Fimbriae reprogram host gene expression - Divergent effects of P and type 1 fimbriae.

Pathogens rely on a complex virulence gene repertoire to successfully attack their hosts. We were therefore surprised to find that a single fimbrial gene reconstitution can return the virulence-attenuated commensal strain Escherichia coli 83972 to virulence, defined by a disease phenotype in human hosts. E. coli 83972pap stably reprogrammed host gene expression, by activating an acute pyelonephritis-associated, IRF7-dependent gene network. The PapG protein was internalized by human kidney cells and served as a transcriptional agonist of IRF-7, IFN-beta and MYC, suggesting direct involvement of the fimbrial adhesin in this process. IRF-7 was further identified as a potent upstream regulator (-log (p-value) = 61), consistent with the effects in inoculated patients. In contrast, E. coli 83972fim transiently attenuated overall gene expression in human hosts, enhancing the effects of E. coli 83972. The inhibition of RNA processing and ribosomal assembly indicated a homeostatic rather than a pathogenic end-point. In parallel, the expression of specific ion channels and neuropeptide gene networks was transiently enhanced, in a FimH-dependent manner. The studies were performed to establish protective asymptomatic bacteriuria in human hosts and the reconstituted E. coli 83972 variants were developed to improve bacterial fitness for the human urinary tract. Unexpectedly, P fimbriae were able to drive a disease response, suggesting that like oncogene addiction in cancer, pathogens may be addicted to single super-virulence factors. Author summary Urinary tract infections affect millions of individuals annually, and many patients suffer from recurring infections several times a year. Antibiotic resistance is increasing rapidly and new strategies are needed to treat even these common bacterial infections. One approach is to use the protective power of asymptomatic bacterial carriage, which has been shown to protect the host against symptomatic urinary tract infection. Instilling nice bacteria in the urinary bladder is therefore a promising alternative approach to antibiotic therapy. In an effort to increase the therapeutic use of asymptomatic bacteriuria, we reintroduced bacterial adhesion molecules into the therapeutic Escherichia coli strain 83972 and inoculated patients who are in need of alternative therapy. To our great surprise, the P fimbriated variant caused symptoms, despite lacking other virulence factors commonly thought to be necessary to cause disease. In contrast, type 1 fimbriae, did not provoke symptoms but enhanced the beneficial properties of the wild-type strain. This is explained by a divergent effect of these fimbrial types on host gene expression, where P fimbriae activate the IRF-7 transcription factor that regulates pathology in infected kidneys, suggesting that a single, potent virulence gene may be sufficient to create virulence in human hosts.