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Extrapulmonary tissue responses in cynomolgus macaques (Macaca fascicularis) infected with highly pathogenic avian
A-E Tolnay1, C R Baskin, T M Tumpey
1Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
Abstract:
The mechanisms responsible for virulence of influenza viruses in humans remain poorly understood. A prevailing hypothesis is that the highly pathogenic virus isolates cause a severe cytokinemia precipitating acute respiratory distress syndrome and multiple organ dysfunction syndrome. Cynomolgus macaques (Macaca fascicularis) infected with a human highly pathogenic avian influenza (HPAI) H5N1 virus isolate (A/Vietnam/1203/2004) or reassortants of human influenza virus A/Texas/36/91 (H1N1) containing genes from the 1918 pandemic influenza A (H1N1) virus developed severe pneumonia within 24 h postinfection. However, virus spread beyond the lungs was only detected in the H5N1 group, and signs of extrapulmonary tissue reactions, including microglia activation and sustained up-regulation of inflammatory markers, most notably hypoxia inducible factor-1alpha (HIF-1alpha), were largely limited to this group. Extrapulmonary pathology may thus contribute to the morbidities induced by H5N1 viruses.
Insights
Highly pathogenic avian influenza (HPAI) H5N1 virus causes severe pneumonia and extrapulmonary inflammation in macaques. This suggests that spread beyond the lungs contributes to H5N1 virus severity.
Area of Science:
- Virology
- Pathology
- Immunology
Background:
- Influenza virus virulence mechanisms in humans are not fully understood.
- A hypothesis suggests severe cytokinemia leading to acute respiratory distress syndrome and multiple organ dysfunction syndrome.
- Highly pathogenic influenza virus isolates are implicated in severe human disease.
Purpose of the Study:
- To investigate the mechanisms of virulence in highly pathogenic influenza viruses.
- To compare the pathological effects of HPAI H5N1 and reassortant H1N1 influenza viruses in cynomolgus macaques.
- To determine the role of extrapulmonary pathology in influenza virus-induced morbidity.
Main Methods:
- Infection of cynomolgus macaques with HPAI H5N1 virus (A/Vietnam/1203/2004) or reassortant H1N1 influenza viruses.
- Assessment of pneumonia development within 24 hours postinfection.
- Detection of virus spread beyond the lungs and extrapulmonary tissue reactions, including microglia activation and inflammatory marker up-regulation (e.g., hypoxia inducible factor-1alpha).
Main Results:
- Both H5N1 and reassortant H1N1 viruses caused severe pneumonia in macaques.
- Virus spread beyond the lungs was detected only in the H5N1 infection group.
- Extrapulmonary pathology, including microglia activation and sustained hypoxia inducible factor-1alpha up-regulation, was primarily observed in the H5N1 group.
Conclusions:
- Extrapulmonary spread and pathology may be key factors contributing to the severe morbidity caused by H5N1 influenza viruses.
- Understanding these extrapulmonary effects is crucial for addressing H5N1 pathogenesis.
- Further research into H5N1 extrapulmonary pathology is warranted.
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