Burnham Institute
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MICROBIOLOGY
Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus
Bo-Jian Zheng*,{dagger},{ddagger}, Kwok-Wah Chan?, Yong-Ping Lin{dagger}, Guang-Yu Zhao{dagger}, Chris Chan{dagger}, Hao-Jie Zhang{dagger}, Hong-Lin Chen*,{dagger},{ddagger}, Samson S. Y. Wong*,{dagger},{ddagger}, Susanna K. P. Lau*,{dagger},{ddagger}, Patrick C. Y. Woo*,{dagger},{ddagger}, Kwok-Hung Chan*,{dagger},{ddagger}, Dong-Yan Jin?, and Kwok-Yung Yuen*,{dagger},{ddagger},||
*State Key Laboratory of Emerging Infectious Diseases, {dagger}Department of Microbiology, {ddagger}Research Centre of Infection and Immunology, and Departments of ?Pathology and ?Biochemistry, University of Hong Kong, Pok Fu Lam, Hong Kong
Edited by Tak Wah Mak, University of Toronto, Toronto, ON, Canada, and approved April 7, 2008 (received for review December 20, 2007)
Abstract
The mortality of human infection by influenza A/H5N1 virus can exceed 80%. The high mortality and its poor response to the neuraminidase inhibitor oseltamivir have been attributed to uncontrolled virus-induced cytokine storm. We challenged BALB/c mice with 1,000 LD50 of influenza A/Vietnam/1194/04. Survival, body weight, histopathology, inflammatory markers, viral loads, T lymphocyte counts, and neutralizing antibody response were documented in infected mice treated individually or in combination with zanamvir, celecoxib, gemfibrozil, and mesalazine. To imitate the real-life scenario, treatment was initiated at 48 h after viral challenge. There were significant improvements in survival rate (P = 0.02), survival time (P < 0.02), and inflammatory markers (P < 0.01) in the group treated with a triple combination of zanamivir, celecoxib, and mesalazine when compared with zanamivir alone. Zanamivir with or without immunomodulators reduced viral load to a similar extent. Insignificant prolongation of survival was observed when individual agents were used alone. Significantly higher levels of CD4+ and CD8+ T lymphocytes and less pulmonary inflammation were also found in the group receiving triple therapy. Zanamivir alone reduced viral load but not inflammation and mortality. The survival benefits of adding celecoxib and mesalazine to zanamivir could be caused by their synergistic effects in reducing cytokine dysfunction and preventing apoptosis.
Combinations of a neuraminidase inhibitor with these immunomodulators should be considered in randomized controlled treatment trials of patients suffering from H5N1 infection.
zanamivir | celecoxib | mesalazine
Footnotes
Author contributions: B.-J.Z. and K.-Y.Y. designed research; B.-J.Z., K.-W.C., Y.-P.L., G.-Y.Z., C.C., H.-J.Z., and H.-L.C. performed research; K.-W.C., S.S.Y.W., S.K.P.L., P.C.Y.W., K.-H.C., D.-Y.J., and K.-Y.Y. analyzed data; and B.-J.Z., S.S.Y.W., S.K.P.L., P.C.Y.W., and K.-Y.Y. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
http://www.pnas.org/cgi/content/abs...1&searchid=1&FIRSTINDEX=10&resourcetype=HWCIT
Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus
Bo-Jian Zheng*,{dagger},{ddagger}, Kwok-Wah Chan?, Yong-Ping Lin{dagger}, Guang-Yu Zhao{dagger}, Chris Chan{dagger}, Hao-Jie Zhang{dagger}, Hong-Lin Chen*,{dagger},{ddagger}, Samson S. Y. Wong*,{dagger},{ddagger}, Susanna K. P. Lau*,{dagger},{ddagger}, Patrick C. Y. Woo*,{dagger},{ddagger}, Kwok-Hung Chan*,{dagger},{ddagger}, Dong-Yan Jin?, and Kwok-Yung Yuen*,{dagger},{ddagger},||
*State Key Laboratory of Emerging Infectious Diseases, {dagger}Department of Microbiology, {ddagger}Research Centre of Infection and Immunology, and Departments of ?Pathology and ?Biochemistry, University of Hong Kong, Pok Fu Lam, Hong Kong
Edited by Tak Wah Mak, University of Toronto, Toronto, ON, Canada, and approved April 7, 2008 (received for review December 20, 2007)
Abstract
The mortality of human infection by influenza A/H5N1 virus can exceed 80%. The high mortality and its poor response to the neuraminidase inhibitor oseltamivir have been attributed to uncontrolled virus-induced cytokine storm. We challenged BALB/c mice with 1,000 LD50 of influenza A/Vietnam/1194/04. Survival, body weight, histopathology, inflammatory markers, viral loads, T lymphocyte counts, and neutralizing antibody response were documented in infected mice treated individually or in combination with zanamvir, celecoxib, gemfibrozil, and mesalazine. To imitate the real-life scenario, treatment was initiated at 48 h after viral challenge. There were significant improvements in survival rate (P = 0.02), survival time (P < 0.02), and inflammatory markers (P < 0.01) in the group treated with a triple combination of zanamivir, celecoxib, and mesalazine when compared with zanamivir alone. Zanamivir with or without immunomodulators reduced viral load to a similar extent. Insignificant prolongation of survival was observed when individual agents were used alone. Significantly higher levels of CD4+ and CD8+ T lymphocytes and less pulmonary inflammation were also found in the group receiving triple therapy. Zanamivir alone reduced viral load but not inflammation and mortality. The survival benefits of adding celecoxib and mesalazine to zanamivir could be caused by their synergistic effects in reducing cytokine dysfunction and preventing apoptosis.
Combinations of a neuraminidase inhibitor with these immunomodulators should be considered in randomized controlled treatment trials of patients suffering from H5N1 infection.
zanamivir | celecoxib | mesalazine
Footnotes
Author contributions: B.-J.Z. and K.-Y.Y. designed research; B.-J.Z., K.-W.C., Y.-P.L., G.-Y.Z., C.C., H.-J.Z., and H.-L.C. performed research; K.-W.C., S.S.Y.W., S.K.P.L., P.C.Y.W., K.-H.C., D.-Y.J., and K.-Y.Y. analyzed data; and B.-J.Z., S.S.Y.W., S.K.P.L., P.C.Y.W., and K.-Y.Y. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
http://www.pnas.org/cgi/content/abs...1&searchid=1&FIRSTINDEX=10&resourcetype=HWCIT