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 (HS), a respiratory tract irritant and toxic gas, is ubiquitous in the environment. The interaction of environmental HS exposure and influenza is unknown. In this pilot study we tested the hypothesis that subchronic exposure to ambient HS 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 HS 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 HS alone suppressed growth. Mice challenged with IAV following exposure to 5 or 10 ppm HS 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 HS 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 HS and challenged with IAV compared to sham groups. Lung pathology was most severe in mice exposed to HS and challenged with IAV. Collectively, the study shows that mice subchronically exposed to low levels of HS overly reacted to a nonlethal dose of IAV, suffering severe lung injury and mortality. This suggests that communities and workers subchronically exposed to ambient HS concentrations used in this study or higher are at higher risk for developing very severe IAV infections and mortality.