathogen factors affect TB outcome. Inflammation exacerbation is deleterious in TB. Obesity is associated with low-grade and systemic inflammation, which can aggravate infections in the respiratory tract. Our previous results show that obesity induced by a high-fat diet (HFD) exacerbated pulmonary inflammation and accentuated the susceptibility to M. tuberculosis infection. In experimental tuberculosis, we found that the lungs of IL-1a deficient obese animals had an increase in inflammation and bacteria replication, accompanied by a reduction of CD4+ IL-17+ cells. In summary, these findings indicate a protective role for IL-1a, associated with tissue damage tolerance, control of inflammation, and increase of resistance to infection. Our study hypothesis is that IL-1a contributes to the maintenance and/or expansion of CD4+ IL-17+ cells. In this project, we propose to investigate whether IL-1a mediates myeloid and CD4+ IL-17+ cell influx to the lungs of animals infected with M. tuberculosis. Moreover, we are interested to evaluate the implication of the IL-17/HIF-1a interface for pulmonary inflammation. For this proposal, wild-type (WT) and IL-1a-/- mice fed with HFD will be infected and 21 days post infection, the number of bacteria, frequency of myeloid cells, degree of inflammation, and the levels of ATP, HMGB-1, IL-1a, IL-17, and HIF-1a will evaluated. To investigate whether IL-1a increases the resistance to infection, lean and obese IL-1a-/- animals will be treated with recombinant IL-1a (rIL-1a). In this project, we aim also to investigate whether IL-1a modulates the bacterial killing by alveolar macrophages and a possible function in the differentiation of the CD4+ IL-17+ cells. It is important to emphasize that all methodologies are already standardized in our laboratory. In the context of obesity and type 2 diabetes subjects with TB exhibit a worse outcome compared to those with tuberculosis only. Thus, the identification of molecular and cellular new targets for host-directed immunotherapy is important to prevent immunopathology. This study is supported by São Paulo Research Foundation (FAPESP) under agreement 2017/21629-5.
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