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.
Kuiken
T
T
Institute of Virology, National Influenza Center, Erasmus Medical Center, Rotterdam, The Netherlands. t.kuiken@erasmusmc.nl.
Rimmelzwaan
G F
GF
Van Amerongen
G
G
Osterhaus
A D M E
AD
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