Modeling influenza virus infection: A roadmap for influenza research

Viruses

Volumn 7, Issue 10, 2015, Pages 5274-5304

  Boianelli, Alessandro ^a   Nguyen, Van Kinh ^a   Ebensen, Thomas ^a   Schulze, Kai ^a   Wilk, Esther ^a   Sharma, Niharika ^a   Stegemann Koniszewski, Sabine ^a   Bruder, Dunja ^a,b   Toapanta, Franklin R ^c   Guzmán, Carlos A ^a   Meyer Hermann, Michael ^a,d   Hernandez Vargas, Esteban A ^a  

^a HELMHOLTZ CENTRE FOR INFECTION RESEARCH   (Germany)

^b OTTO VON GUERICKE UNIVERSITY   (Germany)

^c University of Maryland School of Medicine Center for Vaccine Development   (United States)

^d TECHNICAL UNIVERSITY OF BRAUNSCHWEIG   (Germany)

Author keywords

Aging; Coinfection; Host genetic factors; Influenza; Mathematical models; Parameters estimation; Vaccinology

Indexed keywords

ALPHA INTERFERON; GAMMA INTERFERON; INTERFERON; TUMOR NECROSIS FACTOR ALPHA; VIRUS RNA;

BACTERIAL INFECTION; HEREDITY; HUMAN; IMMUNE RESPONSE; INFLUENZA; INFLUENZA A VIRUS; MATHEMATICAL MODEL; MORBIDITY; MORTALITY; NATURAL KILLER CELL; NONHUMAN; REVIEW; STREPTOCOCCUS PNEUMONIAE; VACCINATION; VIROGENESIS; VIRUS LOAD; ADAPTIVE IMMUNITY; ANIMAL; COMPLICATION; DISEASE MODEL; GROWTH, DEVELOPMENT AND AGING; HOST PATHOGEN INTERACTION; IMMUNOLOGY; MICROBIOLOGY; MIXED INFECTION; ORTHOMYXOVIRIDAE; PATHOLOGY; STREPTOCOCCUS PNEUMONIA; THEORETICAL MODEL; VIROLOGY;

ADAPTIVE IMMUNITY; ANIMALS; COINFECTION; DISEASE MODELS, ANIMAL; HOST-PATHOGEN INTERACTIONS; HUMANS; INFLUENZA, HUMAN; MODELS, THEORETICAL; ORTHOMYXOVIRIDAE; PNEUMONIA, PNEUMOCOCCAL;

EID: 84944055938     PISSN: None     EISSN: 19994915     Source Type: Journal    
DOI: 10.3390/v7102875     Document Type: Review

References (172)

1. World Health Organization (WHO). Influenza (Seasonal) Factsheet N 211; WHO: Geneva, Switzerland, 2009
2. Lang, P.O.; Mendes, A.; Socquet, J.; Assir, N.; Govind, S.; Aspinall, R. Effectiveness of influenza vaccine in aging and older adults: Comprehensive analysis of the evidence. Clin. Interv. Aging 2012, 7, 55–64
3. Potter, C.W. A history of influenza. J. Appl. Microbiol. 2001, 91, 572–579
4. Kilbourne, E.D. Influenza pandemics of the 20th century. Emerg. Infect. Dis. 2006, 12, 9–14
5. World Health Organization (WHO). Influenza (Seasonal): Fact Sheet N_211; WHO: Geneva, Switzerland, 2014
6. Carrat, F.; Flahault, A. Influenza vaccine: The challenge of antigenic drift. Vaccine 2007, 25, 6852–6862
7. Hensley, S.E. Challenges of selecting seasonal influenza vaccine strains for humans with diverse pre-exposure histories. Curr. Opin. Virol. 2014, 8, 85–89
8. Madhi, S.A.; Cutland, C.L.; Kuwanda, L.; Weinberg, A.; Hugo, A.; Jones, S.; Adrian, P.V.; van Niekerk, N.; Treurnicht, F.; Ortiz, J.R., et al. Influenza Vaccination of PregnantWomen and Protection of Their Infants. Obstet. Gynecol. Survey 2015, 70, 3–5
9. Beauchemin, C.A.A.; Handel, A. A review of mathematical models of influenza A infections within a host or cell culture: Lessons learned and challenges ahead. BMC Public Health 2011, 11, S7, doi:10.1186/1471-2458-11-S1-S7
10. Smith, A.M.; Perelson, A.S. Influenza A virus infection kinetics: Quantitative data and models. Syst. Biol. Med. 2011, 3, 429–445
11. Dobrovolny, H.M.; Reddy, M.B.; Kamal, M.A.; Rayner, C.R.; Beauchemin, C.A. Assessing Mathematical Models of Influenza Infections Using Features of the Immune Response. PLoS ONE 2013, 8, e57088
12. De Wit, E.; Rasmussen, A.L.; Feldmann, F.; Bushmaker, T.; Martellaro, C.; Haddock, E.; Okumura, A.; Proll, S.C.; Chang, J.; Gardner, D., et al. Influenza virus A/Anhui/1/2013 (H7N9) replicates efficiently in the upper and lower respiratory tracts of cynomolgus macaques. mBio 2014, 5, e01331-14
13. Welliver, T.P.; Garofalo, R.P.; Hosakote, Y.; Hintz, K.H.; Avendano, L.; Sanchez, K.; Velozo, L.; Jafri, H.; Chavez-Bueno, S.; Ogra, P.L., et al. Severe Human Lower Respiratory Tract Illness Caused by Respiratory Syncytial Virus and Influenza Virus Is Characterized by the Absence of Pulmonary Cytotoxic Lymphocyte Responses. J. Infect. Dis. 2007, 195, 1126–1136
14. Van Riel, D.; Munster, V.J.; de Wit, E.; Rimmelzwaan, G.F.; Fouchier, R.A.M.; Osterhaus, A.D.M.E.; Kuiken, T. H5N1 Virus Attachment to Lower Respiratory Tract. Science 2006, 312, 399
15. Reeth, K.V. Cytokines in the pathogenesis of influenza. Vet. Microbiol. 2000, 74, 109–116
16. Valkenburg, S.A.; Rutigliano, J.A.; Ellebedy, A.H.; Doherty, P.C.; Thomas, P.G.; Kedzierska, K. Immunity to seasonal and pandemic influenza A viruses. Microbes Infect. 2011, 13, 489–501
17. Lindsley, W.G.; Noti, J.D.; Blachere, F.M.; Thewlis, R.E.; Martin, S.B.; Othumpangat, S.; Noorbakhsh, B.; Goldsmith, W.T.; Vishnu, A.; Palmer, J.E., et al. Viable Influenza A Virus in Airborne Particles from Human Coughs. J. Occup. Environ. Hyg. 2015, 12, 107–113
18. Oldstone, M.B.A.; Compans, R.W. Influenza Pathogenesis and Control; Current Topics in Microbiology and Immunology 386; Springer International Publishing: Berlin, Germany, 2015
19. Oguin, T.H.; Sharma, S.; Stuart, A.D.; Duan, S.; Scott, S.A.; Jones, C.K.; Daniels, J.S.; Lindsley, C.W.; Thomas, P.G.; Brown, H.A. Phospholipase D facilitates efficient entry of influenza virus, allowing escape from innate immune inhibition. J. Biol. Chem. 2014, 289, 25405–25417
20. White, D.O.; Cheyne, I.M. Early events in the eclipse phase of influenza and parainfluenza virus infection. Virology 1966, 29, 49–59
21. Pinilla, L.T.; Holder, B.P.; Abed, Y.; Boivin, G.; Beauchemin, C.A.A. The H275Y neuraminidase mutation of the pandemic A/H1N1 influenza virus lengthens the eclipse phase and reduces viral output of infected cells, potentially compromising fitness in ferrets. J. Virol. 2012, 86, 10651–10660
22. Horsfall, F.L. On the reproduction of influenza virus quantitative studies with procedures which enumerate infective and hemagglutinating virus particles. J. Exp. Med. 1954, 100, 135–161
23. Banatvala, J.E.; Griffiths, P.; Schoub, B.; Mortimer, P. Principles and Practice of Clinical Virology; Wiley: Hoboken, NJ, USA, 2009
24. Tamura, S.I.; Kurata, T. Defense mechanisms against influenza virus infection in the respiratory tract mucosa. Jpn. J. Infect. Dis. 2004, 57, 236–247
25. Miao, H.; Hollenbaugh, J.A.; Zand, M.S.; Holden-Wiltse, J.; Mosmann, T.R.; Perelson, A.S.; Wu, H.; Topham, D.J. Quantifying the early immune response and adaptive immune response kinetics in mice infected with influenza A virus. J. Virol. 2010, 84, 6687–6698
26. Baccam, P.; Beauchemin, C.A.A.; Macken, C.A.A.; Hayden, F.G.; Perelson, A.S. Kinetics of influenza A virus infection in humans. J. Virol. 2006, 80, 7590–7599
27. Larson, E.W.; Dominik, J.W.; Rowberg, A.H.; Higbee, G.A. Influenza virus population dynamics in the respiratory tract of experimentally infected mice. Infect. Immun. 1976, 13, 438–447
28. Nowak, M.A.; May, R. Virus Dynamics: Mathematical Principles of Immunology and Virology; Oxford University Press: Oxford, UK, 2000; Volume 291, pp. 1–256
29. Perelson, A.S. Modelling viral and immune system dynamics. Nat. Rev. Immunol. 2002, 2, 28–36
30. Ribeiro, R.M.; Lo, A.; Perelson, A.S. Dynamics of hepatitis B virus infection. Microbes Infect. 2002, 4, 829–835
31. Beauchemin, C.A.A.; McSharry, J.J.; Drusano, G.L.; Nguyen, J.T.; Went, G.T.; Ribeiro, R.M.; Perelson, A.S. Modeling amantadine treatment of influenza A virus in vitro. J. Theor. Biol. 2008, 254, 439–451
32. Holder, B.P.; Beauchemin, C.A.A. Exploring the effect of biological delays in kinetic models of influenza within a host or cell culture. BMC Public Health 2011, 11, S10, doi:10.1186/1471-2458-11-S1-S10
33. Handel, A.; Longini, I.M., Jr.; Antia, R. Neuraminidase inhibitor resistance in influenza: Assessing the danger of its generation and spread. PLoS Comput. Biol. 2007, 3, e240, doi:10.1371/journal.pcbi.0030240
34. Dobrovolny, H.M.; Gieschke, R.; Davies, B.E.; Jumbe, N.L.; Beauchemin, C.A.A. Neuraminidase inhibitors for treatment of human and avian strain influenza: A comparative modeling study. J. Theor. Biol. 2011, 269, 234–244
35. Dobrovolny, H.M.; Baron, M.J.; Gieschke, R.; Davies, B.E.; Jumbe, N.L.; Beauchemin, C.A.A. Exploring cell tropism as a possible contributor to influenza infection severity. PLoS ONE 2010, 5, e13811–e13826
36. Petrie, S.M.; Guarnaccia, T.; Laurie, K.L.; Hurt, A.C.; McVernon, J.; McCaw, J.M. Reducing Uncertainty in Within-Host Parameter Estimates of Influenza Infection by Measuring Both Infectious and Total Viral Load. PLoS ONE 2013, 8, e64098
37. Doherty, P.C.; Turner, S.J.; Webby, R.G.; Thomas, P.G. Influenza and the challenge for immunology. Nat. Immunol. 2006, 7, 449–455
38. Bocharov, G.; Romanyukha, A. Mathematical model of antiviral immune response III. Influenza A virus infection. J. Theor. Biol. 1994, 167, 323–360
39. Hancioglu, B.; Swigon, D.; Clermont, G. A dynamical model of human immune response to influenza A virus infection. J. Theor. Biol. 2007, 246, 70–86
40. Pawelek, K.A.; Huynh, G.T.; Quinlivan, M.; Cullinane, A.; Rong, L.; Perelson, A.S. Modeling within-host dynamics of influenza virus infection including immune responses. PLoS Comput. Biol. 2012, 8, e1002588
41. Saenz, R.A.; Quinlivan, M.; Elton, D.; Macrae, S.; Blunden, A.S.; Mumford, J.A.; Daly, J.M.; Digard, P.; Cullinane, A.; Grenfell, B.T., et al. Dynamics of influenza virus infection and pathology. J. Virol. 2010, 84, 3974–3983
42. Hernandez-Vargas, E.A.; Wilk, E.; Canini, L.; Toapanta, F.R.; Binder, S.C.; Uvarovskii, A.; Ross, T.M. ; Guzmán, C.A.; Perelson, A.S.; Meyer-Hermann, M. Effects of aging on influenza virus infection dynamics. J. Virol. 2014, 88, 4123–4131
43. Cao, P.; Yan, A.W.; Heffernan, J.M.; Petrie, S.; Moss, R.G.; Carolan, L.A.; Guarnaccia, T.A.; Kelso, A.; Barr, I.G.; McVernon, J., et al. Innate Immunity and the Inter-exposure Interval Determine the Dynamics of Secondary Influenza Virus Infection and Explain Observed Viral Hierarchies. PLoS Comput. Biol. 2015, 11, e1004334
44. Laurie, K.L.; Guarnaccia, T.A.; Carolan, L.A.; Yan, A.W.; Aban, M.; Petrie, S.; Cao, P.; Heffernan, J.M.; McVernon, J.; Mosse, J., et al. The time-interval between infections and viral hierarchies are determinants of viral interference following influenza virus infection in a ferret model. J. Infect. Dis. 2015, doi:10.1093/infdis/jiv260
45. Canini, L.; Carrat, F. Population modeling of influenza A/H1N1 virus kinetics and symptom dynamics. J. Virol. 2011, 85, 2764–2770
46. Hernandez-Vargas, E.A.; Meyer-Hermann, M. Innate immune system dynamics to influenza virus. In Proceedings of the 8th IFAC Symposium on Biological and Medical Systems, Budapest, Hungary, 29–31 August 2012; Volume 8, pp. 1–6
47. Handel, A.; Longini, I.M.; Antia, R. Towards a quantitative understanding of the within-host dynamics of influenza A infections. J. Royal Soc. Interface Royal Soc. 2010, 7, 35–47
48. Antia, R.; Bergstrom, C.T.; Pilyugin, S.S.; Kaech, S.M.; Ahmed, R. Models of CD8+ responses: 1. What is the antigen-independent proliferation program. J. Theor. Biol. 2003, 221, 585–598
49. Handel, A.; Antia, R. A simple mathematical model helps to explain the immunodominance of CD8 T cells in influenza A virus infections. J. Virol. 2008, 82, 7768–7772
50. Le, D.; Miller, J.D.; Ganusov, V.V. Mathematical modeling provides kinetic details of the human immune response to vaccination. Front. Cell. Infect. Microbiol. 2014, 4, doi:10.3389/fcimb.2014.00177
51. Price, I.; Mochan-Keef, E.D.; Swigon, D.; Ermentrout, G.B.; Lukens, S.; Toapanta, F.R.; Ross, T.M.; Clermont, G. The inflammatory response to influenza A virus (H1N1): An experimental and mathematical study. J. Theor. Biol. 2015, 374, 83–93
52. Lee, H.Y.; Topham, D.J.; Park, S.Y.; Hollenbaugh, J.; Treanor, J.; Mosmann, T.R.; Jin, X.; Ward, B.M.; Miao, H.; Holden-Wiltse, J., et al. Simulation and prediction of the adaptive immune response to influenza A virus infection. J. Virol. 2009, 83, 7151–7165
53. De Boor, C. A Practical Guide to Splines, revised Ed.; Applied Mathematical Sciences; Springer: Berlin, Germany, 2001; Volume 27
54. Tridane, A.; Kuang, Y. Modeling the interaction of cytotoxic T lymphocytes and influenza virus infected epithelial cells. Math. Biosci. Eng. 2010, 7, 171–185
55. Moehler, L.; Flockerzi, D.; Sann, H.; Reichl, U. Mathematical model of influenza A virus production in large-scale microcarrier culture. Biotechnol. Bioeng. 2005, 90, 46–58
56. Schulze-Horsel, J.; Schulze, M.; Agalaridis, G.; Genzel, Y.; Reichl, U. Infection dynamics and virus-induced apoptosis in cell culture-based influenza vaccine production Flow cytometry and mathematical modeling. Vaccine 2009, 27, 2712–2722
57. Holder, B.P.; Simon, P.; Liao, L.E.; Abed, Y.; Bouhy, X.; Beauchemin, C.A.A.; Boivin, G. Assessing the in vitro fitness of an oseltamivir-resistant seasonal A/H1N1 influenza strain using a mathematical model. PLoS ONE 2011, 6, e14767
58. Paradis, E.G.; Pinilla, L.T.; Holder, B.P.; Abed, Y.; Boivin, G.; Beauchemin, C.A.A. Impact of the H275Y and I223V Mutations in the Neuraminidase of the 2009 Pandemic Influenza Virus in Vitro and Evaluating Experimental Reproducibility. PLoS ONE 2015, 10, e0126115
59. Reperant, L.A.; Kuiken, T.; Osterhaus, A.D. Adaptive pathways of zoonotic influenza viruses: From exposure to establishment in humans. Vaccine 2012, 30, 4419–4434
60. Chen, S.; You, S.; Liu, C.; Chio, C.; Liao, C. Using experimental human influenza infections to validate a viral dynamic model and the implications for prediction. Epidemiol. Infect. 2012, 140, 1557–1568
61. Heldt, F.S.; Frensing, T.; Pflugmacher, A.; Gröpler, R.; Peschel, B.; Reichl, U. Multiscale modeling of influenza A virus infection supports the development of direct-acting antivirals. PLoS Comput. Biol. 2013, 9, e1003372
62. Mitchell, H.; Levin, D.; Forrest, S.; Beauchemin, C.A.A.; Tipper, J.; Knight, J.; Donart, N.; Layton, R.C.; Pyles, J.; Gao, P., et al. Higher level of replication efficiency of 2009 (H1N1) pandemic influenza virus than those of seasonal and avian strains: Kinetics from epithelial cell culture and computational modeling. J. Virol. 2011, 85, 1125–1135
63. Reperant, L.A.; Kuiken, T.; Grenfell, B.T.; Osterhaus, A.D. The immune response and within-host emergence of pandemic influenza virus. Lancet 2014, 384, 2077–2081
64. Smith, A.M.; Adler, F.R.; Ribeiro, R.M.; Gutenkunst, R.N.; McAuley, J.L.; McCullers, J.A.; Perelson, A.S. Kinetics of coinfection with influenza A virus and Streptococcus pneumoniae. PLoS Pathog. 2013, 9, e1003238
65. Burnham, K.P.; Anderson, D.R. Multimodel inference understanding AIC and BIC in model selection. Sociol. Methods Res. 2004, 33, 261–304
66. Li, P.; Vu, Q.D. Identification of parameter correlations for parameter estimation in dynamic biological models. BMC Syst. Biol. 2013, 7, 91, doi:10.1186/1752-0509-7-91
67. Xia, X.; Moog, C. Identifiability of nonlinear systems with application to HIV/AIDS models. IEEE Trans. Autom. Control 2003, 48, 330–336
68. Miao, H.; Xia, X.; Perelson, A.S.; Wu, H. On Identifiability of Nonlinear Ode Models and Applications in Viral Dynamics. SIAM Rev. Soc. Ind. Appl. Math. 2011, 53, 3–39
69. Chis, O.T.; Banga, J.R.; Balsa-Canto, E. Structural identifiability of systems biology models: A critical comparison of methods. PLoS ONE 2011, 6, e27755
70. Brun, R.; Reichert, P.; Kuensch, H.R. Practical identifiability analysis of large environmental simulation models. Water Resour. Res. 2001, 37, 1015–1030
71. Prill, R.J.; Marbach, D.; Saez-Rodriguez, J.; Sorger, P.K.; Alexopoulos, L.G.; Xue, X.; Clarke, N.D.; Altan-Bonnet, G.; Stolovitzky, G. Towards a rigorous assessment of systems biology models: The DREAM3 challenges. PLoS ONE 2010, 5, e9202
72. Raue, A.; Kreutz, C.; Maiwald, T.; Bachmann, J.; Schilling, M.; Klingmüller, U.; Timmer, J. Structural and practical identifiability analysis of partially observed dynamical models by exploiting the profile likelihood. Bioinform. (Oxf. Engl.) 2009, 25, 1923–1929
73. Efron, B.; Tibshirani, R.J. An Introduction to the Bootstrap; CRC Press: Boca Raton, FL, USA, 1994
74. Nguyen, V.K.; Binder, S.C.; Boianelli, A.; Meyer-Hermann, M.; Hernandez-Vargas, E.A. Ebola Virus Infection Modelling and Identifiability Problems. Front. Microbiol. 2015, 6, doi:10.3389/fmicb.2015.00257
75. Ma, S.; Kosorok, M.R. Robust semiparametric M-estimation and the weighted bootstrap. J. Multivar. Anal. 2005, 96, 190–217
76. Xue, H.; Miao, H.; Wu, H. Sieve estimation of constant and time-varying coefficients in nonlinear ordinary differential equation models by considering both numerical error and measurement error. Ann. Stat. 2010, 38, 2351–2387
77. Vinod, H.D. Maximum Entropy Bootstrap Algorithm Enhancements. Available at SSRN 2285041 2013
78. Lesaffre, E.; Lawson, A.B. Bayesian Biostatistics; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2012
79. Raue, A.; Kreutz, C.; Joachim Theis, F.; Timmer, J. Joining forces of Bayesian and frequentist methodology: A study for inference in the presence of non-identifiability. Philos. Trans. Ser. A 2013, 371, doi:10.1098/rsta.2011.0544
80. Chou, I.C.; Voit, E.O. Recent developments in parameter estimation and structure identification of biochemical and genomic systems. Math. Biosci. 2009, 219, 57–83
81. Toapanta, F.R.; Ross, T.M. Impaired immune responses in the lungs of aged mice following influenza infection. Respir. Res. 2009, 10, 112–131
82. McDonagh, M.; Bell, E. The survival and turnover of mature and immature CD8 T cells. Immunology 1995, 84, 514–520
83. Smith, A.M.; Adler, F.R.; McAuley, J.L.; Gutenkunst, R.N.; Ribeiro, R.M.; McCullers, J.A.; Perelson, A.S. Effect of 1918 PB1-F2 expression on influenza A virus infection kinetics. PLoS Comput. Biol. 2011, 7, e1001081
84. Storn, R.; Price, K. Differential evolution—A simple and efficient heuristic for global optimization over continuous spaces. J. Global Optim. 1997, 11, 341–359
85. Murillo, L.N.; Murillo, M.S.; Perelson, A.S. Towards multiscale modeling of influenza infection. J. Theor. Biol. 2013, 332, 267–290
86. Morens, D.M.; Taubenberger, J.K.; Fauci, A.S. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: Implications for pandemic influenza preparedness. J. Infect. Dis. 2008, 198, 962–970
87. McCullers, J.A. Insights into the interaction between influenza virus and pneumococcus. Clin. Microbiol. Rev. 2006, 19, 571–582
88. Louie, J.; Jean, C.; Chen, T.; Park, S.; Ueki, R.; Harper, T.; Chmara, E.; Myers, J.; Stoppacher, R.; Catanese, C., et al. Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1)-United States, May-August 2009. Morb. Mortal. Wkly. Rep. 2009, 58, 1071–1074
89. Chertow, D.S.; Memoli, M.J. Bacterial coinfection in influenza: A grand rounds review. JAMA 2013, 309, 275–282
90. Louria, D.B.; Blumenfeld, H.L.; Ellis, J.T.; Kilbourne, E.D.; Rogers, D.E. Studies on influenza in the pandemic of 1957-1958. II. Pulmonary complications of influenza. J. Clin. Investig. 1959, 38, 213–265
91. Martin, C.M.; Kunin, C.M.; Gottlieb, L.S.; Barnes, M.W.; Liu, C.; Finland, M. Asian Influenza A in Boston. 1957–1958: I. Observations in Thirty-Two Influenza-Associated Fatal Cases. AMA Arch. Intern. Med. 1959, 103, 515–531
92. McCullers, J.A. The co-pathogenesis of influenza viruses with bacteria in the lung. Nat. Rev. Microbiol. 2014, 12, 252–262
93. Robinson, K.M.; Kolls, J.K.; Alcorn, J.F. The immunology of influenza virus-associated bacterial pneumonia. Curr. Opin. Immunol. 2015, 34, 59–67
94. Didierlaurent, A.; Goulding, J.; Patel, S.; Snelgrove, R.; Low, L.; Bebien, M.; Lawrence, T.; van Rijt, L.S.; Lambrecht, B.N.; Sirard, J.C., et al. Sustained desensitization to bacterial Toll-like receptor ligands after resolutionof respiratory influenza infection. J. Exp. Med. 2008, 205, 323–329
95. Sun, K.; Metzger, D.W. Inhibition of pulmonary antibacterial defense by interferon- during recovery from influenza infection. Nat. Med. 2008, 14, 558–564
96. Stegemann-Koniszewski, S.; Gereke, M.; Orrskog, S.; Lienenklaus, S.; Pasche, B.; Bader, S.R.; Gruber, A.D.; Akira, S.; Weiss, S.; Henriques-Normark, B., et al. TLR7 contributes to the rapid progression but not to the overall fatal outcome of secondary pneumococcal disease following influenza A virus infection. J. Innate Immun. 2013, 5, 84–96
97. McNamee, L.A.; Harmsen, A.G. Both influenza-induced neutrophil dysfunction and neutrophil-independent mechanisms contribute to increased susceptibility to a secondary Streptococcus pneumoniae infection. Infect. Immun. 2006, 74, 6707–6721
98. Small, C.L.; Shaler, C.R.; McCormick, S.; Jeyanathan, M.; Damjanovic, D.; Brown, E.G.; Arck, P.; Jordana, M.; Kaushic, C.; Ashkar, A.A.; et al. Influenza infection leads to increased susceptibility to subsequent bacterial superinfection by impairing NK cell responses in the lung. J. Immunol. 2010, 184, 2048–2056
99. Li, W.; Moltedo, B.; Moran, T.M. Type I interferon induction during influenza virus infection increases susceptibility to secondary Streptococcus pneumoniae infection by negative regulation of gdT cells. J. Virol. 2012, 86, 12304–12312
100. Shahangian, A.; Chow, E.K.; Tian, X.; Kang, J.R.; Ghaffari, A.; Liu, S.Y.; Belperio, J.A.; Cheng, G.; Deng, J.C. Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice. J. Clin. Investig. 2009, 119, 1910–1920
101. Kash, J.C.; Walters, K.A.; Davis, A.S.; Sandouk, A.; Schwartzman, L.M.; Jagger, B.W.; Chertow, D.S.; Qi, L.; Kuestner, R.E.; Ozinsky, A., et al. Lethal synergism of 2009 pandemic H1N1 influenza virus and Streptococcus pneumoniae coinfection is associated with loss of murine lung repair responses. mBio 2011, 2, e00172-11
102. Goulding, J.; Godlee, A.; Vekaria, S.; Hilty, M.; Snelgrove, R.; Hussell, T. Lowering the threshold of lung innate immune cell activation alters susceptibility to secondary bacterial superinfection. J. Infect. Dis. 2011, 204, 1086–1094
103. McCullers, J.A.; McAuley, J.L.; Browall, S.; Iverson, A.R.; Boyd, K.L.; Normark, B.H. Influenza enhances susceptibility to natural acquisition of and disease due to Streptococcus pneumoniae in ferrets. J. Infect. Dis. 2010, 202, 1287–1295
104. Siegel, S.J.; Roche, A.M.; Weiser, J.N. Influenza promotes pneumococcal growth during coinfection by providing host sialylated substrates as a nutrient source. Cell Host Microbe 2014, 16, 55–67
105. Mina, M.J.; Klugman, K.P. The role of influenza in the severity and transmission of respiratory bacterial disease. Lancet Respir. Med. 2014, 2, 750–763
106. Mina, M.J.; McCullers, J.A.; Klugman, K.P. Live attenuated influenza vaccine enhances colonization of Streptococcus pneumoniae and Staphylococcus aureus in mice. mBio 2014, 5, e01040-13
107. Department of Economic, U.N. World Population Ageing, 1950–2050; Number 207; United Nations: New York, NY, USA, 2002
108. Goronzy, J.J.; Weyand, C.M. Understanding immunosenescence to improve responses to vaccines. Nat. Immunol. 2013, 14, 428–436
109. Miller, R.A. The aging immune system: Primer and prospectus. Science 1996, 273, 70–74
110. Wick, G.; Grubeck-Loebenstein, B. The aging immune system: Primary and secondary alterations of immune reactivity in the elderly. Exp. Gerontol. 1997, 32, 401–413
111. Shaw, A.C.; Joshi, S.; Greenwood, H.; Panda, A.; Lord, J.M. Aging of the innate immune system. Curr. Opin. Immunol. 2010, 22, 507–513
112. Mahbub, S.; Brubaker, A.L.; Kovacs, E.J. Aging of the innate immune system: An update. Curr. Immunol. Rev. 2011, 7, 104–115
113. Solana, R.; Tarazona, R.; Gayoso, I.; Lesur, O.; Dupuis, G.; Fulop, T. Innate immunosenescence: Effect of aging on cells and receptors of the innate immune system in humans. Semin. Immunol. 2012, 24, 331–341
114. Goronzy, J.J.; Lee, W.W.; Weyand, C.M. Aging and T-cell diversity. Exp. Gerontol. 2007, 42, 400–406
115. Gupta, S.; Bi, R.; Su, K.; Yel, L.; Chiplunkar, S.; Gollapudi, S. Characterization of naive, memory and effector CD8+ T cells: Effect of age. Exp. Gerontol. 2004, 39, 545–550
116. Vallejo, A.N. CD28 extinction in human T cells: Altered functions and the program of T-cell senescence. Immunol. Rev. 2005, 205, 158–169
117. Fulop, T.; Le Page, A.; Fortin, C.; Witkowski, J.M.; Dupuis, G.; Larbi, A. Cellular signaling in the aging immune system. Curr. Opin. Immunol. 2014, 29, 105–111
118. Ling, W.; Yan, X.; Li-Jing, Z.; Chang, T.T.; Jie, L. An association between immunosenescence and CD4+ CD25+ regulatory T cells: A systematic review. Biomed. Environ. Sci. 2010, 23, 327–332
119. Poland, G.A.; Kennedy, R.B.; McKinney, B.A.; Ovsyannikova, I.G.; Lambert, N.D.; Jacobson, R.M.; Oberg, A.L. Vaccinomics, adversomics, and the immune response network theory: Individualized vaccinology in the 21st century. Semin. Immunol. 2013, 25, 89–103
120. Poland, G.A.; Ovsyannikova, I.G.; Kennedy, R.B.; Lambert, N.D.; Kirkland, J.L. A systems biology approach to the effect of aging, immunosenescence and vaccine response. Curr. Opin. Immunol. 2014, 29, 62–68
121. Durando, P.; Iudici, R.; Alicino, C.; Alberti, M.; de Florentis, D.; Ansaldi, F.; Icardi, G. Adjuvants and alternative routes of administration towards the development of the ideal influenza vaccine. Hum. Vaccines 2011, 7, 29–40
122. Monto, A.S.; Ansaldi, F.; Aspinall, R.; McElhaney, J.E.; Montano, L.F.; Nichol, K.L.; Puig-Barberà, J.; Schmitt, J.; Stephenson, I. Influenza control in the 21st century: Optimizing protection of older adults. Vaccine 2009, 27, 5043–5053
123. Hsieh, Y.C.; Wu, T.Z.; Liu, D.P.; Shao, P.L.; Chang, L.Y.; Lu, C.Y.; Lee, C.Y.; Huang, F.Y.; Huang, L.M. Influenza pandemics: Past, present and future. J. Formos. Med. Assoc. 2006, 105, 1–6
124. Zhang, H.; Chen, L. Possible origin of current influenza A H1N1 viruses. Lancet Infect. Dis. 2009, 9, 456–457
125. Garten, R.J.; Davis, C.T.; Russell, C.A.; Shu, B.; Lindstrom, S.; Balish, A.; Sessions, W.M.; Xu, X.; Skepner, E.; Deyde, V., et al. Antigenic and genetic characteristics of swine-origin 2009 A (H1N1) influenza viruses circulating in humans. Science 2009, 325, 197–201
126. Monto, A.S.; Black, S.; Plotkin, S.A.; Orenstein, W.A. Response to the 2009 pandemic: Effect on influenza control in wealthy and poor countries. Vaccine 2011, 29, 6427–6431
127. Clegg, C.H.; Rininger, J.A.; Baldwin, S.L. Clinical vaccine development for H5N1 influenza. Expert Rev. Vaccines 2013, 12, 767–777
128. Del Giudice, G.; Weinberger, B.; Grubeck-Loebenstein, B. Vaccines for the Elderly. Gerontology, 2015, 61, 203–210
129. Amorij, J.P.; Hinrichs, W.L.; Frijlink, H.W.; Wilschut, J.C.; Huckriede, A. Needle-free influenza vaccination. Lancet Infect. Dis. 2010, 10, 699–711
130. Neutra, M.R.; Kozlowski, P.A. Mucosal vaccines: The promise and the challenge. Nat. Rev. Immunol. 2006, 6, 148–158
131. Lycke, N. Recent progress in mucosal vaccine development: Potential and limitations. Nat. Rev. Immunol. 2012, 12, 592–605
132. Fujihashi, K.; Sato, S.; Kiyono, H. Mucosal adjuvants for vaccines to control upper respiratory infections in the elderly. Exp. Gerontol. 2014, 54, 21–26
133. Van Ginkel, F.W.; Jackson, R.J.; Yuki, Y.; McGhee, J.R. Cutting edge: The mucosal adjuvant cholera toxin redirects vaccine proteins into olfactory tissues. J. Immunol. 2000, 165, 4778–4782
134. Mutsch, M.; Zhou, W.; Rhodes, P.; Bopp, M.; Chen, R.T.; Linder, T.; Spyr, C.; Steffen, R. Use of the inactivated intranasal influenza vaccine and the risk of Bell’s palsy in Switzerland. N. Engl. J. Med. 2004, 350, 896–903
135. Wegmann, F.; Gartlan, K.H.; Harandi, A.M.; Brinckmann, S.A.; Coccia, M.; Hillson, W.R.; Kok, W.L.; Cole, S.; Ho, L.P.; Lambe, T., et al. Polyethyleneimine is a potent mucosal adjuvant for viral glycoprotein antigens. Nat. Biotechnol. 2012, 30, 883–888
136. Stanberry, L.; Simon, J.; Johnson, C.; Robinson, P.; Morry, J.; Flack, M.; Gracon, S.; Myc, A.; Hamouda, T.; Baker, J. Safety and immunogenicity of a novel nanoemulsion mucosal adjuvant W 80 5EC combined with approved seasonal influenza antigens. Vaccine 2012, 30, 307–316
137. Huleatt, J.W.; Nakaar, V.; Desai, P.; Huang, Y.; Hewitt, D.; Jacobs, A.; Tang, J.; McDonald, W.; Song, L.; Evans, R.K., et al. Potent immunogenicity and efficacy of a universal influenza vaccine candidate comprising a recombinant fusion protein linking influenza M2e to the TLR5 ligand flagellin. Vaccine 2008, 26, 201–214
138. Ebrahimi, S.M.; Tebianian, M. Influenza A viruses: Why focusing on M2e-based universal vaccines. Virus Genes 2011, 42, 1–8
139. Atsmon, J.; Kate-Ilovitz, E.; Shaikevich, D.; Singer, Y.; Volokhov, I.; Haim, K.Y.; Ben-Yedidia, T. Safety and immunogenicity of multimeric-001-a novel universal influenza vaccine. J. Clin. Immunol. 2012, 32, 595–603
140. Ben-Yedidia, T.; Arnon, R. Epitope-based vaccine against influenza. Expert Rev. Vaccines 2007, 6, 939–948
141. Kaur, K.; Sullivan, M.; Wilson, P.C. Targeting B cell responses in universal influenza vaccine design. Trends Immunol. 2011, 32, 524–531
142. Wei, C.J.; Boyington, J.C.; McTamney, P.M.; Kong, W.P.; Pearce, M.B.; Xu, L.; Andersen, H.; Rao, S.; Tumpey, T.M.; Yang, Z.Y., et al. Induction of broadly neutralizing H1N1 influenza antibodies by vaccination. Science 2010, 329, 1060–1064
143. Price, G.E.; Soboleski, M.R.; Lo, C.Y.; Misplon, J.A.; Quirion, M.R.; Houser, K.V.; Pearce, M.B.; Pappas, C.; Tumpey, T.M.; Epstein, S.L. Single-dose mucosal immunization with a candidate universal influenza vaccine provides rapid protection from virulent H5N1, H3N2 and H1N1 viruses. PLoS ONE 2010, 5, e13162
144. Poon, L.L.; Leung, Y.C.; Nicholls, J.M.; Perera, P.Y.; Lichy, J.H.; Yamamoto, M.; Waldmann, T.A.; Peiris, J.M.; Perera, L.P. Vaccinia virus-based multivalent H5N1 avian influenza vaccines adjuvanted with IL-15 confer sterile cross-clade protection in mice. J. Immunol. 2009, 182, 3063–3071
145. Suter, R.; Summerfield, A.; Thomann-Harwood, L.J.; McCullough, K.C.; Tratschin, J.D.; Ruggli, N. Immunogenic and replicative properties of classical swine fever virus replicon particles modified to induce IFN-α/β and carry foreign genes. Vaccine 2011, 29, 1491–1503
146. McCullough, K.C.; Bassi, I.; Démoulins, T.; Thomann-Harwood, L.J.; Ruggli, N. Functional RNA delivery targeted to dendritic cells by synthetic nanoparticles. Ther. Deliv. 2012, 3, 1077–1099
147. Pica, N.; Palese, P. Toward a universal influenza virus vaccine: Prospects and challenges. Annu. Rev. Med. 2013, 64, 189–202
148. Bolton, K.J.; McCaw, J.M.; Brown, L.; Jackson, D.; Kedzierska, K.; McVernon, J. Prior Population Immunity Reduces the Expected Impact of CTL-Inducing Vaccines for Pandemic Influenza Control. PLoS ONE 2015, 10, e0120138
149. Baguelin, M.; Flasche, S.; Camacho, A.; Demiris, N.; Miller, E.; Edmunds, W.J. Assessing optimal target populations for influenza vaccination programmes: An evidence synthesis and modelling study. PLoS Med. 2013, 10, e1001527
150. Pettini, E.; Prota, G.; Ciabattini, A.; Boianelli, A.; Fiorino, F.; Pozzi, G.; Vicino, A.; Medaglini, D. Vaginal Immunization to Elicit Primary T-Cell Activation and Dissemination. PLoS ONE 2013, 8, e80545
151. Boianelli, A.; Pettini, E.; Prota, G.; Medaglini, D.; Vicino, A. Identification of a branching process model for adaptive immune response. In Proceedings of the 2013 IEEE 52nd Annual Conference on Decision and Control (CDC), Firenze, Italy, 10–13 December 2013; pp. 7205–7210
152. Boianelli, A.; Pettini, E.; Prota, G.; Medaglini, D.; Vicino, A. A Stochastic Model for CD4+ T Cell Proliferation and Dissemination Network in Primary Immune Response. PLoS ONE 2015, 10, e0135787
153. Meyer-Hermann, M.; Mohr, E.; Pelletier, N.; Zhang, Y.; Victora, G.D.; Toellner, K.M. A theory of germinal center B cell selection, division, and exit. Cell Rep. 2012, 2, 162–174
154. Victora, G.D.; Nussenzweig, M.C. Germinal centers. Annu. Rev. Immunol. 2012, 30, 429–457
155. Meyer-Hermann, M. Overcoming the Dichotomy of Quantity and Quality in Antibody Responses. J. Immunol. 2014, 193, 5414–5419
156. Chaudhury, S.; Reifman, J.; Wallqvist, A. Simulation of B Cell Affinity Maturation Explains Enhanced Antibody Cross-Reactivity Induced by the Polyvalent Malaria Vaccine AMA1. J. Immunol. 2014, 193, 2073–2086
157. Srivastava, B.; Błażejewska, P.; Heßmann, M.; Bruder, D.; Geffers, R.; Mauel, S.; Gruber, A.D.; Schughart, K. Host genetic background strongly influences the response to influenza a virus infections. PLoS ONE 2009, 4, e4857
158. Consortium, C.C. The genome architecture of the Collaborative Cross mouse genetic reference population. Genetics 2012, 190, 389–401
159. Bottomly, D.; Ferris, M.T.; Aicher, L.D.; Rosenzweig, E.; Whitmore, A.; Aylor, D.L.; Haagmans, B.L.; Gralinski, L.E.; Bradel-Tretheway, B.G.; Bryan, J.T., et al. Expression quantitative trait Loci for extreme host response to influenza a in pre-collaborative cross mice. G3 Genes Genomes Genet. 2012, 2, 213–221
160. Ferris, M.T.; Aylor, D.L.; Bottomly, D.; Whitmore, A.C.; Aicher, L.D.; Bell, T.A.; Bradel-Tretheway, B.; Bryan, J.T.; Buus, R.J.; Gralinski, L.E., et al. Modeling host genetic regulation of influenza pathogenesis in the collaborative cross. PLoS Pathog. 2013, 9, e1003196
161. Bailey, C.C.; Huang, I.C.; Kam, C.; Farzan, M. Ifitm3 limits the severity of acute influenza in mice. PLoS Pathog. 2012, 8, e1002909
162. Everitt, A.R.; Clare, S.; Pertel, T.; John, S.P.; Wash, R.S.; Smith, S.E.; Chin, C.R.; Feeley, E.M.; Sims, J.S.; Adams, D.J., et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature 2012, 484, 519–523
163. Xuan, Y.; Wang, L.; Li, W.; Zi, H.; Guo, Y.; Yan, W.; Chen, X.; Wei, P. IFITM3 rs12252 T > C polymorphism is associated with the risk of severe influenza: A meta-analysis. Epidemiol. Infect. 2015, 143, 1–10
164. Mak, C.M.; Lam, C.W.; Fong, N.C.; Siu, W.K.; Lee, H.C.H.; Siu, T.S.; Lai, C.K.; Law, C.Y.; Tong, S.F.; Poon, W.T., et al. Fatal viral infection-associated encephalopathy in two Chinese boys: A genetically determined risk factor of thermolabile carnitine palmitoyltransferase II variants. J. Hum. Genet. 2011, 56, 617–621
165. Hatesuer, B.; Bertram, S.; Mehnert, N.; Bahgat, M.M.; Nelson, P.S.; Pöhlman, S.; Schughart, K. TMPRSS2 is essential for influenza H1N1 virus pathogenesis in mice. PLoS Pathog. 2013, 9, e1003774
166. Sakai, K.; Ami, Y.; Tahara, M.; Kubota, T.; Anraku, M.; Abe, M.; Nakajima, N.; Sekizuka, T.; Shirato, K.; Suzaki, Y., et al. The host protease TMPRSS2 plays a major role in in vivo replication of emerging H7N9 and seasonal influenza viruses. J. Virol. 2014, 88, 5608–5616
167. Tarnow, C.; Engels, G.; Arendt, A.; Schwalm, F.; Sediri, H.; Preuss, A.; Nelson, P.S.; Garten, W.; Klenk, H.D.; Gabriel, G., et al. TMPRSS2 is a host factor that is essential for pneumotropism and pathogenicity of H7N9 influenza A virus in mice. J. Virol. 2014, 88, 4744–4751
168. Kollmus, H.; Wilk, E.; Schughart, K. Systems biology and systems genetics-novel innovative approaches to study host—pathogen interactions during influenza infection. Curr. Opin. Virol. 2014, 6, 47–54
169. Elowitz, M.B.; Levine, A.J.; Siggia, E.D.; Swain, P.S. Stochastic gene expression in a single cell. Science 2002, 297, 1183–1186
170. El Samad, H.; Khammash, M.; Petzold, L.; Gillespie, D. Stochastic modelling of gene regulatory networks. Int. J. Robust Nonlinear Control 2005, 15, 691–711
171. Paulsson, J. Summing up the noise in gene networks. Nature 2004, 427, 415–418
172. Eldar, A.; Elowitz, M.B. Functional roles for noise in genetic circuits. Nature 2010, 467, 167–173.