A PARTICIPAÇÃO DO GENE SIGIRR NA RESPOSTA IMUNE A Mycobacterium tuberculosis DEPENDENTE DE TLR E IL18

Abstract

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), constitutes a serious global public health problem and thousands of people still fall ill and die due to the disease and its complications. It is believed that variations in the immune response may be related to the high number of tuberculosis cases. Therefore, this work aims to correlate the genes and signaling pathways of interleukin 18 and SIGIRR in the immune response to Mtb through in silico analysis of transcriptomes. To this end, an integrative analysis was performed by searching the NCBI GEO database to identify publicly available gene expression data on Mtb infection. Initially, we defined signaling pathways on the STRING, Revelen and Signor 3.0 platforms, which provided 54, 26 and 25 genes, respectively. The Veen diagram was applied and gene expression data extraction was synthesized for the set of 19 target genes/proteins to evaluate the participation of SIGIRR in the TLR/IL18/IFNG activation pathway. Information about the expression of these genes, in the context of Mtb infection, was extracted from DataSets GSE52819, GSE20050, GSE139871, GSE148731. In the analysis of DataSet 52819, monocytes infected with Mtb H37Rv, 7 genes showed changes in expression, including TLR4 with upregulation; for GSE20050, macrophages, with the exception of IL-37, all genes were differentially expressed; for GSE139871, monocytes from tuberculosis patients subsequently infected with strain UT127, 12 genes with differential expression were found, including IFNG, IL18, IRAK2, TICAM1, while in those reinfected with UT205, 12 genes were found, including IFNG, IL18, IRAK2, IRF7, SIGIRR; in DataSet 148731, differentiated macrophages with M1 and M2 phenotypes infected with Mtb H37Rv strains, changes to the M1 profile were observed in all 19 genes evaluated at 4 hours of infection and in 17 genes evaluated at 24 hours of infection. The genes IFNGR2, IL18R1, IRAK2, IRF7 and TICAM1 showed positive regulation in all DataSets evaluated. Specifically in relation to our gene and pathways of interest, SIGIRR and IL18 were not correlated. Therefore, our initial idea of the direct participation of SIGIRR in the induction of IL18 production has not been proven. However, SIGIRR showed strong positive correlations with TLR4 and accessory proteins of its activation pathway, such as CD14, LY96 and IRAK4, proving its importance in pathogen recognition. Most importantly, SIGIRR showed a strong positive correlation with IL18BP, IFNGR1 and NOX4. This demonstrates the potential of SIGIRR to negatively regulate the action of IL18, maintaining the IFNG-dependent immune response by increasing the expression of IFNGR1. Finally, SIGIRR increases NOX4 expression, which increases microbicidal activity. Thus, SIGIRR has the potential to increase phagocytosis and microbicidal activity, without a deleterious exacerbated inflammatory process in the response to Mtb. Analyzes of different contexts of Mtb infection provide reliability in our data, which provide evidence of the importance of molecules not classically described in tuberculosis, such as SIGIRR, IRAK2 and IRF7, opening up a range of biomarker possibilities for diagnosis and prognosis, in addition to points of modulation of the inflammatory response, which must be considered in this pathology.