The immunological consequences of obesity on primary and secondary immune defenses to the 2009 pandemic H1N1 influenza virus

Milner, John Justin

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March 22, 2019

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Milner, John Justin
- Affiliation: Gillings School of Global Public Health, Department of Nutrition

Abstract

Obese individuals are more susceptible to hospitalization and death from infection with the 2009 pandemic H1N1 influenza virus (pH1N1). Greater pH1N1 severity in the obese is a global public health concern given the persistent threat of influenza outbreaks and the current obesity epidemic. In this dissertation, the consequences of obesity on pH1N1 immunity were investigated in mice to uncover mechanisms by which obesity enhances pH1N1 illness. During a primary pH1N1 infection, 80% of obese mice died compared with 40% of lean, low fat diet fed mice and no mortality in lean, chow fed mice. Further, a genetic model of obesity was generated in which leptin signaling was conditionally disrupted in hypothalamic neurons to confirm that obesity, independent of diet, enhances pH1N1 mortality. Both diet- and genetic-induced obese mice exhibited greater lung damage during infection, likely due to fewer lung regulatory T cells and impaired regulatory T cell function. We extended our analysis to include a secondary heterologous pH1N1 infection model. Obese mice had fewer cross-reactive, non-neutralizing pH1N1 antibodies, overactive CD8+ effector memory T cell responses and greater lung damage in this model. During the primary pH1N1 infection, obese mice had greater serum and bronchoalveolar lavage leptin concentrations compared with lean mice. Given that leptin regulates T cell function, we then determined if conditional disruption of leptin signaling in T cells ameliorates obesity-induced pH1N1 mortality. However, obese mice lacking leptin signaling in T cells were not protected from pH1N1 mortality compared with control, obese mice. The pathophysiological complications of obesity are diverse and complex. Therefore, we also extended our analysis to include 1H NMR-based metabolic profiling of urine, feces, serum, lungs, bronchoalveolar lavage fluid, mesenteric white adipose tissue, and livers to obtain a more comprehensive examination of infection responses in obese mice. We uncovered a number of metabolites and metabolic signatures uniquely altered in obese mice that, ultimately, may facilitate early prediction of influenza infection outcomes and help to identify mechanisms for impaired. In summary, novel immunologic and metabolic techniques were integrated in this dissertation to establish that obesity enhances greater lung damage during primary and secondary pH1N1 infections in mice.

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