Avaliação de genes relacionados à hipóxia associados à resposta imune inata de pacientes com tuberculose pulmonar ativa e latente

Abstract

Mycobacterium tuberculosis (Mtb) is an intracellular pathogen, the causative agent of Tuberculosis (TB), which infects a large part of the world's population. About 90-95% of individuals infected with Mtb develop latent tuberculosis infection (LTBI), characterized by the formation of a structure called a granuloma, which maintains Mtb bacilli within a set of defense cells. The granuloma is considered hypoxic, and the response to hypoxia is regulated by the hypoxia-induced factor - HIF-1α, which has been associated with several infections, including bacterial ones. In addition to the hypoxia response, other mechanisms involved in active infection may contribute to the establishment of latent Mtb infection. The present study investigated how HIF-1α interferes in the innate immune response of individuals with active or latent infection. Therefore, patients with active pulmonary TB, before the start of treatment, individuals with latent tuberculosis infection (LTBI), who had PPD+ and IGRAs+ and healthy individuals were recruited. Expression of cytokines (IL-15, IL-18, IL-6 and TNF-α) and specific transcription factors (A20 and HIF-1α) that mediate mechanisms of the immune response in patients with active pulmonary TB, LTBI and healthy controls was performed. In addition, the activation of the vitamin D-dependent antimicrobial pathway, which is active by pro-inflammatory cytokines, was analyzed. IL-15 expression was decreased in LTBI subjects and active TB patients, while IL-18 expression was similar between LTBI subjects and healthy controls, both cytokines converge for vitamin D activation, which did not show a significant decrease. The expression of TNF-α and IL-6 were also lower in LTBI subjects. Regarding the transcription factors analyzed, there was a decrease in A20 and HIF-1α. The blockade of HIF-1α in PBMC of individuals with LTBI led to a decrease in the activation of phosphorylated NF-κB and an increase in the production of TNF-α, which may be determinant for the individual's latency condition. The decrease in cytokine production is relevant to keep the infection latent and influence the activation of the NF-κB signaling pathway. The results of this study demonstrate that LTBI is multifactorial, and several factors contribute to its establishment in the host.