Abstract
Uropathogenic Escherichia coli (UPEC) represent the predominant cause of urinary tract infections (UTIs). A key UPEC molecular virulence mechanism is type 1 fimbriae, whose expression is controlled by the orientation of an invertible chromosomal DNA element—the fim switch. Temperature has been shown to act as a major regulator of fim switching behavior and is overall an important indicator as well as functional feature of many urologic diseases, including UPEC host-pathogen interaction dynamics. Given this panoptic physiological role of temperature during UTI progression and notable empirical challenges to its direct in vivo studies, in silico modeling of corresponding biochemical and biophysical mechanisms essential to UPEC pathogenicity may significantly aid our understanding of the underlying disease processes. However, rigorous computational analysis of biological systems, such as fim switch temperature control circuit, has hereto presented a notoriously demanding problem due to both the substantial complexity of the gene regulatory networks involved as well as their often characteristically discrete and stochastic dynamics. To address these issues, we have developed an approach that enables automated multiscale abstraction of biological system descriptions based on reaction kinetics. Implemented as a computational tool, this method has allowed us to efficiently analyze the modular organization and behavior of the E. coli fimbriation switch circuit at different temperature settings, thus facilitating new insights into this mode of UPEC molecular virulence regulation. In particular, our results suggest that, with respect to its role in shutting down fimbriae expression, the primary function of FimB recombinase may be to effect a controlled down-regulation (rather than increase) of the ON-to-OFF fim switching rate via temperature-dependent suppression of competing dynamics mediated by recombinase FimE. Our computational analysis further implies that this down-regulation mechanism could be particularly significant inside the host environment, thus potentially contributing further understanding toward the development of novel therapeutic approaches to UPEC-caused UTIs.
Highlights
Type 1 fimbriae represent the foremost virulence factor in lower urinary tract infections (UTIs) by uropathogenic Escherichia coli (UPEC)—the main causative agent that accounts for 80–90 percent of all community-acquired UTIs in the United States [1,2,3,4]
This, in turn, has made computational analysis possible, and essential to any efforts aimed at understanding the increasingly intricate structures and functions of multiscale biological systems that are being uncovered through empirical means
Accurate molecular-scale biochemical descriptions could be formulated for a large number of experimentally observed systems, their complexity is rapidly exceeding our present as well as near-future computational capabilities—the issue that has become more pronounced with the emerging understanding of the ubiquitous role played by nonlinear and discrete-stochastic (‘‘noisy’’) molecular dynamics in gene regulatory, signal transduction, and other biological systems [39]
Summary
Type 1 fimbriae (pili) represent the foremost virulence factor in lower urinary tract infections (UTIs) by uropathogenic Escherichia coli (UPEC)—the main causative agent that accounts for 80–90 percent of all community-acquired UTIs in the United States [1,2,3,4]. Type 1 fimbriae are further thought to aid the UPEC infection process by enhancing the ability of bacteria to form biofilms and to develop intracellular bacterial communities (IBCs) with biofilm-like properties [13,14,15,16,17,18] The latter allow E. coli to establish quiescent pathogen reservoirs shielded from native host defenses and antibiotic treatments as well as serve to seed subsequent UTIs in a type 1 fimbriae-dependent manner [2,13,19,20,21]. This may both contribute to the widespread emergence of multi-drug-resistant UPEC strains (up to 20–50 percent of isolates) as well as help account for the notably high rates of UTI incidence (lifetime risk of over 50 percent for women and nearly 14 percent for men) and recurrence (40 percent in women and 26 percent in men per annum) – along with leading to a number of other significant public health implications
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