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PLoS One. 2014 Sep 18;9(9):e107966. doi: 10.1371/journal.pone.0107966. eCollection 2014.

Avian influenza A H7N9 virus induces severe pneumonia in mice without prior adaptation and responds to a combination of zanamivir and COX-2 inhibitor.

Author information

1
Department of Microbiology, The University of Hong Kong, Hong Kong, China.
2
Department of Microbiology, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China.
3
Department of Medicine, The University of Hong Kong, Hong Kong, China.
4
Department of Microbiology, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China.
5
Department of Microbiology, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China; Zhejiang University, Hangzhou, China.
6
Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China.
7
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China; Zhejiang University, Hangzhou, China.

Abstract

BACKGROUND:

Human infection caused by the avian influenza A H7N9 virus has a case-fatality rate of over 30%. Systematic study of the pathogenesis of avian H7N9 isolate and effective therapeutic strategies are needed.

METHODS:

BALB/c mice were inoculated intranasally with an H7N9 virus isolated from a chicken in a wet market epidemiologically linked to a fatal human case, (A/chicken/Zhejiang/DTID-ZJU01/2013 [CK1]), and with an H7N9 virus isolated from a human (A/Anhui/01/2013 [AH1]). The pulmonary viral loads, cytokine/chemokine profiles and histopathological changes of the infected mice were compared. The therapeutic efficacy of a non-steroidal anti-inflammatory drug (NSAID), celecoxib, was assessed.

RESULTS:

Without prior adaptation, intranasal inoculation of 106 plaque forming units (PFUs) of CK1 caused a mortality rate of 82% (14/17) in mice. Viral nucleoprotein and RNA expression were limited to the respiratory system and no viral RNA could be detected from brain, liver and kidney tissues. CK1 caused heavy alveolar inflammatory exudation and pulmonary hemorrhage, associated with high pulmonary levels of proinflammatory cytokines. In the mouse lung cell line LA-4, CK1 also induced high levels of interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) mRNA. Administration of the antiviral zanamivir did not significantly improve survival in mice infected with CK1, but co-administration of the non-steroidal anti-inflammatory drug (NSAID) celecoxib in combination with zanamivir improved survival and lung pathology.

CONCLUSIONS:

Our findings suggested that H7N9 viruses isolated from chicken without preceding trans-species adaptation can cause lethal mammalian pulmonary infection. The severe proinflammatory responses might be a factor contributing to the mortality. Treatment with combination of antiviral and NSAID could ameliorate pulmonary inflammation and may improve survival.

PMID:
25232731
PMCID:
PMC4169509
DOI:
10.1371/journal.pone.0107966
[Indexed for MEDLINE]
Free PMC Article

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