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SATURDAY - HMB-422 - MrpJ Alters the Innate Immune Response to Proteus mirabilis Urinary Tract Infection

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Author Block: M. M. Pearson1, I. Debnath2, H. L. T. Mobley1; 1Univ. of Michigan Med. Sch., Ann Arbor, MI, 2Univ. of California, San Francisco, San Francisco, CA
Disclosure Block: M.M. Pearson: None. I. Debnath: None. H.L.T. Mobley: None.
Proteus mirabilis is an enteric opportunistic pathogen most frequently associated with catheter-associated urinary tract infections (UTIs). Its genome encodes a surprisingly high number, 17, of conserved chaperone-usher fimbriae. Of these, mannose-resistant Proteus-like (MR/P) fimbriae are the best-characterized. MR/P fimbriae are required for normal bladder colonization and also contribute to formation of biofilm-like clusters in the bladder lumen. The transcriptional regulator MrpJ is encoded at the end of the mrp operon and acts to repress motility when MR/P fimbriae are produced. Transcriptomic analysis of MrpJ showed that it regulates a diverse set of genes, including genes encoding flagella, other fimbriae, and type VI secretion; many of these genes are either known or predicted to contribute to experimental UTI. We hypothesized that mutation of mrpJ would affect both host and bacterial responses during UTI. To address this question, we used RNA-seq on bladder homogenates from mice inoculated with either wild-type P. mirabilis or an isogenic mrpJ mutant. As expected, flagellar and fimbrial gene expression was altered in the mrpJ mutant. Furthermore, examination of murine transcription revealed the anticipated hallmarks of an acute innate immune response during wild-type P. mirabilis UTI. Interestingly, genes encoding neutrophil, macrophage, and complement markers were differentially regulated in mice infected with the mrpJ mutant, and this was further supported by distinct cytokine profiles in the bladders of mrpJ mutant-inoculated mice. Neutrophil infiltration of the urine was reduced in mrpJ mutant-infected mice at three to six hours post-inoculation, despite similar numbers of bacteria in the urine compared with wild type-infected mice. Finally, the mrpJ mutant was more sensitive to complement-mediated killing in vitro. Taken together, the data indicate that the MrpJ regulon manipulates the host innate response during UTI, although how this differential response affects bacterial colonization or disease progression is yet to be elucidated.