Brucella abortus down-regulates MHC class II by the IL-6-dependent inhibition of CIITA through the downmodulation of IFN regulatory factor-1 (IRF-1)

Abstract

is an intracellular pathogen capable of surviving inside of macrophages. The success of as a chronic pathogen relies on its ability to orchestrate different strategies to evade the adaptive CD4 T cell responses that it elicits. Previously, we demonstrated that inhibits the IFN-γ-induced surface expression of MHC class II (MHC-II) molecules on human monocytes, and this phenomenon correlated with a reduction in antigen presentation. However, the molecular mechanisms, whereby is able to down-regulate the expression of MHC-II, remained to be elucidated. In this study, we demonstrated that infection inhibits the IFN-γ-induced transcription of MHC-II, transactivator (CIITA) and MHC-II genes. Accordingly, we observed that the synthesis of MHC-II proteins was also diminished. was not only able to reduce the expression of mature MHC-II, but it also inhibited the expression of invariant chain (Ii)-associated immature MHC-II molecules. Outer membrane protein 19 (Omp19), a prototypical lipoprotein, diminished the expression of MHC-II and CIITA transcripts to the same extent as infection. IL-6 contributes to these down-regulatory phenomena. In addition, and its lipoproteins, through IL-6 secretion, induced the transcription of the negative regulators of IFN-γ signaling, suppressor of cytokine signaling (SOCS)-1 and -3, without interfering with STAT1 activation. Yet, lipoproteins via IL-6 inhibit the expression of IFN regulatory factor 1 (IRF-1), a critical regulatory transcription factor for CIITA induction. Overall, these results indicate that inhibits the expression of MHC-II molecules at very early points in their synthesis and in this way, may prevent recognition by T cells establishing a chronic infection.

IL-6 and INF-γ levels in patients with brucellosis in severe epidemic region, Xinjiang, China

“…This indicates IL-6 is the main factor for the chronicization of brucellosis infection. In addition, the positive rate of blood culture and ESR, as well as the RF, PCT, and CRP levels, were elevated in those with high antibody titer, reflecting the development of the disease [26,27].…”

Outer Membrane Vesicles From Brucella melitensis Modulate Immune Response and Induce Cytoskeleton Rearrangement in Peripheral Blood Mononuclear Cells

“…IL-6 is a pleiotropic cytokine involved in inflammatory and anti-inflammatory responses. B. abortus 2308 cells and B. abortus Omp19 down-regulated the IFNγ-induced MHC-II expression via IL-6 secretion in THP-1 monocytes (Velásquez et al, 2016). TNFα is an important cytokine in Th1 immune responses to eliminate intracellular pathogens.…”

Intracellular Pathogens: Host Immunity and Microbial Persistence Strategies

“…Other bacterial pathogens reduce MHC antigen presentation and evade host T cell response; e.g., M. tuberculosis -infected cells export antigen for uptake and presentation by uninfected bystander cells, which reduce MHC class II antigen presentation by infected cells and limits host-mediated CD4 + T cell control [300]. B. abortus infection inhibits the expression of MHC-II molecules by IL-6-dependent inhibition of transactivator (CIITA), which prevents its recognition by T cells establishing a chronic infection [301]. Another evasion strategy adopted by bacterial pathogens is to secrete enzymes such as IgA proteases that degrade immunoglobulins; e.g., secreted IgA protease from N. meningitidis is transported to the nucleus of infected cells where it cleaves the p65/RelA component of the NF- κ B complex [302].…”