Project Summary
Klebsiella pneumoniae is one of the most common nosocomial pathogens and is typically associated with
urinary tract infections (UTIs), pneumonia, and septicemia. Two lineages of K. pneumoniae have emerged from
classical strains that challenge the successful treatment of these infections. One lineage includes hypervirulent
strains causing invasive community-acquired infections and the other encompasses carbapenem-resistant (CR)
isolates, primarily causing multi-drug resistant UTIs; the transfer of CR to hypervirulent strains is a real and
imminent threat as evidenced by the emergence of such strains in Asia. Infections caused by either lineage have
greater morbidity and mortality. Hypervirulent strains often exhibit a hypermucoviscous (hmv) phenotype evident
when bacterial colonies are pulled off a surface form a long, adherent string. Typically, hmv K. pneumoniae
expresses K1 or K2 capsule type and if capsule is ablated the strain becomes non-mucoid and avirulent. The
supposition that capsule and hypermucoidy are inextricably linked to hypervirulence is tenuous as UTI isolates
are often non-mucoid, encapsulated and infectious; moreover, some reports have identified strains that are
encapsulated but avirulent, non-encapsulated but hypermucoid, or hypervirulent but non-mucoid. These
observations identify a major gap in our understanding of the molecular mechanisms that control
hypermucoviscosity and how it influences K. pneumoniae pathogenesis. Preliminary data suggests that hmv
strains phenotypically switch to non-mucoid when grown in human urine, without loss of capsule. We have
capitalized on this groundbreaking phenotype to identify genes that, when disrupted, restore hmv in urine or
suppress hmv under standard culture conditions. This proposal will use these mutants as a tool to identify
capsule-independent mechanisms that control mucoidy and delineate how hmv distinctly influences K.
pneumoniae uropathogenesis versus invasive disease. We hypothesize that capsule and mucoidy are linked,
but non-synonymous, and that each distinctly influences K. pneumoniae via different infectious routes.
Experiments proposed in Aim 1 will investigate the roles of capsule and mucoidy during primary pneumonia and
dissemination, identifying capsule-dependent and -independent genes that control mucoidy and their individual
contribution to invasive infection. Studies in Aim 2 will evaluate the functional role of mucoidy and capsule during
UTI using a model hmv K. pneumoniae strain and two clinical UTI isolates. The successful execution of this
proposal will deepen our understanding of the cellular factors that drive mucoidy and capsule, and dissect their
contribution to invasive infections versus UTIs. The identification of these cellular factors may provide novel
targets for therapeutics and diagnostics, improving our ability to diagnose and treat the most challenging K.
pneumoniae infections.