Biological Models of Influenza A Virus

Summary

Principal Investigator: Gilles Clermont
Abstract: The objectives of this proposal are to develop multiscale models of lung injury caused by either primary Influenza infection or secondary pneumonia, and identify from simulations optimal intervention strategies in non-trivial situations, such as highly virulent pathogens and sub-optimal immunization. This effort will include the development of reduced and more detailed models of the host-influenza interaction, the innate and adaptive immune response and pulmonary gas exchange under evolving lung injury. These models will be calibrated with prospective data from a series of experiment of mice infected with strains of Influenza of varying virulence, with or without immunization, and with or without antiviral pharmacotherapy. This group of interdisciplinary investigators has a track record of several years of developing theoretical and animal models of infection and inflammation, and of prior collaboration. When completed, this proposal will have accomplished three important scientific goals: (1) provide a solid biological basis for assumptions used in the design of individual and population-based containment strategies of highly virulent Influenza, (2) provide a foundation for further studies of multiscale whole organ models including mechanisms of organ failure and (3) provide quantitative methods to assess the uncertainty associated with model predictions when such models are calibrated from imperfect or sparse empirical data. The proposed activities will involve the training post-doctoral fellows, graduate and undergraduate students in an interdisciplinary environment strongly dedicated to scientific dissemination to clinicians, biologists and quantitative scientists. This proposal will confirm these investigators strong continued commitment to the training of women scientists, and will reach out to underrepresented minorities, particularly at the undergraduate level. This project will also enhance existing resources such as the XPP freeware, widely used by trainees and accomplished scientists, web accessible resource (models and software), and web based data repositories. It is the belief of this group of investigator that mathematical modeling and computation are essential tools in translating large streams of data in knowledge that will benefit patient care and societal preparedness to potentially catastrophic emerging infectious threats.
Funding Period: ----------------2007 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi A dynamical model of human immune response to influenza A virus infection
    Baris Hancioglu
    Department of Mathematics, 301 Thackeray, University of Pittsburgh, Pittsburgh, PA 15260, USA
    J Theor Biol 246:70-86. 2007
  2. pmc Immune history shapes specificity of pandemic H1N1 influenza antibody responses
    Yang Li
    Wistar Institute, Philadelphia, PA 19104, USA
    J Exp Med 210:1493-500. 2013
  3. ncbi Intranasal antibody gene transfer in mice and ferrets elicits broad protection against pandemic influenza
    Maria P Limberis
    Gene Therapy Program, University of Pennsylvania, Philadelphia, PA 19104, USA
    Sci Transl Med 5:187ra72. 2013
  4. pmc Sequential seasonal H1N1 influenza virus infections protect ferrets against novel 2009 H1N1 influenza virus
    Donald M Carter
    Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    J Virol 87:1400-10. 2013
  5. pmc Complex patterns of human antisera reactivity to novel 2009 H1N1 and historical H1N1 influenza strains
    Donald M Carter
    Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
    PLoS ONE 7:e39435. 2012
  6. pmc Influenza virus infection elicits protective antibodies and T cells specific for host cell antigens also expressed as tumor-associated antigens: a new view of cancer immunosurveillance
    Uzoma K Iheagwara
    Authors Affiliations Departments of Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania
    Cancer Immunol Res 2:263-73. 2014
  7. ncbi Adjuvants that stimulate TLR3 or NLPR3 pathways enhance the efficiency of influenza virus-like particle vaccines in aged mice
    Kirsten Schneider-Ohrum
    Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261, USA
    Vaccine 29:9081-92. 2011
  8. pmc A mathematical model of pulmonary gas exchange under inflammatory stress
    Angela Reynolds
    Department of Mathematics, 301 Thackeray, University of Pittsburgh, Pittsburgh, PA 15260, USA
    J Theor Biol 264:161-73. 2010
  9. pmc Influenza virus H1N1pdm09 infections in the young and old: evidence of greater antibody diversity and affinity for the hemagglutinin globular head domain (HA1 Domain) in the elderly than in young adults and children
    Nitin Verma
    Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA
    J Virol 86:5515-22. 2012
  10. pmc C3d adjuvant activity is reduced by altering residues involved in the electronegative binding of C3d to CR2
    Franklin R Toapanta
    University of Pittsburgh, School of Medicine, Center for Vaccine Research, 9047 Biomedical Science Tower 3, 3501 Fifth Avenue, Pittsburgh, PA 15261, USA
    Immunol Lett 129:32-8. 2010

Scientific Experts

  • Franklin R Toapanta
  • Rachel Brower-Sinning
  • Ted M Ross
  • Donald M Carter
  • Brendan M Giles
  • Uzoma K Iheagwara
  • Yang Li
  • Maria P Limberis
  • Joshua L Cherry
  • David J Lipman
  • Jodi K Craigo
  • Chalise E Bloom
  • Corey J Crevar
  • Nitin Verma
  • Dilhari R DeAlmeida
  • Kirsten Schneider-Ohrum
  • Angela Reynolds
  • Gilles Clermont
  • Baris Hancioglu
  • Jonathan S Minden
  • Pamela L Beatty
  • Phu T Van
  • Olivera J Finn
  • Susanna Esposito
  • Darwyn Kobasa
  • Jonathan Madara
  • Anna Tretiakova
  • Virginie S Adam
  • Nicola Principi
  • Ernesto T A Marques
  • Eduardo J M Nascimento
  • David L Bostick
  • Susanne L Linderman
  • Patrick C Wilson
  • Qin Liu
  • Colleen B Sullivan
  • Gary Wong
  • James M Wilson
  • Jaclyn L Myers
  • Jason Gren
  • Scott E Hensley
  • Gary P Kobinger
  • Rafi Ahmed
  • Joshua B Plotkin
  • Jens Wrammert
  • Hai Rong Lu
  • Clayton A Wiley
  • Milena Dimitrova
  • Stephanie J Bissel
  • Terrence M Tumpey
  • Hana Golding
  • Surender Khurana
  • Brianne L Williams
  • Heather K Weirback
  • G Bard Ermentrout
  • David Swigon

Detail Information

Publications14

  1. ncbi A dynamical model of human immune response to influenza A virus infection
    Baris Hancioglu
    Department of Mathematics, 301 Thackeray, University of Pittsburgh, Pittsburgh, PA 15260, USA
    J Theor Biol 246:70-86. 2007
    ..This behavior is robust to a wide range of parameter values. The absence of antibody response leads to recurrence of disease and appearance of a chronic state with nontrivial constant viral load...
  2. pmc Immune history shapes specificity of pandemic H1N1 influenza antibody responses
    Yang Li
    Wistar Institute, Philadelphia, PA 19104, USA
    J Exp Med 210:1493-500. 2013
    ..These data suggest that the specificity of pH1N1 antibody responses can be shifted to epitopes near the HA receptor-binding domain after sequential infections with sH1N1 and pH1N1 viruses that share homology in this region. ..
  3. ncbi Intranasal antibody gene transfer in mice and ferrets elicits broad protection against pandemic influenza
    Maria P Limberis
    Gene Therapy Program, University of Pennsylvania, Philadelphia, PA 19104, USA
    Sci Transl Med 5:187ra72. 2013
    ..This approach serves as a platform for the prevention of natural or deliberate respiratory diseases for which a protective antibody is available...
  4. pmc Sequential seasonal H1N1 influenza virus infections protect ferrets against novel 2009 H1N1 influenza virus
    Donald M Carter
    Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    J Virol 87:1400-10. 2013
    ..Exposure to multiple seasonal H1N1 influenza viruses, and not to any single H1N1 influenza virus, elicits a breadth of antibodies that neutralize novel H1N1 even though the host was never exposed to the novel H1N1 influenza viruses...
  5. pmc Complex patterns of human antisera reactivity to novel 2009 H1N1 and historical H1N1 influenza strains
    Donald M Carter
    Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
    PLoS ONE 7:e39435. 2012
    ..It was proposed that older people had pre-existing antibodies induced by previous 1918-like virus infection(s) that cross-reacted to novel H1N1 strains...
  6. pmc Influenza virus infection elicits protective antibodies and T cells specific for host cell antigens also expressed as tumor-associated antigens: a new view of cancer immunosurveillance
    Uzoma K Iheagwara
    Authors Affiliations Departments of Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania
    Cancer Immunol Res 2:263-73. 2014
    ..Finally, we show that immune responses generated through vaccination against peptides derived from these antigens correlated with improved tumor control...
  7. ncbi Adjuvants that stimulate TLR3 or NLPR3 pathways enhance the efficiency of influenza virus-like particle vaccines in aged mice
    Kirsten Schneider-Ohrum
    Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261, USA
    Vaccine 29:9081-92. 2011
    ..Influenza VLPs used in combination with two different inflammatory adjuvants during vaccination allow for the immune system to overcome the deficiency in the aged immune system to influenza virus infection...
  8. pmc A mathematical model of pulmonary gas exchange under inflammatory stress
    Angela Reynolds
    Department of Mathematics, 301 Thackeray, University of Pittsburgh, Pittsburgh, PA 15260, USA
    J Theor Biol 264:161-73. 2010
    ....
  9. pmc Influenza virus H1N1pdm09 infections in the young and old: evidence of greater antibody diversity and affinity for the hemagglutinin globular head domain (HA1 Domain) in the elderly than in young adults and children
    Nitin Verma
    Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA
    J Virol 86:5515-22. 2012
    ..These findings may help explain the age-related morbidity and mortality pattern observed during the H1N1pdm09 pandemic...
  10. pmc C3d adjuvant activity is reduced by altering residues involved in the electronegative binding of C3d to CR2
    Franklin R Toapanta
    University of Pittsburgh, School of Medicine, Center for Vaccine Research, 9047 Biomedical Science Tower 3, 3501 Fifth Avenue, Pittsburgh, PA 15261, USA
    Immunol Lett 129:32-8. 2010
    ..In summary, residues that alter the electronegative status of C3d (D163A and N170R) impair the binding of chimera proteins to CR2, reducing the adjuvant activity of this molecule...
  11. pmc Impaired immune responses in the lungs of aged mice following influenza infection
    Franklin R Toapanta
    Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA
    Respir Res 10:112. 2009
    ..Among the several factors that contribute to the increased susceptibility in elderly populations are the higher prevalence of chronic diseases (e.g. diabetes) and the senescence of the immune system...
  12. pmc The role of RNA folding free energy in the evolution of the polymerase genes of the influenza A virus
    Rachel Brower-Sinning
    Department of Computational Biology, School of Medicine, University of Pittsburgh, Fifth Avenue, Pittsburgh, PA 15260, USA
    Genome Biol 10:R18. 2009
    ..Current efforts to understand the host-specificity of the virus have largely focused on the amino acid differences between avian and human isolates...
  13. pmc Elicitation of anti-1918 influenza virus immunity early in life prevents morbidity and lower levels of lung infection by 2009 pandemic H1N1 influenza virus in aged mice
    Brendan M Giles
    Center for Vaccine Research, a Graduate Program in Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    J Virol 86:1500-13. 2012
    ..These findings show that immunity acquired early in life can restrict the anatomical location of influenza viral replication, rather than preventing infection, in the aged...