Pathogenesis of influenza A (H5N1) virus infection in a primate model

Abstract

Cynomolgus macaques (Macaca fascicularis) infected with influenza virus A/Hong Kong/156/97 (H5N1) developed acute respiratory distress syndrome and fever associated with a necrotizing interstitial pneumonia. Reverse transcription PCR, virus isolation, and immunohistochemistry showed that the respiratory tract is the major target of the virus.

FIG. 1

Recordings of body temperatures (lines) and respiratory rates (bars) of cynomolgus macaques upon intratracheal infection with 2.5 × 10⁴ TCID₅₀ of influenza virus A/HK/156/97. Body temperatures were recorded by telemetry using a transponder which was brought in 30 days prior to the infection. Respiratory rates were monitored by observing the animals without disturbing them.

FIG. 2

Infectious virus titers in the indicated organs obtained from monkeys no. 1 (hatched bars) and no. 2 (black bars) 4 days p.i. The results are expressed as TCID₅₀ per gram of organ tissue.

FIG. 3

Demonstration by immunohistochemistry of virus-infected cells in the respiratory tract of monkey no. 1 4 days after intratracheal infection with 2.5 × 10⁴ TCID₅₀ of influenza virus A/HK/156/97. Specifically stained cells have a dark brown granular precipitate in the nucleus and cytoplasm. Hematoxylin counterstain was used. Original magnification, ×100. (A) Lung with bronchointerstitial pneumonia. The alveolar lumina are not apparent due to flooding with inflammatory cells. There is specific staining for influenza virus nucleoprotein of alveolar macrophages (black arrowhead) and small mononuclear cells (white arrowhead), while most neutrophils (black arrow) do not show specific staining. (B) Bronchus. There is specific staining for influenza virus nucleoprotein in bronchial epithelial cells.