Nitrate-mediated luminal expansion ofSalmonellaTyphimurium is dependent on the ER stress protein CHOP
Authors: Sweet Lydia A. , Kuss-Duerkop Sharon K. , Byndloss Mariana X. , Keestra-Gounder A. Marijke 
Published: November 2023

SalmonellaTyphimurium is an enteric pathogen that employs a variety of mechanisms to exploit inflammation resulting in expansion in the intestinal tract, but host factors that contribute to or counteract the luminal expansion are not well-defined. Endoplasmic reticulum (ER) stress induces inflammation and plays an important role in the pathogenesis of infectious diseases. However, little is known about the contribution of ER stress-induced inflammation duringSalmonellapathogenesis. Here, we demonstrate that the ER stress markersHspa5andXbp1are induced in the colon ofS. Typhimurium infected mice, but the pro-apoptotic transcription factorDdit3,that encodes for the protein CHOP, is significantly downregulated.S. Typhimurium-infected mice deficient for CHOP displayed a significant decrease in inflammation, colonization, dissemination, and pathology compared to littermate control mice. Preceding the differences inS. Typhimurium colonization, a significant decrease inNos2gene and iNOS protein expression was observed. Deletion ofChopdecreased the bioavailability of nitrate in the colon leading to reduced fitness advantage of wild typeS. Typhimurium over anapA narZ narGmutant strain (deficient in nitrate respiration). CD11b+ myeloid cells, but not intestinal epithelial cells, produced iNOS resulting in nitrate bioavailability forS. Typhimurium to expand in the intestinal tract in a CHOP-dependent manner. Altogether our work demonstrates that the host protein CHOP facilitates iNOS expression in CD11b+ cells thereby contributing to luminal expansion ofS. Typhimurium via nitrate respiration.

Author Summary

SalmonellaTyphimurium is a gastroenteric bacterium that replicates to large numbers within the gastrointestinal (GI) tract allowing for efficient host-to-host transmission. One strategy that allowsSalmonellato expand in the GI tract is via nitrate respiration that is generated duringSalmonellainfections. Our results presented here provide more insight into the role of the host protein CHOP in the production of nitrate and the subsequent growth ofSalmonellain the GI tract. CHOP expression is regulated within the unfolded protein response (UPR), an adaptive response pathway that is activated when cells are undergoing endoplasmic reticulum (ER) stress. ER stress has been implicated in several infectious and inflammatory diseases; however, little is known about the contribution of ER stress and the UPR duringSalmonellainfections. Here, we demonstrate thatChopis downregulated in mice infected withS. Typhimurium, and that mice deficient for CHOP have reduced bacterial numbers in the colon, suggesting that downregulation ofChopis a host response to resist intestinal colonization bySalmonella. Our results further show that CHOP contributes to increased expression of iNOS, responsible for nitrate production, thereby increasing the bioavailability of nitrate that allows forSalmonellagrowth. Altogether, our research provides a better understanding of the contribution of the ER stress protein CHOP in intestinal health and disease.