ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

A history of obesity increases the severity of influenza and induces innate immune training (#257)

Ellesandra C Noye 1 , Katina D Hulme 1 , Nathalie A.J Verzele 1 , Marcus Z.W Tong 1 , David Burgner 2 3 4 , Larisa Labzin 5 6 , Kirsty R Short 1 6
  1. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia
  2. Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia
  3. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
  4. Department of Paediatrics, Monash University, Melbourne, Victoria, Australia
  5. Institute for Molecular Bioscience, Brisbane, Queensland, Australia
  6. Australian Infectious Diseases Research Centre, Brisbane, Queensland, Australia

INTRODUCTION: Obesity increases the severity of influenza. Whether this susceptibility is reversed with weight loss is unknown. Obesity can epigenetically ‘train’ the innate immune system in an NLRP3-dependent manner, such that it becomes hyper-responsive. This may result in an exacerbated pro-inflammatory response and increased influenza severity, despite a history of weight loss. METHODS: To understand the effect of weight loss on influenza severity, a murine model was established. Mice were given ad libitum access to either a high-fat or low-fat diet for 20-weeks, or they received 10 weeks of a high-fat diet followed by 10 weeks of a low-fat diet (previously obese, PO). After 10 weeks on low-fat diet, PO mice had equivalent body weight and percentage body fat to ‘lean’ mice that received low-fat diet only. RESULTS: When inoculated intranasally with influenza virus, PO mice displayed increased disease severity compared to lean mice. When repeated in NLRP3-deficient mice, obesity no longer had long-term effects on susceptibility to infection. To investigate if influenza severity in PO mice was associated with a ‘trained’ immune response, CD45+ (hematopoietic) lung cells, splenocytes and bone marrow were isolated from uninfected mice and stimulated ex vivo with viral mimetic R848. Following stimulation, CD45+ lung cells from obese and PO mice exhibited enhanced mRNA expression of TNF-α, and BM from obese and PO mice exhibited enhanced proinflammatory cytokine responses, relative to lean mice. PO mice also demonstrated significant alterations in BM progenitor populations relative to obese and lean mice. CONCLUSION: This study provides the first experimental evidence that obesity can have long-lasting effects on the innate immune response to viral infections, which may contribute to the severity of influenza in PO mice. Given the current obesity pandemic, understanding the effects of weight on the innate immune response is of significant importance to human health.