Abstract
Mycobacterium tuberculosis (Mtb) pathogenesis encompasses a plethora of finely regulated alterations within the host which eventually coin the outcome of infection. Chemokines are important components in directing immune cell recruitment to the site of infection, and shaping the disease progression. Here, we demonstrate that Hippo (mammalian sterile 20–like 1 and 2 kinases, MST1/2, in mammals), is activated during mycobacterial infection in a toll-like receptor (TLR) 2-interleukin receptor-1 associated kinases (IRAK1/4)-dependent manner. Mtb-triggered Hippo signaling modulates the expression and secretion of chemokines (CXCL1 and CXCL2); as silencing MST1/2 compromised the ability of Mtb to furnish the same. Further insight into the mechanism of Hippo-mediated regulation of chemokines revealed the role for a non-canonical Hippo effector interferon (IFN) regulatory factor (IRF) 3 in the process and marked the effect to be independent of LATS1. Alongside their ability to guide directed recruitment of immune cells, we have uncovered a paracrine role for Hippo-mediated secretion of CXCL1 and CXCL2 in the production of anti-microbial peptides (beta-defensins), iNOS, NOX2 and pro-inflammatory molecules during mycobacterial infection of the host. This study highlights the involvement of TLR2-IRAK1/4-MST1/2-IRF3 axis in Mtb-triggered modulation of chemokines and identifies Hippo signaling as a novel regulator of host-mycobacterial interactions.
Highlights
The core components of the Hippo pathway include two serine threonine kinases, MST1/2 (Hippo in Drosophila) and LATS1/2; and two transcriptional coactivators YAP and TAZ20
The present study demonstrates that pathogen-specific TLR2-mediated activation of Hippo signaling in macrophages through IRAK1 and IRAK4 renders MST1/2 to be a regulatory node in the modulation of chemokines, CXCL1 and CXCL2, through IRF3; and identifies these chemokines as novel paracrine regulators for the production of anti-microbial molecules and inflammatory mediators during mycobacterial infection of the host
We found activation of Hippo signaling in Mycobacterium tuberculosis (Mtb) H37Rv infected mouse peritoneal macrophages (PM) (Fig. 1a) as evaluated by increase in the phosphorylation status of canonical Hippo pathway components; MST1/2, LATS1
Summary
The core components of the Hippo pathway include two serine threonine kinases, MST1/2 (Hippo in Drosophila) and LATS1/2; and two transcriptional coactivators YAP and TAZ20. Identified in Drosophila to promote apoptosis[24], inhibit cell proliferation and tumorigenesis[23,25]; Hippo signaling components are being implicated in T-cell deficiency associated with viral, bacterial and fungal infections[26,27,28,29] and in autoimmune manifestations[30]. In view of the available literature background, we set out to understand the status of Hippo pathway during mycobacterial infection and its implication in steering the production of chemokines during the pathogenesis of Mtb. The present study demonstrates that pathogen-specific TLR2-mediated activation of Hippo signaling in macrophages through IRAK1 and IRAK4 renders MST1/2 to be a regulatory node in the modulation of chemokines, CXCL1 and CXCL2, through IRF3; and identifies these chemokines as novel paracrine regulators for the production of anti-microbial molecules and inflammatory mediators during mycobacterial infection of the host
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