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

Date Published: June 10, 2019

Publisher: Public Library of Science

Author(s): Ines Ambite, Daniel S. C. Butler, Christoph Stork, Jenny Grönberg-Hernández, Bela Köves, Jaroslaw Zdziarski, Jerome Pinkner, Scott J. Hultgren, Ulrich Dobrindt, Björn Wullt, Catharina Svanborg, Andreas J. Baumler.

http://doi.org/10.1371/journal.ppat.1007671

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 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-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 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.

Partial Text

Mucosal surfaces provide ideal living conditions for the normal flora but paradoxically, they also serve as attack sites for numerous bacterial pathogens that cause extensive morbidity and mortality. Understanding this dichotomy is critical for efforts to selectively target and remove pathogens without disturbing the commensal flora or its protective effects. The complex nature of disease predicts that virulence is multifaceted and that pathogens need multiple virulence factors to initiate tissue attack, disrupt immune homeostasis and create symptoms and pathology [1–8]. It is also well established that commensals fail to cause disease, due to a lack of critical virulence genes [9, 10]. About 50% of asymptomatic bacteriuria (ABU) isolates have a smaller genome size than acute pyelonephritis strains due, in part, to inactivating virulence gene deletions or point mutations [11–13]. These strains continue to accumulate loss of function mutations in vivo, supporting the notion of a virtually irreversible reductive evolution process, where spontaneous recovery of a virulent phenotype is not likely to occur.

Bacterial pathogens have evolved sophisticated molecular strategies to colonize the appropriate host niche and adherence is an essential first step to enhance their virulence [39]. Like pathogens, commensals have evolved adhesive surface ligands to enhance their fitness, but the outcome is very different, suggesting that the quality of the adhesive interactions may distinguish commensals from pathogens (Fig 9). Here, we address this question by comparing P fimbriae, which are expressed by uropathogenic E. coli strains [49] to type 1 fimbriae, which are expressed among Gram-negative bacteria, with no apparent disease association. By reconstituting the pap or fim gene clusters in the non-virulent E. coli strain 83972 and inoculating human hosts with the fimbriated variants of this strain, we have had the unique opportunity to study fimbrial function and define molecular effects in human hosts.

 

Source:

http://doi.org/10.1371/journal.ppat.1007671

 

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