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Influenza A virus transmission: contributing factors and clinical implications

  • Jessica A. Belser (a1), Taronna R. Maines (a1), Terrence M. Tumpey (a1) and Jacqueline M. Katz (a1)
Abstract

Efficient human-to-human transmission is a necessary property for the generation of a pandemic influenza virus. To date, only influenza A viruses within the H1–H3 subtypes have achieved this capacity. However, sporadic cases of severe disease in individuals following infection with avian influenza A viruses over the past decade, and the emergence of a pandemic H1N1 swine-origin virus in 2009, underscore the need to better understand how influenza viruses acquire the ability to transmit efficiently. In this review, we discuss the biological constraints and molecular features known to affect virus transmissibility to and among humans. Factors influencing the behaviour of aerosols in the environment are described, and the mammalian models used to study virus transmission are presented. Recent progress in understanding the molecular determinants that confer efficient transmission has identified crucial roles for the haemagglutinin and polymerase proteins; nevertheless, influenza virus transmission remains a polygenic trait that is not completely understood. The clinical implications of this research, including methods currently under investigation to mitigate influenza virus human-to-human transmission, are discussed. A better understanding of the viral determinants necessary for efficient transmission will allow us to identify avian influenza viruses with pandemic potential.

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Corresponding author
*Corresponding author: Jacqueline M. Katz, Influenza Division MS G-16, 1600 Clifton Road NE, Atlanta, GA 30333, USA. E-mail: jkatz@cdc.gov
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1W. Chen (2001) A novel influenza A virus mitochondrial protein that induces cell death. Nature Medicine 7, 1306-1312

3R.A. Fouchier (2005) Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls. Journal of Virology 79, 2814-2822

5J.A. Belser (2009) Past, present, and possible future human infection with influenza virus A subtype H7. Emerging Infectious Diseases 15, 859-865

6R.H. Alford (1966) Human influenza resulting from aerosol inhalation. Proceedings of the Society for Experimental Biology and Medicine 122, 800-804

7B. Bean (1982) Survival of influenza viruses on environmental surfaces. Journal of Infectious Diseases 146, 47-51

10J.M. Miller (2000) Cruise ships: high-risk passengers and the global spread of new influenza viruses. Clinical Infectious Diseases 31, 433-438

12K.C. Earhart (2001) Outbreak of influenza in highly vaccinated crew of U.S. Navy ship. Emerging Infectious Diseases 7, 463-465

13J.P. Horcajada (2003) A nosocomial outbreak of influenza during a period without influenza epidemic activity. European Respiratory Journal 21, 303-307

14J.T. Horman (1986) An outbreak of influenza A in a nursing home. American Journal of Public Health 76, 501-504

16K. Leder and D. Newman (2005) Respiratory infections during air travel. Internal Medicine Journal 35, 50-55

17K. Khan (2009) Spread of a novel influenza A (H1N1) virus via global airline transportation. New England Journal of Medicine 361, 212-214

18J.K. Taubenberger and D.M. Morens (2006) 1918 Influenza: the mother of all pandemics. Emerging Infectious Diseases 12, 15-22

19W.W. Thompson (2004) Influenza-associated hospitalizations in the United States. Journal of the American Medical Association 292, 1333-1340

20A.S. Beare and R.G. Webster (1991) Replication of avian influenza viruses in humans. Archives of Virology 119, 37-42

21T.M. Uyeki (2002) Lack of evidence for human-to-human transmission of avian influenza A (H9N2) viruses in Hong Kong, China 1999. Emerging Infectious Diseases 8, 154-159

22M. Peiris (1999) Human infection with influenza H9N2. Lancet 354, 916-917

23M. Koopmans (2004) Transmission of H7N7 avian influenza A virus to human beings during a large outbreak in commercial poultry farms in the Netherlands. Lancet 363, 587-593

24I.N. Kandun (2006) Three Indonesian clusters of H5N1 virus infection in 2005. New England Journal of Medicine 355, 2186-2194

25S.J. Olsen (2005) Family clustering of avian influenza A (H5N1). Emerging Infectious Diseases 11, 1799-1801

26K. Ungchusak (2005) Probable person-to-person transmission of avian influenza A (H5N1). New England Journal of Medicine 352, 333-340

27G. Brankston (2007) Transmission of influenza A in human beings. Lancet Infectious Diseases 7, 257-265

28S. Mubareka (2009) Transmission of influenza virus via aerosols and fomites in the guinea pig model. Journal of Infectious Diseases 199, 858-865

29T.M. Uyeki (2009) Human infection with highly pathogenic avian influenza A (H5N1) virus: review of clinical issues. Clinical Infectious Diseases 49, 279-290

30G.F. Rimmelzwaan (2006) Influenza A virus (H5N1) infection in cats causes systemic disease with potential novel routes of virus spread within and between hosts. American Journal of Pathology 168, 176-183; quiz 364

31A.S. Lipatov (2009) Pathogenesis of H5N1 influenza virus infections in mice and ferret models differs according to respiratory tract or digestive system exposure. Journal of Infectious Diseases 199, 717-725

32S. Olofsson (2005) Avian influenza and sialic acid receptors: more than meets the eye? Lancet Infectious Diseases 5, 184-188

34H. Smith and C. Sweet (1988) Lessons for human influenza from pathogenicity studies with ferrets. Review of Infectious Diseases 10, 56-75

36D. van Riel (2007) Human and avian influenza viruses target different cells in the lower respiratory tract of humans and other mammals. American Journal of Pathology 171, 1215-1223

37D. van Riel (2006) H5N1 Virus Attachment to Lower Respiratory Tract. Science 312, 399

39M.L. Herlocher (2001) Ferrets as a transmission model for influenza: sequence changes in HA1 of type A (H3N2) virus. Journal of Infectious Diseases 184, 542-546

40T.R. Maines (2006) Lack of transmission of H5N1 avian–human reassortant influenza viruses in a ferret model. Proceedings of the National Academy of Sciences of the United States of America 103, 12121-12126

41T.M. Tumpey (2007) A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission. Science 315, 655-659

42S. Squires and G. Belyavin (1975) Free contact infection in ferret groups. Journal of Antimicrobial Chemotherapy 1 (Supplement 4), 35-42

43H.L. Yen (2007) Inefficient transmission of H5N1 influenza viruses in a ferret contact model. Journal of Virology 81, 6890-6898

44E. Azoulay-Dupuis (1984) Lung alterations in guinea-pigs infected with influenza virus. Journal of Comparative Pathology 94, 273-283

45A.C. Lowen (2006) The guinea pig as a transmission model for human influenza viruses. Proceedings of the National Academy of Sciences of the United States of America 103, 9988-9992

47A.C. Lowen and P. Palese (2007) Influenza virus transmission: basic science and implications for the use of antiviral drugs during a pandemic. Infectious Disorders Drug Targets 7, 318-328

48N. Van Hoeven (2009) Pathogenesis of 1918 pandemic and H5N1 influenza virus infections in a guinea pig model: antiviral potential of exogenous alpha interferon to reduce virus shedding. Journal of Virology 83, 2851-2861

49L.M. Pastor (1992) Histochemical study of glycoconjugates in the nasal mucosa of the rat and guinea pig. Histochemical Journal 24, 727-736

50P.H. Jarreau (1992) Effects of neuraminidase on airway reactivity in the guinea pig. American Review of Respiratory Disease 145(4 Pt 1), 906-910

51A.C. Lowen (2007) Influenza virus transmission is dependent on relative humidity and temperature. PLoS Pathogens 3, 1470-1476

52J.L. Schulman and E.D. Kilbourne (1962) Airborne transmission of influenza virus infection in mice. Nature 195, 1129-1130

53R. Wu (2010) Transmission of avian H9N2 influenza viruses in a murine model. Veterinary Microbiology 142, 211-216

54J.L. Schulman and E.D. Kilbourne (1963) Experimental transmission of influenza virus infection in mice. II. Some factors affecting the incidence of transmitted infection. Journal of Experimental Medicine 118, 267-275

55C.R. Baskin (2009) Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus. Proceedings of the National Academy of Sciences of the United States of America 106, 3455-3460

56R.J. Garten (2009) Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 325, 197-201

57K.P. Myers , C.W. Olsen and G.C. Gray (2007) Cases of swine influenza in humans: a review of the literature. Clinical Infectious Diseases 44, 1084-1088

58V. Shinde (2009) Triple-reassortant swine influenza A (H1) in humans in the United States, 2005-2009. New England Journal of Medicine 360, 2616-2625

59A. De Vleeschauwer (2009) Efficient transmission of swine-adapted but not wholly avian influenza viruses among pigs and from pigs to ferrets. Journal of Infectious Diseases 200, 1884-1892

60W. Ma (2007) Identification of H2N3 influenza A viruses from swine in the United States. Proceedings of the National Academy of Sciences of the United States of America 104, 20949-20954

63S. Cauchemez (2009) Household transmission of 2009 pandemic influenza A (H1N1) virus in the United States. New England Journal of Medicine 361, 2619-2627

64B.J. Cowling (2010) Comparative epidemiology of pandemic and seasonal influenza A in households. New England Journal of Medicine 362, 2175-2184

67S. Herfst (2010) Introduction of virulence markers in PB2 of pandemic swine-origin influenza virus does not result in enhanced virulence or transmission. Journal of Virology 84, 3752-3758

68E. Hoffmann (2000) A DNA transfection system for generation of influenza A virus from eight plasmids. Proceedings of the National Academy of Sciences of the United States of America 97, 6108-6113

70S. Stelzer-Braid (2009) Exhalation of respiratory viruses by breathing, coughing, and talking. Journal of Medical Virology 81, 1674-1679

71M. Nicas , W.W. Nazaroff and A. Hubbard (2005) Toward understanding the risk of secondary airborne infection: emission of respirable pathogens. Journal of Occupational and Environmental Hygiene 2, 143-154

73D. Verreault , S. Moineau and C. Duchaine (2008) Methods for sampling of airborne viruses. Microbiology and Molecular Biology Reviews 72, 413-444

74R. Tellier (2009) Aerosol transmission of influenza A virus: a review of new studies. Journal of the Royal Society, Interface 6 (Supplement 6), S783-S790

75X. Xie (2007) How far droplets can move in indoor environments – revisiting the Wells evaporation-falling curve. Indoor Air 17, 211-225

76S.C. Chen (2009) Viral kinetics and exhaled droplet size affect indoor transmission dynamics of influenza infection. Indoor Air 19, 401-413

77A. Lowen and P. Palese (2009) Transmission of influenza virus in temperate zones is predominantly by aerosol, in the tropics by contact: a hypothesis. PLoS Currents: Influenza Aug 17; 1:RRN1002

78A.C. Lowen (2008) High temperature (30 degrees C) blocks aerosol but not contact transmission of influenza virus. Journal of Virology 82, 5650-5652

79E. Lofgren (2007) Influenza seasonality: underlying causes and modeling theories. Journal of Virology 81, 5429-5436

80I.V. Polozov (2008) Progressive ordering with decreasing temperature of the phospholipids of influenza virus. Nature Chemical Biology 4, 248-255

81H.L. Nguyen (2007) Epidemiology of influenza in Hanoi, Vietnam, from 2001 to 2003. Journal of Infection 55, 58-63

82C.M. Wong (2004) Influenza-associated mortality in Hong Kong. Clinical Infectious Diseases 39, 1611-1617

83C. Viboud (2004) Association of influenza epidemics with global climate variability. European Journal of Epidemiology 19, 1055-1059

84J.J. Skehel and D.C. Wiley (2000) Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annual Review of Biochemistry 69, 531-569

85T. Ito and Y. Kawaoka (2000) Host-range barrier of influenza A viruses. Veterinary Microbiology 74, 71-75

86G.N. Rogers and J.C. Paulson (1983) Receptor determinants of human and animal influenza virus isolates: differences in receptor specificity of the H3 hemagglutinin based on species of origin. Virology 127, 361-373

87M.N. Matrosovich (2004) Human and avian influenza viruses target different cell types in cultures of human airway epithelium. Proceedings of the National Academy of Sciences of the United States of America 101, 4620-4624

88K. Shinya (2006) Avian flu: influenza virus receptors in the human airway. Nature 440, 435-436

89J.A. Belser (2008) Contemporary North American influenza H7 viruses possess human receptor specificity: implications for virus transmissibility. Proceedings of the National Academy of Sciences of the United States of America 105, 7558-7563

90J. Stevens (2006) Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 312, 404-410

91C.I. Thompson (2006) Infection of human airway epithelium by human and avian strains of influenza a virus. Journal of Virology 80, 8060-8068

92A. Chandrasekaran (2008) Glycan topology determines human adaptation of avian H5N1 virus hemagglutinin. Nature Biotechnology 26, 107-113

93A. Srinivasan (2008) Quantitative biochemical rationale for differences in transmissibility of 1918 pandemic influenza A viruses. Proceedings of the National Academy of Sciences of the United States of America 105, 2800-2805

94R. Xu (2010) Structure, receptor binding, and antigenicity of influenza virus hemagglutinins from the 1957 H2N2 pandemic. Journal of Virology 84, 1715-1721

95J. Liu (2009) Structures of receptor complexes formed by hemagglutinins from the Asian influenza pandemic of 1957. Proceedings of the National Academy of Sciences of the United States of America 106, 17175-17180

96L. Glaser (2005) A single amino acid substitution in 1918 influenza virus hemagglutinin changes receptor binding specificity. Journal of Virology 79, 11533-11536

97A. Gambaryan (2006) Evolution of the receptor binding phenotype of influenza A (H5) viruses. Virology 344, 432-438

98H. Song (2009) Partial direct contact transmission in ferrets of a mallard H7N3 influenza virus with typical avian-like receptor specificity. Virology Journal 6, 126

99H. Wan (2008) Replication and transmission of H9N2 influenza viruses in ferrets: evaluation of pandemic potential. PLoS One 3, e2923

100Z.Y. Yang (2007) Immunization by avian H5 influenza hemagglutinin mutants with altered receptor binding specificity. Science 317, 825-828

101J. Stevens (2008) Recent avian H5N1 viruses exhibit increased propensity for acquiring human receptor specificity. Journal of Molecular Biology 381, 1382-1394

102S. Chutinimitkul (2010) Virulence-associated substitution D222G in hemagglutinin of 2009 pandemic influenza A(H1N1) virus affects receptor binding. Journal of Virology 84, 11802-11813

103N. Van Hoeven (2009) Human HA and polymerase subunit PB2 proteins confer transmission of an avian influenza virus through the air. Proceedings of the National Academy of Sciences of the United States of America 106, 3366-3371

104E.M. Sorrell (2009) Minimal molecular constraints for respiratory droplet transmission of an avian–human H9N2 influenza A virus. Proceedings of the National Academy of Sciences of the United States of America 106, 7565-7570

106P. Massin , S. van der Werf and N. Naffakh (2001) Residue 627 of PB2 is a determinant of cold sensitivity in RNA replication of avian influenza viruses. Journal of Virology 75, 5398-5404

107M. Hatta (2001) Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293, 1840-1842

108M. Hatta (2007) Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice. PLoS Pathogens 3, 1374-1379

109J. Steel (2009) Transmission of influenza virus in a mammalian host is increased by PB2 amino acids 627K or 627E/701N. PLoS Pathogens 5, e1000252

110Z. Li (2005) Molecular basis of replication of duck H5N1 influenza viruses in a mammalian mouse model. Journal of Virology 79, 12058-12064

111G. Gabriel (2005) The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host. Proceedings of the National Academy of Sciences of the United States of America 102, 18590-18595

112Y. Gao (2009) Identification of amino acids in HA and PB2 critical for the transmission of H5N1 avian influenza viruses in a mammalian host. PLoS Pathogens 5, e1000709

113M.W. Leigh (1995) Receptor specificity of influenza virus influences severity of illness in ferrets. Vaccine 13, 1468-1473

114P.N. Dinh (2006) Risk factors for human infection with avian influenza A H5N1, Vietnam, 2004. Emerging Infectious Diseases 12, 1841-1847

115D. Normile (2007) Epidemiology. Indonesia taps village wisdom to fight bird flu. Science 315, 30-33

117V.E. Pitzer (2007) Little evidence for genetic susceptibility to influenza A (H5N1) from family clustering data. Emerging Infectious Diseases 13, 1074-1076

118F.S. Albright (2008) Evidence for a heritable predisposition to death due to influenza. Journal of Infectious Diseases 197, 18-24

119R. Ahmed , M.B. Oldstone and P. Palese (2007) Protective immunity and susceptibility to infectious diseases: lessons from the 1918 influenza pandemic. Nature Immunology 8, 1188-1193

120K.Y. Yuen (1998) Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet 351, 467-471

121J.S. Peiris (2004) Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet 363, 617-619

122C.Y. Cheung (2002) Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 360, 1831-1837

123M.D. de Jong (2006) Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nature Medicine 12, 1203-1207

124L. Zhang (2009) Systems-based candidate genes for human response to influenza infection. Infection, Genetics and Evolution 9, 1148-1157

125R.A. Trammell and L.A. Toth (2008) Genetic susceptibility and resistance to influenza infection and disease in humans and mice. Expert Review of Molecular Diagnostics 8, 515-529

126A.C. Boon (2009) Host genetic variation affects resistance to infection with a highly pathogenic H5N1 influenza A virus in mice. Journal of Virology 83, 10417-10426

127T.C. Germann (2006) Mitigation strategies for pandemic influenza in the United States. Proceedings of the National Academy of Sciences of the United States of America 103, 5935-5940

128A.W. Park (2009) Quantifying the impact of immune escape on transmission dynamics of influenza. Science 326, 726-728

131P.A. Piedra (2005) Herd immunity in adults against influenza-related illnesses with use of the trivalent-live attenuated influenza vaccine (CAIV-T) in children. Vaccine 23, 1540-1548

132W.P. Glezen (2006) Herd protection against influenza. Journal of Clinical Virology 37, 237-243

133J. Potter (1997) Influenza vaccination of health care workers in long-term-care hospitals reduces the mortality of elderly patients. Journal of Infectious Diseases 175, 1-6

134W.F. Carman (2000) Effects of influenza vaccination of health-care workers on mortality of elderly people in long-term care: a randomised controlled trial. Lancet 355, 93-97

135A.C. Lowen (2009) Blocking interhost transmission of influenza virus by vaccination in the guinea pig model. Journal of Virology 83, 2803-2818

136I.M. Longini Jr., (2004) Containing pandemic influenza with antiviral agents. American Journal of Epidemiology 159, 623-633

137L.H. Pinto , L.J. Holsinger and R.A. Lamb (1992) Influenza virus M2 protein has ion channel activity. Cell 69, 517-528

139L. Simonsen (2007) The genesis and spread of reassortment human influenza A/H3N2 viruses conferring adamantane resistance. Molecular Biology and Evolution 24, 1811-1820

140M.L. Herlocher (2003) Assessment of development of resistance to antivirals in the ferret model of influenza virus infection. Journal of Infectious Diseases 188, 1355-1361

141C. Sweet (1991) Virulence of rimantadine-resistant human influenza A (H3N2) viruses in ferrets. Journal of Infectious Diseases 164, 969-972

142F.G. Hayden (1989) Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. New England Journal of Medicine 321, 1696-1702

143R.A. Bright (2006) Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States. Journal of the American Medical Association 295, 891-894

144M. von Itzstein (1993) Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 363, 418-423

145L.V. Gubareva , L. Kaiser and F.G. Hayden (2000) Influenza virus neuraminidase inhibitors. Lancet 355, 827-835

146J. Carr (2002) Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo. Antiviral Research 54, 79-88

147J.A. Ives (2002) The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo. Antiviral Research 55, 307-317

148M.L. Herlocher (2002) Influenza virus carrying an R292K mutation in the neuraminidase gene is not transmitted in ferrets. Antiviral Research 54, 99-111

149H.L. Yen (2007) Neuraminidase inhibitor-resistant recombinant A/Vietnam/1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and in vivo. Journal of Virology 81, 12418-12426

150M.L. Herlocher (2004) Influenza viruses resistant to the antiviral drug oseltamivir: transmission studies in ferrets. Journal of Infectious Diseases 190, 1627-1630

151N.M. Bouvier , A.C. Lowen and P. Palese (2008) Oseltamivir-resistant influenza A viruses are transmitted efficiently among guinea pigs by direct contact but not by aerosol. Journal of Virology 82, 10052-10058

152H.L. Yen (2005) Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility. Antimicrobial Agents and Chemotherapy 49, 4075-4084

153A. Patel and S.E. Gorman (2009) Stockpiling antiviral drugs for the next influenza pandemic. Clinical Pharmacology and Therapeutics 86, 241-243

154F.G. Hayden (2004) Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis. Journal of Infectious Diseases 189, 440-449

155V.J. Lee (2010) Oseltamivir ring prophylaxis for containment of 2009 H1N1 influenza outbreaks. New England Journal of Medicine 362, 2166-2174

156A. Garcia-Sastre and C.A. Biron (2006) Type 1 interferons and the virus-host relationship: a lesson in detente. Science 312, 879-882

157S.J. Keam and R.S. Cvetkovic (2008) Peginterferon-alpha-2a (40 kD) plus ribavirin: a review of its use in the management of chronic hepatitis C mono-infection. Drugs 68, 1273-1317

158M.W. Beilharz , J.M. Cummins and A.L. Bennett (2007) Protection from lethal influenza virus challenge by oral type 1 interferon. Biochemical and Biophysical Research Communications 355, 740-744

159D. Kugel (2009) Intranasal administration of alpha interferon reduces seasonal influenza A virus morbidity in ferrets. Journal of Virology 83, 3843-3851

160T.M. Tumpey (2007) The Mx1 gene protects mice against the pandemic 1918 and highly lethal human H5N1 influenza viruses. Journal of Virology 81, 10818-10821

161J. Steel (2010) Transmission of pandemic H1N1 influenza virus and impact of prior exposure to seasonal strains or interferon treatment. Journal of Virology 84, 21-26

M.L. Perdue and D.E. Swayne (2005). Public health risk from avian influenza viruses. Avian Diseases 49, 317327

J.A. Belser (2009). Use of animal models to understand the pandemic potential of highly pathogenic avian influenza viruses. Advances in Virus Research 73, 5597

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