Urinary tract infection (UTI) is the second most common infection in humans, resulting in over 10 million physician visits per year at a cost of >$1.6 billion. Uropathogenic Escherichia coli (UPEC) accounts for approximately 80% of UTIs and is increasingly resistant to antibiotics, limiting the available oral therapies and driving up costs and complications. A major step in the pathogenesis of UTI is the proliferation of UPEC in biofilm-like intracellular bacterial communities (IBC). As evidence of the importance of IBC formation, we have found that abrogation or modification of IBC development stages attenuates UTI. The K antigen capsule and sialic acid regulation are ubiquitous among UPEC, and appear to play a central role in IBC development. In particular, we have found that failure to synthesize capsule components and failure to export these components as an assembled capsule result in decreased intracellular proliferation and reduction in virulence in the presence and absence of TLR4-mediated innate immunity. In addition, we have identified a regulatory role for sialic acid intermediates and the sialic acid-responsive E. coli regulator NanR during intracellular proliferation. Based on these preliminary data, we hypothesize that sialic acid homeostasis and K antigen are integral to the development of IBC and the establishment of UTIs. We plan to explore this hypothesis through the following aims: 1) To determine the temporal and spatial regulation of NanR-sialic acid-dependent targets during UTI, 2) To elucidate the relationship between intracellular sialic acid levels, NanR regulation, and UPEC virulence, and 3) To distinguish the role of K antigen from sialic acid metabolism in IBC development.
K-type polysaccharide capsules are ubiquitous among extraintestinal pathogenic Escherichia coli as protection during invasive infections, including those of the urinary tract. Capsule and the sugar regulatory molecule sialic acid are required for virulence. Dissecting the molecular mechanisms through which encapsulation and sialic-acid- dependent regulation contribute to the virulence of E. coli will provide critical insights into the molecular pathogenesis of urinary tract infections. This work will rationalize and facilitate the development of novel therapeutic approaches to combat this increasingly antibiotic-resistant organism.
|Madden-Fuentes, Ramiro J; Arshad, Mehreen; Ross, Sherry S et al. (2015) Efficacy of Fluoroquinolone/Probiotic Combination Therapy for Recurrent Urinary Tract Infection in Children: A Retrospective Analysis. Clin Ther 37:2143-7|