Influenza-Induced Priming and Leak of Human Lung Microvascular Endothelium upon Exposure to Staphylococcus aureus
Changsen Wang1, Susan M Armstrong1,2, Michael G Sugiyama1,3
11 Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.
Abstract:
A major cause of death after influenza virus infection is lung injury due to a bacterial superinfection, yet the mechanism is unknown. Death has been attributed to virus-induced immunosuppression and bacterial overgrowth, but this hypothesis is based on data from the preantibiotic era and animal models that omit antimicrobial therapy. Because of diagnostic uncertainty, most patients with influenza receive antibiotics, making bacterial overgrowth unlikely. Respiratory failure after superinfection presents as acute respiratory distress syndrome, a disorder characterized by lung microvascular leak and edema. The objective of this study was to determine whether the influenza virus sensitizes the lung endothelium to leak upon exposure to circulating bacterial-derived molecular patterns from Staphylococcus aureus. In vitro as well as in vivo models of influenza followed by S. aureus superinfection were used. Molecular mechanisms were explored using molecular biology, knockout mice, and human autopsy specimens. Influenza virus infection sensitized human lung endothelium to leak when challenged with S. aureus, even at low doses of influenza and even when the pathogens were given days apart. Influenza virus increased endothelial expression of TNFR1 both in vitro and in intact lungs, a finding corroborated by human autopsy specimens of patients with influenza. Leak was recapitulated with protein A, a TNFR1 ligand, and sequential infection caused protein A-dependent loss of IκB, cleavage of caspases 8 and 3, and lung endothelial apoptosis. Mice infected sequentially with influenza virus and S. aureus developed significantly increased lung edema that was protein A and TNFR1 dependent. Influenza virus primes the lung endothelium to leak, predisposing patients to acute respiratory distress syndrome upon exposure to S. aureus.
Insights
Influenza virus primes lung endothelium to leak, increasing susceptibility to bacterial superinfections like Staphylococcus aureus. This mechanism contributes to acute respiratory distress syndrome (ARDS) and lung injury following influenza.
Area of Science:
- Pulmonary Medicine
- Infectious Diseases
- Critical Care Medicine
Background:
- Bacterial superinfections post-influenza are a major cause of mortality, often leading to lung injury.
- The precise mechanisms underlying influenza-induced susceptibility to bacterial superinfections remain largely unknown.
- Traditional hypotheses of virus-induced immunosuppression and bacterial overgrowth are challenged by modern antimicrobial use.
Purpose of the Study:
- To investigate if influenza virus sensitizes lung endothelium to bacterial-derived molecular patterns.
- To elucidate the molecular mechanisms by which influenza virus exacerbates bacterial superinfection-induced lung injury.
- To determine the role of tumor necrosis factor receptor 1 (TNFR1) in influenza-associated endothelial dysfunction.
Main Methods:
- Utilized in vitro and in vivo models of sequential influenza and Staphylococcus aureus infections.
- Employed molecular biology techniques, knockout mice, and analysis of human autopsy specimens.
- Investigated endothelial expression of TNFR1 and downstream signaling pathways.
Main Results:
- Influenza virus infection sensitized human lung endothelium to leak upon challenge with S. aureus, even with low viral doses and delayed bacterial exposure.
- Influenza virus increased endothelial TNFR1 expression in vitro, in intact lungs, and in human autopsy samples.
- Sequential infection led to protein A- and TNFR1-dependent loss of IκB, caspase cleavage, endothelial apoptosis, and increased lung edema in mice.
Conclusions:
- Influenza virus primes the lung endothelium, making it hyper-responsive to bacterial stimuli like Staphylococcus aureus.
- This priming mechanism, involving TNFR1 and protein A, predisposes individuals to acute respiratory distress syndrome (ARDS) following influenza.
- Understanding this pathway offers potential targets for mitigating severe lung injury after influenza infection.
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