Pathology of human influenza A (H5N1) virus infection in cynomolgus macaques (Macaca fascicularis).
Infection with influenza A (H5N1) virus, which has not been associated with respiratory disease in humans previously, caused clinical signs of acute respiratory distress syndrome and multiple-organ dysfunction syndrome with high mortality in humans in Hong Kong in 1997. To study the pathogenesis of this disease, we infected four cynomolgus monkeys (Macaca fascicularis) with 2.5 x 104 median tissue culture infectious dose (TCID50) of influenza virus A/Hong Kong/156/97 (H5N1) and euthanatized them 4 or 7 days after infection. The main lesion was a necrotizing broncho-interstitial pneumonia (4/4) similar to those found in primary influenza virus pneumonia in humans, with desquamation of respiratory epithelium (4/4), intra-alveolar hemorrhage (4/4), hyaline membrane formation (2/4), and infiltration with neutrophils and macrophages (4/4). Lesions in other organs consisted of a suppurative tonsillitis (2/4) and necrosis in lymphoid organs (1/4), kidney (1/4), and liver (1/4). By immunohistochemistry, influenza virus antigen was limited to pulmonary tissue (4/4) and tonsils (2/4). Based on these results, we suggest that the cynomolgus monkey is a suitable animal model for studying the pathogenesis of human H5N1 virus infection and that multiple-organ dysfunction syndrome in this disease may be caused by diffuse alveolar damage from virus replication in the lungs alone.
Institute of Virology, National Influenza Center, Erasmus Medical Center, Rotterdam, The Netherlands. t.kuiken@erasmusmc.nl.
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Kuiken
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Rimmelzwaan
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Van Amerongen
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Osterhaus
D000818:Animals; D000956:Antigens, Viral / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000662:veterinary; D053124:Influenza A Virus, H5N1 Subtype; D009980:Influenza A virus / Q000254:growth & development*; D007251:Influenza, Human / Q000473:pathology* / Q000662:veterinary* / Q000821:virology; D008168:Lung / Q000473:pathology / Q000821:virology; D008252:Macaca fascicularis; D008297:Male; D008992:Monkey Diseases / Q000473:pathology* / Q000821:virology*; D014066:Palatine Tonsil / Q000473:pathology / Q000821:virology
D000956:Antigens, Viral