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Context: 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 carbapenem resistant Enterobacterales.
Our main goal is to understand the host-pathogen interactions that underly K. pneumoniae infection in order to define mechanisms of pathogenesis that fuel Gram-negative bacteremia.
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Background: 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 (Holmes, 2021). As K. pneumoniae is linked to pneumonia, the lung can serve as an initial site that seeds bacteremia. Previous work on K. pneumoniae fitness genes and immune responses has revealed that these factors display tissue specificity (Holmes, 2023). Together, 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 with the host across tissues will reveal novel opportunities for preventing infection and sepsis.
K. pneumoniae (green) associated with macrophages (red).
Major Areas of Interest
Innate immunity and K. pneumoniae. Macrophages are required to control K. pneumoniae infection but the mechanisms used by these cells to elicit stress on K. pneumoniae is not fully understood, particularly in the context of systemic disease. We seek to understand how macrophages and innate immunity contribute to the control of systemic K. pneumoniae infection.
K. pneumoniae evasion of immune stress. The innate immune system elicits a robust inflammatory response to K. pneumoniae, yet the bacteria is effective at growing in multiple tissues during infection. We aim to define bacterial factors used by K. pneumoniae to evade stress responses elicited by the host.
Defining systemic disease. Bacteremia is a complex infection involving multiple tissues. We apply bacterial barcoding (Holmes, 2025) to trace K. pneumoniae throughout the stages of bacteremia in order to understand the host and bacterial factors that contribute to the onset and progression of disease.
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