MOLECULAR SIGNALING UNDERLYING ESCHERICHIA COLI O157:H7 INTESTINAL COLONIZATION AND THE PROTECTIVE ROLE OF QUERCETIN TO INHIBIT PATHOGEN INFECTION

Yansong Xue

Escherichia coli (E. coli) O157:H7 can cause severe human diseases when attaches to the intestinal epithelial cells. In this dissertation, the molecular signaling alteration underling E. coli O157:H7 colonization was investigated and the preventive effects of quercetin on bacterial infection were also observed. Autophagy is characterized as the formation of a double-membrane autophagosome and is considered a vital defense mechanism to bacterial infection. In our study, E. coli O157:H7 suppressed host autophagy and promoted bacterial adhesion via a Tir-mediated and protein kinase A (PKA)-dependent mechanism. PKA activation inhibited ERK signaling and endoplasmic reticulum (ER) stress, which subsequently inhibited autophagy. Notably, enhancing host cell autophagy reduced the bacterial adherence. However, impaired autophagy may cause sustained host inflammatory response such as inflammasomes. Inflammasomes are critical molecule platforms mediating host inflammation and processing inflammatory cytokines such interleukin (IL)-1β and IL-18. E. coli O157:H7 infection stimulated NOD-like receptor (NLR) superfamily, pyrin domain containing 3 (NLRP3) inflammasome activation and host production of IL-1β and IL-18 due to the impaired mitochondrial function and enhanced reactive oxidative species (ROS) release. Quercetin, a natural polyphenolic compound that has multiple beneficial health effects, abrogated NLRP3-induced inflammation in infected cells by inhibiting mitochondrial ROS release and enhancing host autophagy. Moreover, in order to have a better colonization, E. coli O157:H7 utilized cell surface proteins integrins to promote bacterial adhesion to host cells. We found that E. coli O157:H7 mediated epithelial cell adhesion by stabilizing focal adhesions via β1 integrins. Interference with β1 integrin significantly reduced bacterial adhesion. Importantly, quercetin had an inhibitory effect on E. coli O157:H7 adhesion, which we attributed to decreased β1 integrin expression and focal adhesion proteins recruitment. In summary, E. coli O157:H7 1) inhibited host autophagy via Tir-mediated PKA activation, 2) induced a host NLRP3 inflammasome and 3) utilized β1 integrin to favor bacterial persistence. Quercetin protected intestinal epithelial cells from inflammasome activation and adhesion in response to infection in part due to the prevention of ROS production and inhibition of β1 integrin expression and focal adhesion formation.

MOLECULAR SIGNALING UNDERLYING ESCHERICHIA COLI O157:H7 INTESTINAL COLONIZATION AND THE PROTECTIVE ROLE OF QUERCETIN TO INHIBIT PATHOGEN INFECTION

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