Abstract
Cyclic AMP receptor protein (Crp) is a major transcriptional regulator in bacteria. This study demonstrated that Crp affects numerous virulence-related phenotypes, including colonization of mice, motility, fimbria-mediated adhesion, and glucose stress tolerance in uropathogenic Proteus mirabilis. Diabetic mice were more susceptible to kidney colonization by wild-type strain than nondiabetic mice, in which the crp mutant exhibited increased kidney colonization. Loss of crp or addition of 10% glucose increased the P. mirabilis adhesion to kidney cells. Direct negative regulation of pmpA (which encodes the major subunit of P-like fimbriae) expression by Crp was demonstrated using a reporter assay and DNase I footprinting. Moreover, the pmpA/crp double mutant exhibited reduced kidney adhesion comparable to that of the pmpA mutant, and mouse kidney colonization by the pmpA mutant was significantly attenuated. Hence, the upregulation of P-like fimbriae in the crp mutant substantially enhanced kidney colonization. Moreover, increased survival in macrophages, increased stress tolerance, RpoS upregulation, and flagellum deficiency leading to immune evasion may promote kidney colonization by the crp mutant. This is the first study to elucidate the role of Crp in the virulence of uropathogenic P. mirabilis, underlying mechanisms, and related therapeutic potential.
Highlights
Cyclic AMP receptor protein (Crp) is a transcriptional regulator that modulates bacterial metabolism and coordinates the expression of virulence factors through a process known as carbon catabolite repression (CCR), which is triggered in response to the availability of digestible sugars[1,2,3,4,5]
Because E. coli Crp is activated in response to low glucose (LB broth), a condition that activates CyaA for the production of cAMP10, we monitored the expression of the plac-gfpuv reporter, which is regulated by Crp-cAMP at 3, 5, 7, 9, 11 and 24 h in wild-type P. mirabilis after exposure to 0%, 2%, and 10% glucose
P. mirabilis Crp-cAMP regulated the expression of ptsG, cyaA, and hfq to how it did in E. coli
Summary
Cyclic AMP receptor protein (Crp) is a transcriptional regulator that modulates bacterial metabolism and coordinates the expression of virulence factors through a process known as carbon catabolite repression (CCR), which is triggered in response to the availability of digestible sugars[1,2,3,4,5]. The regulation of swarming motility depends on several factors, including the flagellar master regulator FlhDC12 and specific nutrients and environmental cues, such as amino acids (L-arginine and L-glutamine)[18] and some carbohydrates[19] In this regard, Crp mediates glucose repression of the swarming associated sdh operon[19, 20]. Crp-mediated upregulation of P-like fimbriae, increased survival in macrophages, increased stress tolerance, upregulation of RpoS, and flagellum deficiency (leading to immune evasion) caused by crp loss or reduced Crp activity may promote mouse kidney colonization. This is the first study to elucidate the Crp-regulated virulence factors of uropathogenic P. mirabilis, underlying mechanisms, and related therapeutic potential. This study provides new insights into the role of P. mirabilis Crp in urinary tract colonization of a host with diabetes
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