Influenza Virus A/Anhui/1/2013 (H7N9) Replicates Efficiently in the Upper and Lower Respiratory Tracts of Cynomolgus Macaques

Abstract

In March 2013, three fatal human cases of infection with influenza A virus (H7N9) were reported in China. Since then, human cases have been accumulating. Given the public health importance of this virus, we performed a pathogenicity study of the H7N9 virus in the cynomolgus macaque model, focusing on clinical aspects of disease, radiographic, histological, and gene expression profile changes in the upper and lower respiratory tracts, and changes in systemic cytokine and chemokine profiles during infection. Cynomolgus macaques developed transient, mild to severe disease with radiographic evidence of pulmonary infiltration. Virus replicated in the upper as well as lower respiratory tract, with sustained replication in the upper respiratory tract until the end of the experiment at 6 days after inoculation. Virus shedding occurred mainly via the throat. Histopathological changes in the lungs were similar to those observed in humans, albeit less severe, with diffuse alveolar damage, infiltration of polymorphonuclear cells, formation of hyaline membranes, pneumocyte hyperplasia, and fibroproliferative changes. Analysis of gene expression profiles in lung lesions identified pathways involved in tissue damage during H7N9 infection as well as leads for development of therapeutics targeting host responses rather than virus replication. Overall, H7N9 infection was not as severe in cynomolgus macaques as in humans, supporting the possible role of underlying medical complications in disease severity as discussed for human H7N9 infection (H. N. Gao et al., N. Engl. J. Med. 368:2277–2285, 2013, doi:10.1056/NEJMoa1305584).

Emergence of H7N9 Influenza A Virus Resistant to Neuraminidase Inhibitors in Nonhuman Primates

“…H7N9 subtype influenza A virus isolated from a human in 2013 caused viral pneumonia in cynomolgus macaques in the present study that was comparable to pneumonia reported previously in humans and other mammals (3,4,39). These results indicate that the H7N9 virus propagates sufficiently to induce respiratory symptoms in nonhuman primates and humans, although the virus has not obtained characteristics of sustained transmission among humans.…”

“…In addition, we used the same inoculation routes and virus dose of Anhui/1 as those used with other virus strains in previous studies to compare the pathogenicities of the viruses and the efficacies of vaccines and treatments (17,23,27). As a result, the pathogenicity of H7N9 influenza virus isolated in humans seems to be lower than that of H5N1 highly pathogenic avian influenza virus in primates and humans under an immunocompetent condition (4,17,39,60). Although the H7N9 vaccine in the present study conferred sufficient protective immunity to prevent severe viral pneumonia with virus inoculation through the trachea, we need to pay attention to the emergence and containment of resistant viruses during treatment with NA inhibitors even in immunocompetent patients, as confirmed in the present study using healthy macaques.…”

Gene expression signatures as a therapeutic target for severe H7N9 influenza – what do we know so far?

“…Strikingly, this gene expression signature also occurs in the whole lung response to the infamous 1918 H1N1 virus, indicating that it may predict pathogenicity across different strains [15]. Experiments in cynomolgus macaques confirmed the validity of the pathways and molecules identified in the H7N9 mouse model [16].…”

“…Gene expression profiles from H7N9-infected cells and tissues can be utilized to computationally identify small molecules and FDAapproved drugs that reverse the host gene expression patterns that may drive H7N9 pathogenesis. We have characterized the transcriptional response to H7N9 infection in human airway epithelial cells, BALB/c mice and cynomolgus macaques to identify host transcriptional signatures that distinguish H7N9 from other IAVs and are predictive of influenza pathogenicity across a range of influenza serotypes and strains [14][15][16]. Our host-directed approach to drug discovery has also identified drugs that could potentially be used to treat severe influenza caused by H7N9 and other pathogenic IAVs.…”

The use of nonhuman primates in research on seasonal, pandemic and avian influenza, 1893–2014

“…In the most recent report to employ chest radiography to evaluate the extent of pulmonary disease, cynomolgus macaques were exposed to the avian H7N9 virus (De Wit et al, 2014). Interstitial infiltrates were detected in the lungs beginning on day 2 postexposure, and became diffuse by day 6 in most animals.…”