Date of Graduation

Spring 2021

Degree

Master of Science in Biology

Department

Biology

Committee Chair

Christopher Lupfer

Keywords

influenza A virus, inflammation, inflammasome, pyruvate, NOD-like receptor (NLR), metabolite, immunometabolism

Subject Categories

Biochemical Phenomena, Metabolism, and Nutrition | Biological Factors | Immunity | Immunology of Infectious Disease | Immunoprophylaxis and Therapy | Immunotherapy | Medical Immunology | Pathogenic Microbiology | Respiratory Tract Diseases | Virology | Virus Diseases

Abstract

Pyruvate is produced in duplicate at the end of glycolysis in addition to ATP and NADH. Pyruvate is the metabolite of choice in most cells, whether obtained exogenously or endogenously. Recently we found that the addition of pyruvate’s conjugate base, sodium pyruvate, to cell culture media dampened the immune response to influenza A virus (IAV) infection in cultured innate immune cells. Thus, I decided to investigate the mechanism and potential for treatment of IAV. In vitro using bone marrow derived macrophages that were infected with IAV we found that adding sodium pyruvate to the media decreased immune signaling pathways through a decrease in pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α). Additionally, exogenous sodium pyruvate added to the infection media of macrophages, diminished the mitochondrial reactive oxygen species production, without inhibiting virus replication in vitro. To investigate the metabolite’s effects in vivo, we used C57Bl/6J mice to establish a model for sodium pyruvate treatment during IAV infection. We used a moderate infectious dose of IAV at 250PFU. We began by injecting the mice twice daily with diluted sodium pyruvate. While overall animal activity increased, no differences in proportional weight loss between saline controls and sodium pyruvate treated groups were observed. IAV is a respiratory virus and sodium pyruvate a metabolite of choice for cells; therefore, targeting the treatment to the respiratory tract with nebulizer treatments three times a day showed a significant difference (Days 7-14 post infection) in proportional weight loss. Sodium pyruvate treated mice were found to lose less mass, consume more chow, and feel better overall. Sodium pyruvate nebulized mice had decreased viral titer and decreased pro-inflammatory cytokines 7 days post-infection as well. Conclusively, sodium pyruvate ameliorates IAV infection in vitro and in vivo.

Copyright

© Jessica M. Reel

Open Access

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