Elevated body mass index is associated with delayed protective airway mucosal immune responses in mild SARS-CoV-2 infection.

BACKGROUND: SARS-CoV-2 viral load in the upper respiratory tract (URT) typically peaks and declines within days of infection, even in individuals without prior infection or vaccination. Although this implicates the URT innate immune response in effectively restricting viral replication, the nature of the protective responses and how they are affected by demographic factors is poorly defined. METHODS: We recruited 54 seronegative household contacts of recently diagnosed COVID-19 cases and prospectively collected URT samples during and after exposure. Among the 39 individuals who became infected, we quantified airway mucosal cytokine and chemokine responses and virus-specific nasal IgA using Meso Scale Discovery assays, and assessed associations with demographic factors, viral load, and symptoms. FINDINGS: Participants with higher BMI had higher URT viral loads and more marked symptoms. This was significantly associated with delayed induction of protective inflammatory mediators in the airway mucosa but not in blood. Induction of virus-specific nasal IgA at 1-week post-infection also correlated with lower viral load. INTERPRETATION: Elevated BMI retards initial airway mucosal innate immune responses to infection, which may partially explain the pronounced adverse impact of higher BMI on clinical and virological outcomes in COVID-19. FUNDING: This work is supported by the NIHR Health Protection Research Unit in Respiratory Infections, Imperial College London in partnership with the UK Health Security Agency (Grant number: NIHR200927; AL) and the Medical Research Council (Grant number: MR/X004058/1). Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre (BRC).