Thoracic adipose tissue contributes to severe virus infection of the lung

Objective: Obesity is an independent risk factor for severe influenza and COVID-19. While proinflammatory adipose-derived factors are proposed as indirect contributors to infection severity, whether adipose tissue can directly serve as a viral niche remained unclear. Methods: Two murine obesity models (diet-induced obesity, DIO; and ob/ob leptin knockout) were intranasally infected with influenza A virus (IAV) and monitored for 3 weeks post infection. Lung and adipose tissues were harvested for viral load analyses. In vitro, human primary adipocytes and macrophages were infected with IAV, and adipocyte secretory effects during infection were assessed in transwell co-culture with lung fibroblasts. Thoracic adipose and lung tissues from deceased SARS-CoV-2 (omicron) patients were analyzed, and replication of SARS-CoV-2 alpha, delta, and omicron variants was tested in adipocytes and macrophages. Results: Both obesity models exhibited higher IAV titers than non-obese controls, and thoracic adipose tissue adjacent to lungs harbored IAV. Human adipocytes supported IAV replication and mounted antiviral responses; adipocyte–lung fibroblast co-culture increased IL-8 during infection. SARS-CoV-2 RNA and spike protein were detected in thoracic adipose tissue of COVID-19 decedents, yet human adipocytes did not support SARS-CoV-2 replication in vitro. SARS-CoV-2 was detected in macrophages and associated with increased inflammation. Conclusions: Thoracic adipose tissue contributes to respiratory virus infection. Beyond indirect proinflammatory effects, adipocytes and macrophages within thoracic adipose tissue can directly support viral replication (IAV), highlighting adipose tissue as a potential viral niche influencing disease severity.

Franziska Hornung, Luise Schulz, Nilay Köse-Vogel, Antje Häder, Jana Grießhammer, Daniel Wittschieber, Angelina Autsch, Christina Ehrhardt, Gita Mall, Bettina Löffler, Stefanie Deinhardt-Emmer