The role of SARM in the control of immune response driven by Klebsiella pneumonia infection

Klebsiella pneumonia is a Gram-negative, capsulated bacteria, which is an important cause of community-acquired and nosocomial pneumonia. Klebsiella co-opts cellular functions dedicated to control immune balance to limit the activation of inflammatory responses. SARM (Sterile α-and armadillo-motif containing protein), the fifth identified member of the TIR (Toll-interleukin 1 receptor (1LR)) adaptor family, negatively regulates IRF and NF-kB activation by affecting TLR4 and TLR3 TRIF-dependent signalling. It is currently unclear the role, if any, of SARM in bacterial infections. Here, we aim to dissect the contribution of SARM in Klebsiella infections, and, specifically, to investigate whether Klebsiella may exploit SARM as part of the pathogen’s portfolio immune evasion strategies.

SARM contributed to Klebsiella anti-inflammation strategies in macrophages through by increasing AKT phosphorylation (to limit phagosome-lysosome fusion), and preventing the activation of NF-kB (to control inflammatory responses). SARM also negatively regulated type I IFN regulatory factor (IRF3) by decreasing IRF3 phosphorylation. Notably, SARM played a role as inflammasome inhibitor, as observed by increased IL-1β secretion in the supernatants of infected sarm-/-. SARM also inhibited ASC oligomerization in Klebsiella-infected macrophages as seen by the increased ASC monomers release by sarm-/- BMDMs. SARM was also required for pyroptosis following Klebsiella infection. Interestingly, Klebsiella induced the expression of SARM in a TLR4-TRAM-TRIF-IRF3-IFNAR dependent manner, demonstrating that Klebsiella exploits type I IFN to trigger SARM to control inflammasome activation, and the activation of inflammatory responses.

These findings have uncovered how Klebsiella manipulates the TLR adaptor SARM to dampen the activation of host defences.