Thursday, November 21, 2024
11/21/2024
Project Summary Urinary tract infection (UTI) and recurrent UTI (rUTI) significantly reduces the quality of life of millions of women annually and poses a growing health threat due to the increasing prevalence of antibiotic resistant uropathogenic bacteria. Klebsiella spp. represent the second most common bacterial species isolated from the urine of women experiencing rUTI but have been largely understudied in the context of rUTI. Within the Klebsiella genus, Klebsiella pneumoniae is one of the most common human pathogens; however, genome sequence analysis has revealed that that K. pneumoniae isolates encompass at least three distinct species: K. pneumoniae, K. variicola and K. quasipneumoniae. Although K. quasipneumoniae strains are commonly isolated from patients with UTI and encode known virulence factors and antimicrobial resistance genes, no study has evaluated urovirulence phenotypes of K. quasipneumoniae in an animal model. Indeed, the clinical prevalence of K. quasipneumoniae in UTI remains unknown. Among the virulence factors that Klebsiella spp. possess, type 1 (fim operon) and type 3 (mrk operon) fimbriae play a crucial role in mediating bacterial adhesion and invasion of host epithelial surfaces. Type 1 fimbriae are widely conserved among Enterobacteriaceae, but the presence of the gene fimK differentiates the fim operons of Klebsiella spp. from Escherichia coli. In K. pneumoniae, FimK is a regulator of fim operon expression and is comprised of an N-terminal DNA binding domain that binds the fimS regulatory region and a conserved C-terminal EAL domain with phosphodiesterase activity. Through sequence alignment of the fim operons of sequenced K. quasipneumoniae and K. pneumoniae isolates, we have discovered that the fimK gene of K. quasipneumoniae is truncated and lacks the C-terminal EAL domain. This is important because not only is fimK a key regulator of fim operon expression, but it is also proposed to co-regulate mrk operon expression by modulation of cyclic di-GMP levels through its phosphodiesterase activity. We have found that FimK-mediated regulation of type 1 and type 3 fimbriae is distinct in K. quasipneumoniae due to the absence of the FimK EAL domain. We hypothesize that because of this regulatory difference, bladder infection dynamics and the requirement for type 1 versus type 3 fimbriae for bladder colonization may be distinct in K. quasipneumoniae. This proposal will address these hypotheses and produce foundational knowledge of K. quasipneumoniae bladder infection dynamics by i) defining the clinical prevalence of K. quasipneumoniae in UTI in women, ii) evaluating K. quasipneumoniae rUTI isolates in a mouse model of acute UTI, and iii) evaluating the role of K. quasipneumoniae type 1 versus type 3 fimbriae and FimK during acute UTI. Taken together, this work will produce the first foundational knowledge of clinical prevalence and bladder infection dynamics of the understudied human uropathogen K. quasipneumoniae and define the impact of the conserved truncation of the fimbrial regulator FimK on the regulation of type 1 and type 3 fimbriae and bladder colonization.
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