TY - JOUR
T1 - A pharmacologically immunosuppressed mouse model for assessing influenza B virus pathogenicity and oseltamivir treatment
AU - Marathe, Bindumadhav M.
AU - Mostafa, Heba H.
AU - Vogel, Peter
AU - Pascua, Philippe Noriel Q.
AU - Jones, Jeremy C.
AU - Russell, Charles J.
AU - Webby, Richard J.
AU - Govorkova, Elena A.
N1 - Funding Information:
This work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health , Centers of Excellence for Influenza Research and Surveillance ( CEIRS ), contract no. HHSN272201400006C , and by ALSAC. We thank Keith A. Laycock for excellent editing of the manuscript and the staff of the Hartwell Center for Bioinformatics and Biotechnology for their help with the Sanger sequencing. The NAI oseltamivir phosphate was provided by Roche Innovation Centre (Basel, Switzerland ) .
Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/12
Y1 - 2017/12
N2 - Immunocompromised patients are highly susceptible to influenza virus infections. Although neuraminidase inhibitor (NAI) therapy has proved effective in these patients, the treatment regimens require optimization, which can be partly addressed via animal models. Here, we describe a pharmacologically immunosuppressed mouse model for studying the pathogenesis of influenza B viruses and evaluating the efficacy of antiviral treatment. We modeled clinical regimens for dexamethasone and cyclophosphamide to immunosuppress BALB/c mice that were then inoculated with B/Phuket/3073/2013 (Yamagata lineage) or B/Brisbane/60/2008 (BR/08, Victoria lineage) virus. Although both viruses caused morbidity and mortality in immunosuppressed mice, BR/08 was more virulent, consistently inducing greater morbidity and 100% lethality in mice inoculated with at least 103 TCID50/mouse. The replication of both viruses was prolonged in the lungs of immunosuppressed mice, but the extent of pulmonary inflammation in these mice was markedly less than that in immunocompetent animals. Most of the examined cytokines, including IFN-γ, IL-1β, and RANTES, were significantly decreased in the lungs of immunosuppressed mice, as compared to immunocompetent animals, until at least 10 days post-infection. Treatment with the NAI oseltamivir for 8 or 16 days increased the mean survival time and reduced virus spread in the lungs of immunosuppressed mice challenged with a lethal dose of BR/08 but did not completely provide protection or decrease the virus titers. Our data suggests that the synergy of the viral load and aberrant immune responses is a key contributor to the severity of infection, as well as the limited efficacy of oseltamivir, which in immunosuppressed mice curtails virus release without clearing infected cells.
AB - Immunocompromised patients are highly susceptible to influenza virus infections. Although neuraminidase inhibitor (NAI) therapy has proved effective in these patients, the treatment regimens require optimization, which can be partly addressed via animal models. Here, we describe a pharmacologically immunosuppressed mouse model for studying the pathogenesis of influenza B viruses and evaluating the efficacy of antiviral treatment. We modeled clinical regimens for dexamethasone and cyclophosphamide to immunosuppress BALB/c mice that were then inoculated with B/Phuket/3073/2013 (Yamagata lineage) or B/Brisbane/60/2008 (BR/08, Victoria lineage) virus. Although both viruses caused morbidity and mortality in immunosuppressed mice, BR/08 was more virulent, consistently inducing greater morbidity and 100% lethality in mice inoculated with at least 103 TCID50/mouse. The replication of both viruses was prolonged in the lungs of immunosuppressed mice, but the extent of pulmonary inflammation in these mice was markedly less than that in immunocompetent animals. Most of the examined cytokines, including IFN-γ, IL-1β, and RANTES, were significantly decreased in the lungs of immunosuppressed mice, as compared to immunocompetent animals, until at least 10 days post-infection. Treatment with the NAI oseltamivir for 8 or 16 days increased the mean survival time and reduced virus spread in the lungs of immunosuppressed mice challenged with a lethal dose of BR/08 but did not completely provide protection or decrease the virus titers. Our data suggests that the synergy of the viral load and aberrant immune responses is a key contributor to the severity of infection, as well as the limited efficacy of oseltamivir, which in immunosuppressed mice curtails virus release without clearing infected cells.
KW - Antiviral treatment
KW - Immune responses
KW - Immunosuppressed mice
KW - Influenza B virus
KW - Oseltamivir
KW - Pathogenesis
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U2 - 10.1016/j.antiviral.2017.10.021
DO - 10.1016/j.antiviral.2017.10.021
M3 - Article
C2 - 29100887
AN - SCOPUS:85032733499
SN - 0166-3542
VL - 148
SP - 20
EP - 31
JO - Antiviral Research
JF - Antiviral Research
ER -