Dynamics of Influenza Virus Infection and Pathology

ABSTRACT A key question in pandemic influenza is the relative roles of innate immunity and target cell depletion in limiting primary infection and modulating pathology. Here, we model these interactions using detailed data from equine influenza virus infection, combining viral and immune (type I interferon) kinetics with estimates of cell depletion. The resulting dynamics indicate a powerful role for innate immunity in controlling the rapid peak in virus shedding. As a corollary, cells are much less depleted than suggested by a model of human influenza based only on virus-shedding data. We then explore how differences in the influence of viral proteins on interferon kinetics can account for the observed spectrum of virus shedding, immune response, and influenza pathology. In particular, induction of high levels of interferon (“cytokine storms”), coupled with evasion of its effects, could lead to severe pathology, as hypothesized for some fatal cases of influenza.

[1]  Yi Guan,et al.  Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia , 2006, Nature Medicine.

[2]  J. Crapo,et al.  Allometric relationships of cell numbers and size in the mammalian lung. , 1992, American journal of respiratory cell and molecular biology.

[3]  R. Webster,et al.  Lethal H5N1 influenza viruses escape host anti-viral cytokine responses , 2002, Nature Medicine.

[4]  T. Taniguchi,et al.  Distinct and Essential Roles of Transcription Factors IRF-3 and IRF-7 in Response to Viruses for IFN-α/β Gene Induction , 2000 .

[5]  C. Basler,et al.  Progress in identifying virulence determinants of the 1918 H1N1 and the Southeast Asian H5N1 influenza A viruses. , 2008, Antiviral research.

[6]  Yi Guan,et al.  Avian Influenza Virus (H5N1): a Threat to Human Health , 2007, Clinical Microbiology Reviews.

[7]  Ann Cullinane,et al.  Pro-inflammatory and antiviral cytokine expression in vaccinated and unvaccinated horses exposed to equine influenza virus. , 2007, Vaccine.

[8]  J. Mumford,et al.  Experimental infection of ponies with equine influenza (H3N8) viruses by intranasal inoculation or exposure to aerosols. , 1990, Equine veterinary journal.

[9]  A. García-Sastre,et al.  Attenuation of Equine Influenza Viruses through Truncations of the NS1 Protein , 2005, Journal of Virology.

[10]  N. Dimmock,et al.  Insights into neutralization of animal viruses gained from study of influenza virus , 1991, Epidemiology and Infection.

[11]  B. G. Hale,et al.  The multifunctional NS1 protein of influenza A viruses. , 2008, The Journal of general virology.

[12]  C. Cockram,et al.  A Man with Labile Blood Pressure , 2007, PLoS medicine.

[13]  S. Goodbourn,et al.  Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. , 2008, The Journal of general virology.

[14]  Andreas Handel,et al.  Towards a quantitative understanding of the within-host dynamics of influenza A infections , 2010, Journal of The Royal Society Interface.

[15]  Gavin J. D. Smith,et al.  Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic , 2009, Nature.

[16]  R. Webby,et al.  Mutations in the NS1 Protein of Swine Influenza Virus Impair Anti-Interferon Activity and Confer Attenuation in Pigs , 2005, Journal of Virology.

[17]  M. Katze,et al.  Global Host Immune Response: Pathogenesis and Transcriptional Profiling of Type A Influenza Viruses Expressing the Hemagglutinin and Neuraminidase Genes from the 1918 Pandemic Virus , 2004, Journal of Virology.

[18]  A. McMichael,et al.  The immunology of influenza. , 1985, British medical bulletin.

[19]  S. Goodbourn,et al.  NS1 Proteins of Avian Influenza A Viruses Can Act as Antagonists of the Human Alpha/Beta Interferon Response , 2006, Journal of Virology.

[20]  J. Peiris,et al.  Re-emergence of fatal human influenza A subtype H5N1 disease , 2004, The Lancet.

[21]  W. Doyle,et al.  Evidence for cytokine mediation of disease expression in adults experimentally infected with influenza A virus. , 1999, The Journal of infectious diseases.

[22]  Gilles Clermont,et al.  A Dynamical Model of Human Immune Response to Influenza a Virus Infection , 2006 .

[23]  P. Yates,et al.  Experimental infection of ponies with equine influenza A2 (H3N8) virus strains of different pathogenicity elicits varying interferon and interleukin-6 responses. , 2003, Viral immunology.

[24]  Roger E Bumgarner,et al.  Cellular transcriptional profiling in influenza A virus-infected lung epithelial cells: The role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Daly,et al.  Investigation of equine influenza cases exhibiting neurological disease: coincidence or association? , 2006, Journal of comparative pathology.

[26]  J. Taubenberger,et al.  The pathology of influenza virus infections. , 2008, Annual review of pathology.

[27]  I. Clark,et al.  The advent of the cytokine storm , 2007, Immunology and cell biology.

[28]  G. Kochs,et al.  Multiple Anti-Interferon Actions of the Influenza A Virus NS1 Protein , 2007, Journal of Virology.

[29]  A. Perelson,et al.  Kinetics of Influenza A Virus Infection in Humans , 2006, Journal of Virology.

[30]  F. Dianzani,et al.  Tissue culture models of in vivo interferon production and action. , 1978, Advances in experimental medicine and biology.

[31]  A. Perelson,et al.  Simulation and Prediction of the Adaptive Immune Response to Influenza A Virus Infection , 2009, Journal of Virology.

[32]  K. Melén,et al.  Inflammatory responses in influenza A virus infection. , 2000, Vaccine.

[33]  Michelle M. Packard,et al.  Histopathologic and immunohistochemical features of fatal influenza virus infection in children during the 2003-2004 season. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[34]  G. Ada,et al.  The immune response to influenza infection. , 1986, Current topics in microbiology and immunology.

[35]  J. Sedmak,et al.  Interferon bioassay: reduction in yield of myxovirus neuraminidases. , 1973, The Journal of general virology.

[36]  A. Fernández-Sesma.  The influenza virus NS1 protein: inhibitor of innate and adaptive immunity. , 2007, Infectious disorders drug targets.

[37]  Andreas Handel,et al.  Neuraminidase Inhibitor Resistance in Influenza: Assessing the Danger of Its Generation and Spread , 2007, PLoS Comput. Biol..

[38]  Y. Guan,et al.  Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? , 2002, The Lancet.

[39]  A H Rowberg,et al.  Influenza virus population dynamics in the respiratory tract of experimentally infected mice , 1976, Infection and immunity.

[40]  M. Peruggia.  Model Selection and Multimodel Inference: A Practical Information-Theoretic Approach (2nd ed.) , 2003 .

[41]  John Samuel,et al.  A simple cellular automaton model for influenza A viral infections. , 2004, Journal of theoretical biology.

[42]  D. Levy,et al.  Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. , 1998, Virology.

[43]  Hidekazu Nishimura,et al.  Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus , 2004, Nature.

[44]  J. Dai,et al.  Plasmacytoid dendritic cells and type I IFN: 50 years of convergent history. , 2008, Cytokine & growth factor reviews.

[45]  A S Perelson,et al.  Modeling plasma virus concentration during primary HIV infection. , 2000, Journal of theoretical biology.

[46]  S. Goodbourn,et al.  Variation in the ability of human influenza A viruses to induce and inhibit the IFN-beta pathway. , 2006, Virology.

[47]  B. Levin,et al.  Antiviral Resistance and the Control of Pandemic Influenza , 2007, PLoS medicine.

[48]  G. Bocharov,et al.  Mathematical model of antiviral immune response. III. Influenza A virus infection. , 1994, Journal of theoretical biology.

[49]  David R. Anderson,et al.  Model selection and multimodel inference : a practical information-theoretic approach , 2003 .