The main goal of the Holmes Lab is to understand the host-pathogen interactions that
underly K. pneumoniae infection in order to define mechanisms of pathogenesis that
fuel Gram-negative bacteremia and sepsis.
Bloodstream infections can initiate sepsis, a leading cause of global morbidity and
mortality relaying vast socioeconomic burdens. As such, it is critical to define host-
pathogen interactions that mediate effective clearance of bacteremia, the presence of
bacteria in the blood. About half of bacteremia cases are initiated by Gram-negative
pathogens, a number that will continue rising due to the antimicrobial resistance (AMR)
crisis. Klebsiella pneumoniae is the second leading cause of Gram-negative bacteremia
and a major cause of healthcare-associated infections. K. pneumoniae is consistently
classified as an urgent public health threat due to extensive AMR and inclusion within
the ESKAPE pathogens.
The pathogenesis of Gram-negative bacteremia involves three phases: 1) initial site
infection, 2) dissemination to the bloodstream, and 3) survival in blood filtering organs.
As K. pneumoniae is linked to pneumonia, the lung can serve as a common initial site
that seeds bacteremia. Previous work on K. pneumoniae fitness genes and immune
responses in the context of the lung and bloodstream have revealed that infection
virulence factors are tissue specific. This indicates that there is not a singular host-
pathogen interface but many sites and modes of interaction, each with varying
requirements for disease. Exploring K. pneumoniae interactions within the host across
tissues will reveal novel opportunities for preventing systemic infections and sepsis.
Research Interests
Major areas of interest for the Holmes lab include: 1) investigating mechanisms by
which K. pneumoniae evades stress elicited by the immune system, 2) defining how the
immune system successfully clears K. pneumoniae, and 3) characterizing the complex
nature of the onset and containment of bacteremia.
