Background
Severe respiratory viral infections can lead to viral sepsis (VS), a life-threatening condition characterized by lung and extrapulmonary organ dysfunction. However, the pathology of VS is not clear. Specifically, it is unknown how the cytokine storm and direct virus infection contribute to the damage of extrapulmonary organs.
Methods
In this study, we established survival and lethal mouse models of VS by intranasally administering different doses of PR8/H1N1 influenza virus in C57BL/6J male mice, as well as model of bacterial sepsis (BS) caused by Streptococcus pneumoniae as references. Viraemia and extrapulmonary dissemination and infection of the virus were examined. Single-cell sequencing of the lungs and livers was performed at different days post-infection (dpi) in three groups.
Findings
While bacteria can spread and colonize extensively in extrapulmonary organs, causing multiple organ injuries, IAVs mainly replicate and cause damage in pulmonary cells. Live virus can be isolated in the blood and extrapulmonary organs. Disseminating via the bloodstream, IAVs transiently infect the liver and spleen, causing liver dysfunction and spleen atrophy, without affecting kidney function, despite systematically elevated cytokine levels. Compared to BS, a more significant decrease in the proportion of alveolar macrophages, epithelial cells, endothelial cells, and fibroblasts in the lungs, as well as endothelial cells and Kupffer cells in the liver, was observed in VS. This was accompanied by a longer activated PANoptosis pathway and downregulated genes responsible for barrier function and antigen presentation in the epithelial and endothelial cells.
Interpretation
Our study suggests that H1N1 influenza virus disseminates through the bloodstream and infects extrapulmonary organs to varying extents, which may lead to differential cell death, organ dysfunction, and trigger VS.