Mitochondrial DNA damage associated activation of NLRP3 inflammasome impairs host defense during P. aeruginosa infection

Abstract

P. aeruginosa is an opportunistic pathogen and a significant contributor of recalcitrant multidrug resistant infections. Immunocompromised and hospitalized patients are especially susceptible to rapid incessant infections. Therapies modulating innate immune defenses of the host are urgently needed for managing resistant infections. We have previously shown that the respiratory epithelium is an important contributor to host defense against P. aeruginosa and it's (quorum sensing) QS molecule N‐3‐oxo‐dodecanoyl‐L‐Homoserine lactone (C12‐HSL). Infection with PAO1 as well as C12‐HSL treatment induces mitochondrial DNA (mtDNA) damage. Emerging studies have shown that mtDNA acts as potential danger associated molecular patterns (DAMPs), which can in turn act as a driver of downstream inflammatory responses. We hypothesize that P. aeruginosa infection causes increase in mitochondrial membrane potential transition and ROS generation, causing release of damaged mtDNA in the cytosol as a DAMP. Presence of DAMPs in the cellular milieu activates TLR9 and the assembly and activation of the inflammasome mediated innate immune responses such as the secretion of IL‐1b and IL‐18. Exacerbation of inflammatory responses, attenuates host defense and enhances infection susceptibility. Normal bronchial epithelial (BEAS‐2B) cells infected with multiple P. aeruginosa strains, namely PAO1, PA1O3 and PAK showed a significant increase in the mRNA and protein expression of NLRP3, AIM2, nod like receptors (NLRs) and the other components of the inflammasome complex. This increase in expression was concomitant with the increase mtDNA damage. An increase in Toll like receptor 9 expression was also noted in the P. aeruginosa infected BEAS‐2B cells. The functional impact downstream of these interactions is the reduction in expression of epithelial immune mediators such as anti‐microbial peptides (AMPs) including human beta defensin (hBd2) and cathelicidin (LL37) as well as loss of epithelial barrier integrity. Studies exploring the inhibition of NLRP3 inflammasome using compounds such as Glibenclamide are currently underway and can be exploited as a therapeutic target to enhance host defensesSupport or Funding InformationDepartment of Veterans Affairs 2I01BX001786 (RTS)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.