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[Deleterious pathogenic mechanism involving host response in influenza virus infection in mice]
1Department of Microbiology, Kumamoto University School of Medicine.
Abstract:
In the influenza virus infected mice there is a host response which involves free radical generation particularly in the host lung. First, superoxide generation was elevated excessive extent, 200-600 fold in the alveolar lavage fluid (BALF), by induction of xanthine oxidase which becomes maximal at about 8 days after infection while virus yield becomes maximum on day 4. Mice start to die on day 9 although the virus in BALF is undetectable; thus virus disease in the absence of virus. Second, inducible form of nitric oxide synthetase is also triggered exactly in parallel to xanthine oxidase. This indicates NO and O2- is produced simultaneously implicating the formation of peroxynitrite (ONOO-) due to a rapid reaction between NO + O2-. Consequently nitration of lung tissue by ONOO- was demonstrated. ONOO- is also found much toxic than O2- or H2O2 in the cultured cells. Third, proteases are involved in various ways in this infection; activation of xanthine dehydrogenose to xanthine oxidase, activation of viral infectivity and triggering of bradykinin generation and inflammation by activating prekallikrein. Lastly, activation of matrix procollagenase (proMMP) by ONOO- and NO2, generated above, was suggested, which will damage connective tissue. Thus all events involving proteases will augment viral pathogenesis.
Insights
Influenza infection in mice triggers excessive free radical generation, leading to lung tissue damage and host death even after the virus is cleared. This host response, involving superoxide and nitric oxide, drives viral pathogenesis.
Area of Science:
- Immunology
- Pathology
- Biochemistry
Context:
- Influenza virus infection induces a significant host response in mice, particularly in the lungs.
- This response involves excessive free radical generation, with superoxide levels increasing 200-600 fold.
- Host mortality occurs after viral clearance, suggesting a non-viral mechanism of disease.
Purpose:
- To investigate the host response mechanisms contributing to influenza pathogenesis.
- To elucidate the role of free radicals, nitric oxide, and proteases in influenza-induced lung injury.
- To understand the formation and impact of peroxynitrite in influenza infection.
Summary:
- Superoxide generation, mediated by xanthine oxidase, peaks 8 days post-infection, coinciding with host death.
- Inducible nitric oxide synthase activation parallels xanthine oxidase, leading to simultaneous nitric oxide and superoxide production.
- This results in peroxynitrite formation, causing lung tissue nitration and cellular toxicity, implicating proteases in tissue damage and disease progression.
Impact:
- Demonstrates peroxynitrite's toxicity and its role in nitrating lung tissue during influenza.
- Highlights the involvement of proteases, including xanthine oxidase and matrix metalloproteinases, in augmenting viral pathogenesis.
- Provides insights into virus-independent mechanisms of host mortality following influenza infection.