One health: Subchronic exposure to low ambient hydrogen sulfide increases mortality of influenza A virus infection in mice

The environment plays an important role in modulating susceptibility and severity of respiratory tract infections. Influenza is a significant zoonotic disease globally. Hydrogen sulfide (H₂S), a respiratory tract irritant and toxic gas, is ubiquitous in the environment. The interaction of environmental H₂S exposure and influenza is unknown. In this pilot study we tested the hypothesis that subchronic exposure to ambient H₂S worsens the outcome of influenza A virus (IAV) infection in mice. Male C57BL6 mice were exposed either to room air (RA), or to 5 or 10 ppm H₂S for 2 h, 5 days a week for 5 weeks, followed by a single exposure either to phosphate buffered saline (sham) or a sublethal IAV intranasal dose of 10 plaque-forming units and observed for up to 28 days post inoculation (DPI). 10 ppm H₂S alone suppressed growth. Mice challenged with IAV following exposure to 5 or 10 ppm H₂S were most severely affected and euthanized on DPI 6 to 7 or DPI 4, respectively. In contrast, mice exposed to RA and challenged with IAV only showed minor weight loss. Viral titer in lung homogenates was 11-fold higher in mice pre-exposed to 5 ppm H₂S and challenged with IAV compared to the RA-IAV group on DPI 3. BALF concentrations of TNF-α, IL-6, and IL-10 cytokines were significantly higher in mice exposed to H₂S and challenged with IAV compared to sham groups. Lung pathology was most severe in mice exposed to H₂S and challenged with IAV. Collectively, the study shows that mice subchronically exposed to low levels of H₂S overly reacted to a nonlethal dose of IAV, suffering severe lung injury and mortality. This suggests that communities and workers subchronically exposed to ambient H₂S concentrations used in this study or higher are at higher risk for developing very severe IAV infections and mortality.