Avaliação dos polimorfismos genéticos da Gasdermina D e de receptores P2X7 em pacientes com tuberculose

Abstract

Tuberculosis (TB) is an infectious disease, caused by Mycobacterium tuberculosis, and is still a serious global public health problem. In 2020, the state of Amazonas recorded the highest incidence rate of TB cases in Brazil and these worrying data encourage research into genetic factors associated with the disease in our region. The first line of defense against these microorganisms is the innate immune response, in which macrophages act. These cells express receptors on their surface, such as P2X7, with functions of antigen recognition, regulation of the inflammatory response and effecting the immune response. This response activates the inflammasomes responsible for inducing a signaling network for the production of pro-inflammatory cytokines, such as IL-1β and for the cleavage of the Gasdermin D protein. The N-terminal portion of Gasdermin will form pores in the plasma membrane of the infected cell, helping to eliminate the pathogen through pyroptosis and release of secreted cytokines. This study aims to evaluate the single-base polymorphisms of genes that code for Gasdermin D and P2X7 receptors: GSDMD (rs7834318, rs2290414) and P2RX7 (rs2230911, rs3751143, rs208290) and analyze whether there is an association with TB, for risk or protection from the disease. Patients were recruited at the Cardoso Fontes Polyclinic (Manaus – AM), whole blood was collected, DNA extracted by salt precipitation and genotyping, using the qPCR technique, of 504 blood samples, of which 245 patients with tuberculosis pulmonary and 259 healthy contacts. The determination of IL-1β concentrations was performed by ELISA in samples from TB patients (n=44) and in controls (n=39). Of the analyzed polymorphisms, the rs208290 (G/A genotype) of the P2RX7 gene was associated with protection against TB (p=0.0031; OR= 0.54; 95% CI= 0.36-0.82), the same association was made for the combination of haplotypes ACA of P2RX7 (p=0.020; OR= 0.51; 95% CI= 0.33-0.78). Immunogenetic studies reveal important data on how they can affect the regulation of the immune response to pathogens, although these studies are still scarce in patients with TB in Northern Brazil, they can contribute to reveal factors associated with protection and/or risk for TB that justify such high coefficients of the disease in Amazonas.