Immunomodulatory Strategies for the Prevention of Nosocomial Infection
Fensterheim, Benjamin Ari
The growing incidence of nosocomial infection with antibiotic-resistant organisms requires novel approaches to decrease their incidence and severity. Predicting the infection risk of an individual host and restoring host immune function are two attractive strategies. Using in vivo and in vitro murine models of immune function and infection, I determined that the magnitude of the cytokine response to lipopolysaccharide does not predict the host response to infection. Moreover, I uncovered that the clinically available toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) induces broad and persistent resistance to nosocomial pathogens such as Staphylococcus aureus. This resistance arises through a sustained metabolic program in macrophages that supports improved pathogen clearance. MPLA initiates this program via mTOR activation, which spurs persistent glycolysis, mitochondrial biogenesis, increased malate shuttling, and increased ATP production. The enhanced energetic state supports augmented phagocytosis and constitutive monocyte/macrophage-targeted chemokine secretion, while pro-inflammatory cytokine and neutrophil-targeted chemokine secretion is suppressed. Rapamycin, which inhibited the development of the metabolic and functional phenotype, blocked MPLA-induced resistance to infection. This work reveals that TLR4-induced metabolic reprogramming evolves to support the temporal goals of macrophages, and support the use of MPLA as an agent to facilitate broad-spectrum resistance to infection in vulnerable patients.