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

Abstract

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 83972 pap 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-β 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 83972 fim 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.

Horizontally acquired papGII-containing pathogenicity islands underlie the emergence of invasive uropathogenic Escherichia coli lineages

“…The gene papGII has been associated epidemiologically with pyelonephritis and urinary-source bacteremia in directed, usually PCR-based studies [19][20][21][22]47 , and was shown experimentally, with varying degrees of rigor, to contribute to kidney infection in murine and monkey models [48][49][50] . A key role for papGII in the pathogenesis of human pyelonephritis was confirmed recently by the finding that knock-in of papGII was sufficient to enable the iuc-positive but normally non-pathogenic E. coli strain ABU83972 (CC73, phylogroup B2) to cause pyelonephritis in humans 23 . In that study, PapGII was shown to enter kidney cells and to trigger renal tissue inflammation by reprogramming host gene expression 23 .…”

“…A key role for papGII in the pathogenesis of human pyelonephritis was confirmed recently by the finding that knock-in of papGII was sufficient to enable the iuc -positive but normally non-pathogenic E. coli strain ABU83972 (CC73, phylogroup B2) to cause pyelonephritis in humans 23 . In that study, PapGII was shown to enter kidney cells and to trigger renal tissue inflammation by reprogramming host gene expression 23 . These findings, together with ours, support a site (i.e., kidney)-specific and, hence, pathotype-defining role for papGII .…”

“…These VAGs include papGII , which encodes one of several PapG tip adhesin variants of P fimbriae. PapGII binds to the globoseries of glycosphingolipids on uroepithelial cells and transcriptionally regulates host gene expression in kidney cells, leading to a pyelonephritis-associated IRF-7 response 23 . Like many other E. coli VAGs, the pap operon encoding P fimbriae lies on pathogenicity islands (PAIs) 24 .…”

Active bacterial modification of the host environment through RNA polymerase II inhibition

“…Interestingly, the addition of a single virulence gene to E. coli 83972 was sufficient to override the inhibitory effect of NlpD (50), bypassing Pol II inhibition at the transcriptional level. The calm, non-reactive environment created by commensals thus appears to be favored but easily disrupted if the strain acquires a sufficiently potent virulence gene (50).…”

Molecular determinants of disease severity in urinary tract infection

“…3 ; Table 1 ). Importantly, bacteria that express TLR4 agonists, such as P fimbriae, can override this unresponsiveness by engaging different TLR4 coreceptors, such as glycosphingolipids 79 . This mechanism provides mucosal membranes with a much needed, pathogen-specific solution for when to respond to bacteria in the lumen.…”