cAMP receptor protein regulates mouse colonization, motility, fimbria-mediated adhesion, and stress tolerance in uropathogenic Proteus mirabilis

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.

Magnesium lithospermate B improves the gut microbiome and bile acid metabolic profiles in a mouse model of diabetic nephropathy

“…Furthermore, Proteus, Escherichia and Shigella genera were putative biomarkers in DN mice in our study. Genetically related species such as Proteus mirabilis are uropathogenic bacteria that tend to infect DM mice [42]. Escherichia and Shigella species are related genetically to Escherichia coli, which would damage glomerular endothelial cells and tubular epithelial cells in the kidneys by producing one or more Shiga-like toxins [43].…”

The Catabolite Repressor/Activator Cra Is a Bridge Connecting Carbon Metabolism and Host Colonization in the Plant Drought Resistance-Promoting Bacterium Pantoea alhagi LTYR-11Z

“…In addition, pyrD, which is involved in pyrimidine biosynthesis, was shown to be required for biofilm formation in Pseudomonas aeruginosa (50). While a variety of previous studies have documented the crucial roles of the carbon metabolism regulators CsrA and Crp in host colonization (33,35,36), relatively little is known about the regulatory function of Cra in the bacterial colonization process. In this study, we further uncovered a novel carbon source-dependent mechanism controlled by Cra that bridges a connection between carbon metabolism of P. alhagi LTYR-11Z and plant colonization.…”

“…While flagellum-mediated motility can direct bacterial migration toward favorable conditions in response to environmental stimuli (26,64), the initiation of biofilm formation often leads to the inhibition of flagellar synthesis (25,65). In fact, in E. coli the regulators of biofilm formation, such as CsrA, Crp, and BolA, have been shown to regulate flagellar motility by controlling the expression of the flagellar master operon flhDC at the transcriptional or posttranscriptional level (26,36,66). In addition, some proteins, such as FliZ, FliT, and YdiV, have been shown to act as posttranslational activators or inhibitors of FlhD 4 C 2 and thereby regulate the expression of FlhD 4 C 2dependent flagellar genes (52,53).…”

“…As the transition of bacteria from planktonic growth to the sessile lifestyle usually occurs in response to changes in the availability of nutrients, carbon metabolism regulators have been found to contribute to the regulation of biofilm formation and host colonization (33)(34)(35)(36). In E. coli and related species, the carbon storage regulator CsrA, which is involved in regulating stationary-phase metabolism, acts posttranscriptionally to repress glycogen biosynthesis, gluconeogenesis, and biofilm formation, while activating glycolysis, motility, and acetate metabolism (34,37).…”

Pathogenesis of Proteus mirabilis Infection

“…PMP fimbriae have also been implicated in both single-species and polymicrobial CAUTI, where pmpG was identified by Tn-Seq (129), and a pmpA mutant was found to be attenuated in a diabetic mouse UTI model (260). The pmp operon was also reported to be directly regulated by cyclic AMP receptor protein (Crp) (260). …”