Seminar: "Ketogenic Diet Promotes Neutrophil- Mediated Clearance of Klebsiella pneumoniae" - Tania Wong

Department of Biochemistry and Microbiology Seminar

Tania Wong, Ph.D.
Assistant Professor & Chancellor Scholar
Dept. of Microbiology, Biochemistry & Molecular Genetics - Rutgers University

Antimicrobial-resistant and -susceptible strains of Klebsiella pneumoniae (Kp) are major causes of pneumonia and mortality in healthcare settings (1). A key immune evasion strategy employed by Kp is the subversion of host metabolism (2), especially the induction of mitochondrial oxidative phosphorylation (OXPHOS), which elevates reactive oxygen species (ROS). The resulting oxidant-rich airway milieu favors the accumulation of immunosuppressive myeloid cells, which fail to clear the bacteria. We hypothesized that enhancing OXPHOS efficiency through a ketogenic diet would promote effective airway immunity and bacterial clearance by supporting immune cell bioenergetics and effector function.
   
Using a murine pneumonia model, we found that mice fed a ketogenic diet exhibited significantly reduced bacterial burden and improved survival compared to controls. These mice displayed elevated ketone levels in both blood and airway, along with heightened numbers of neutrophils in the lungs by day 2 post-infection. Neutrophils from ketogenic diet-fed mice upregulated genes associated with degranulation, oxidative burst, and inositol trisphosphate synthesis, a key mediator of Ca2+ signaling. In vitro, exposure of neutrophils to physiological concentrations of ketone bodies enhanced intracellular Ca2+ flux and bacterial killing capacity. By day 7 post-infection, ketogenic diet-fed mice also exhibited increased numbers of B and T cells in the lungs. However, functional studies demonstrated that neutrophils, but not B/T cells, were essential for the ketogenic diet-mediated protection: depletion of neutrophils using anti-Ly6G antibodies abrogated the protection, whereas Rag1⁻/⁻ mice lacking B and T lymphocytes retained enhanced airway clearance of Kp when maintained on the diet. Notably, oral administration of ketone esters alone was sufficient to recapitulate the protective effects independently of dietary intervention. Together, our findings demonstrate that ketones enhance pulmonary host defense against Kp by promoting neutrophil bactericidal activity through metabolic reprogramming."