Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-gamma-induced chromatin remodeling of MHC2TA by TLR2 and MAPK signaling

Abstract

During infection of macrophages, prolonged signaling by Mycobacterium tuberculosis (Mtb) or its 19-kDa lipoprotein (LpqH; Rv3763) inhibits IFN-gamma-induced expression of several immune function genes, including class II transactivator (CIITA), which regulates class II MHC. Mtb does not inhibit early IFN-gamma signaling events, e.g., Stat1alpha activation. This study analyzed downstream mechanisms that regulate the transcription of MHC2TA, the gene encoding CIITA. Chromatin immunoprecipitation showed that IFN-gamma induced acetylation of histones H3 and H4 at the CIITA promoter IV (pIV). In contrast, IFN-gamma-dependent histone acetylation at CIITA pIV was inhibited by Mtb or 19-kDa lipoprotein. Mtb 19-kDa lipoprotein also inhibited IFN-gamma-dependent recruitment of Brahma-related gene 1, a chromatin remodeling protein, to CIITA pIV. Mtb 19-kDa lipoprotein did not inhibit histone acetylation in TLR2(-/-) macrophages. Furthermore, 19-kDa lipoprotein did not inhibit CIITA expression or IFN-gamma-dependent histone acetylation of CIITA pIV in macrophages treated with inhibitors of MAPKs p38 or ERK. Thus, CIITA expression was inhibited by TLR2-induced MAPK signaling that caused histone hypoacetylation at CIITA pIV and suppression of CIITA transcription. Chromatin remodeling at MHC2TA is a novel target of inhibition by Mtb. These mechanisms may diminish class II MHC expression by infected macrophages, contributing to immune evasion by Mtb.