Influenza A virus dissemination and infection leads to tissue resident cell injury and dysfunction in viral sepsis.

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.

FUNDING

This research was supported by the National Natural Science Foundation of China (82241056, 82170015, 82030002, 82470007, 824B2001), the National Key R&D Program of China (2023YFC2306300), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-048), the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202208), New Cornerstone Science Foundation, National High Level Hospital Clinical Research Funding (2024-NHLHCRF-LX-01-0101, 2024-NHLHCRF-LX-01-0102), Beijing Research Ward Excellence Program (BRWEP2024W114060103), Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0506200, 2023ZD0506203) and Special Research Fund for Central Universities, Peking Union Medical College (3332024193).