Abstract
Interferon-gamma (IFN-γ) is a key cytokine that mediates immunity to tuberculosis (TB). Mycobacterium tuberculosis (M. tb) is known to downregulate the surface expression of IFN-γ receptor (IFN-γR) on macrophages and peripheral blood mononuclear cells (PBMCs) of patients with active TB disease. Many M. tb antigens also downmodulate IFN-γR levels in macrophages when compared with healthy controls. In the current study, we aimed at deciphering key factors involved in M. tb mediated downregulation of IFN-γR levels on macrophage surface. Our data showed that both M. tb H37Rv and M. bovis BCG infections mediate downmodulation of IFN-γR on human macrophages. This downmodulation is regulated at the level of TLR signaling pathway, second messengers such as calcium and cellular kinases i.e. PKC and ERK-MAPK, indicating that fine tuning of calcium response is critical to maintaining IFN-γR levels on macrophage surface. In addition, genes in the calcium and cysteine protease pathways which were previously identified by us to play a negative role during M. tb infection, also regulated IFN-γR expression. Thus, modulations in IFN-γR levels by utilizing host machinery may be a key immune suppressive strategy adopted by the TB pathogen to ensure its persistence and thwart host defense.
Highlights
Staining on mouse BMDMs was carried out using biotinylated anti-IFN-γ receptor (IFN-γR) monoclonal antibody (BD Biosciences #550582, Clone 2E2) and secondary staining was performed with PE labeled streptavidin
Previous work has already established that pathogenic microorganisms including mycobacteria like M. tb and M. avium intracellulare downregulate IFN-γR levels on macrophages [5, 11]
No significant change in IFN-γR levels was seen at later time points i.e. at 48h (Supplementary Fig. 1)
Summary
A deeper understanding of hostpathogen interaction remains a key factor in tackling this major health menace and may contribute toward discovery of an effective vaccine [1]. IFN-γ is a key cytokine that mediates immunity to TB and many other infections. IFN-γR gene knock-out mice or mice having genetic defects in IFN-γR are extremely susceptible to M. tb infection [2]. This phenotype is further exemplified in HIV+ individuals wherein low CD4+ T cell counts translate into lower production of IFN-γ; eliciting poor immune responses to intracellular pathogens [3]
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