Combined comparative genomics and clinical modeling reveals plasmid-encoded genes are independently associated with Klebsiella infection

Abstract

Members of the Klebsiella pneumoniae species complex frequently colonize the gut and colonization is associated with subsequent infection. To identify genes associated with progression from colonization to infection, we undertook a case-control comparative genomics study. Concordant cases (N = 85), where colonizing and invasive isolates were identical strain types, were matched to asymptomatically colonizing controls (N = 160). Thirty-seven genes are associated with infection, 27 of which remain significant following adjustment for patient variables and bacterial phylogeny. Infection-associated genes are not previously characterized virulence factors, but instead a diverse group of stress resistance, regulatory and antibiotic resistance genes, despite careful adjustment for antibiotic exposure. Many genes are plasmid borne, and for some, the relationship with infection is mediated by gut dominance. Five genes were validated in a geographically-independent cohort of colonized patients. This study identifies several genes reproducibly associated with progression to infection in patients colonized by diverse Klebsiella.

The bacterial genetic determinants ofEscherichia colicapacity to cause bloodstream infections in humans

“…We found that strains from infections are more likely to be resistant to antimicrobials. What is the mechanism behind this association, also found in similar GWAS conducted on other pathogens (52, 53)? Confounding is a first possibility: hosts with co-morbidities are more likely to develop a BSI and to use antibiotics frequently.…”

“…This seems unlikely given their very specific function. Third, there might be a genetic association (linkage disequilibrium) between resistance genes and genetic determinants of infection (52, 54). In the third case, we expect the association to disappear when controlling for population structure.…”

“…The present study compares E. coli whole genomes in colonization and in infection, as done before for Klebsellia pneumoniae (52), S. pneumoniae (55), Staphylococcus aureus (53, 56), Neisseria meningitidi s (57). These GWAS studies presented a range of results, from low heritability (2.6% for S. aureus carriage vs. BSI (53)), to intermediate (36.5% for N. meningitidis carriage vs. invasive meningococcal disease), and an analogously large heritability of 70% for S. pneumoniae invasive disease vs. carriage, along with a handful of significant SNPs (55).…”

A Comprehensive Genomic Analysis of the Emergent Klebsiella pneumoniae ST16 Lineage: Virulence, Antimicrobial Resistance and a Comparison with the Clinically Relevant ST11 Strain

“…A similar scenario was observed for aminoglycosides, with numbers between 2003 and 2011 varying from two to six genes or variants, and between 2012 and 2021 increasing to 10-18. Thirty-one genes associated with this type of resistance were found, the most common being aac(6 )-Ib-cr5 encoding an aminoglycoside acetyltransferase that also has activity against fluoroquinolones [79,80]. The aac(3)-IVa (n = 10 genomes) and aph(4)-Ia (n = 10 genomes) were identified exclusively in the United States.…”

Ompk36 disruption and expression of down-regulated blaKPC-2 in Klebsiella pneumoniae clinical isolates carbapenem resistant

“…Klebsiella pneumoniae is an important opportunistic pathogen in the Enterobacterales order which causes infections related to healthcare (Munoz-Price et al, 2013). Its importance in the hospital environment is mainly due to the number of increasingly frequent outbreaks caused by this microorganism, due to the change in the susceptibility pattern to antimicrobials (Vornhagen et al, 2022).…”