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Christophersen, Olav Albert; Haug, Anna (2011)
Publisher: Microbial Ecology in Health and Disease
Journal: Microbial Ecology in Health and Disease
Languages: English
Types: Article
The world is now extremely poorly prepared to counter a possible pandemic of hypervirulent H5N1 influenza. Most countries are planning for nothing worse than the Spanish flu pandemic. It may be possible that this can in large measure be explained as a consequence of an epidemic of wishful thinking, which may already have infected the health authorities (and parts of the scientific community as well) in most countries in the world. However, it may also be possible that it can have happened as a consequence of too little contact between medical scientists and more general biologists (natural scientists) from disciplines such as ornithology, ecology and evolutionary biology. This may have led to a lack of proper understanding among medical scientists (and health bureaucrats) of the nature of evolutionary processes affecting influenza viruses, as regards the evolution of host species adaptation, infectivity and virulence properties, and also a lack of appreciation of the ways in which such forms of evolutionary adaptation depend on ecological boundary conditions that have radically changed, comparing the world in 2006 to the world in 1918. While the Spanish flu virus possibly might be compared to a one-headed monster, it may be possible that highly virulent varieties of H5N1 virus might better be compared to a three-headed one because there is evidence of at least three independent virulence factors connected with three different genes. It is highly unlikely that all of the high-virulence alleles will simultaneously mutate and disappear if and when the haemagglutinin gene changes so as to make the haemagglutinin molecule better adapted for the human-type (alpha-2,6-linked) receptor (which is a necessary prerequisite in order that a pandemic with H5N1 virus may start). It is more probable that evolutionary adaptation of the haemagglutinin of H5N1 viruses to the human-type receptor will happen without any simultaneous change in those other genetic properties that now are important for explaining the exceptionally high virulence of certain strains of avian-adapted H5N1 influenza virus. The change of the haemagglutinin molecule from avian adaptation to human adaptation must be expected to act as an additional virulence factor because it will enhance the total number of cells that can be infected (per host organism), increase the total rate of virus replication and potentiate the effects of the other virulence factors already present. The monster will then have four heads, not three, and case fatality rates must be expected to become even higher than they have been until now, perhaps reaching as high as 98-99% (at least in poor countries with less than optimal nutrition).Key words: avian influenza, virulence factors, virulence evolution, risk estimates, emergency preparedness
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    • 1. Moxnes JF, Christophersen OA. Counter attacking pandemic H5N1 bird influenza by counter pandemic. Microb Ecol Health Dis. 2006;18:4 25.
    • 2. Laulan Y. Economic consequences: back to the Dark Ages. Ambio. 1982;/11:/149 52.
    • 3. Hampson J. Photochemical war on the atmosphere. Nature. 1974;/250:/189 91.
    • 4. Hampson J. Surface insolation and climate. Potential effect of atmospheric contamination. Physics and Centre for Radio Science, University of Western Ontario, 1977.
    • 5. Advisers for this issue. Reference scenario: how a nuclear war might be fought. Ambio 1982;11:94 9.
    • 6. Arkin W, von Hippel F, Levi BG. The consequences of a ''limited'' nuclear war in East and West Germany. Ambio. 1982;/11:/163 73.
    • 7. Barnaby F. The effects of a global nuclear war: the arsenals. Ambio. 1982;/11:/76 83.
    • 8. Barnaby F, Rotblat J. The effects of nuclear weapons. Ambio. 1982;/11:/84 93.
    • 9. Bondietti EA. Effects on agriculture. Ambio. 1982;/11:/138 42.
    • 10. Chazov EI, Vartanian ME. Effects on human behavior. Ambio. 1982;/11:/158 60.
    • 11. Coggle JE, Lindop PJ. Medical consequences of radiation following a global nuclear war. Ambio. 1982;/11:/106 13.
    • 12. Crutzen PJ, Birks JW. The atmosphere after a nuclear war: twilight at noon. Ambio. 1982;/11:/114 25.
    • 13. Hjort HW. The impact on global food supplies. Ambio. 1982;/11:/155 7.
    • 14. Middleton H. Epidemiology: the future is sickness and death. Ambio. 1982;/11:/100 5.
    • 15. Seymour AH. The impact on ocean ecosystems. Ambio. 1982;/11:/132 7.
    • 16. Advisory Group for this issue. Conclusions. Ambio 1982; 11:161 2.
    • 17. Wetzel KG. Effects on global supplies of freshwater. Ambio. 1982;/11:/126 31.
    • 18. Woodwell GM. The biotic effects of ionizing radiation. Ambio. 1982;/11:/143 8.
    • 19. Izrael YA, Petrov VN, Severov DA. [On the influence of atmospheric nuclear bursts on ozone content of the atmosphere.] Meteorol Hydrol No. 6:5 15 (in Russian) 1983.
    • 20. US National Research Council. The effects on the atmosphere of a major nuclear exchange. Washington DC: National Academy Press, 1985.
    • 21. Budyko MI, Golitsyn GS, Izrael YA. Global climatic catastrophes. Berlin: Springer-Verlag; 1988.
    • 22. Mounier-Jack S, Coker RJ. How prepared is Europe for pandemic influenza? Analysis of national plans. Lancet. 2005;/367:/1405 11.
    • 23. Ho M-W. Where's the bird flu pandemic? ISIS Press Release 11/05/06.
    • 24. McNeill WH. Plagues and peoples, 2nd revised edn. New York: Anchor Books; 1998.
    • 25. Garrett L. The next pandemic? Foreign Affairs 2005;July/ August:3 23.
    • 26. Osterholm MT. Preparing for the next pandemic. Foreign Affairs 2005;July/August:24 37.
    • 27. Olsen B, Munster VJ, Wallensten A, Waldenstr o¨m J, Osterhaus AD, Fouchier RAM. Global patterns of influenza A virus in wild birds. Science. 2006;/312:/384 8.
    • 28. Suarez DL, Perdue ML, Cox N, Rowe T, Bender C, Huang J, et al. Comparisons of highly virulent H5N1 influenza A viruses isolated from humans and chickens from Hong Kong. J Virol. 1998;/72:/6678 88.
    • 29. Subbarao K, Klimov A, Katz J, Regnery H, Lim W, Hall H, et al. Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science. 1998;/279:/393 6.
    • 30. Bender C, Hall H, Huang J, Klimov A, Cox N, Hay A, et al. Characterization of the surface proteins of influenza A (H5N1) viruses isolated from humans in 1997 1998. Virology. 1999;/254:/115 23.
    • 31. Tumpey TM, Basler CF, Aguilar PV, Zeng H, Solorzano A, Swayne DE, et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science. 2005;/310:/ 77 80.
    • 32. Krug RM. Virology. Clues to the virulence of H5N1 viruses in humans. Science. 2006;/311:/1562 3.
    • 33. Seo S, Hoffmann E, Webster RG. Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nat Med. 2002;/8:/950 4.
    • 34. Seo S, Hoffmann E, Webster RG. The NS1 gene of H5N1 influenza viruses circumvents the host anti-viral cytokine responses. Virus Res. 2004;/103:/107 13.
    • 35. Jefferson T, Demicheli V, Rivetti D, Jones M, Di Pietrantonj C, Rivetti A. Antivirals for influenza in healthy adults: systematic review. Lancet. 2006;/367:/303 13.
    • 36. Di Marco S, Mazroui R, Dallaire P, Chittur S, Tenenbaum SA, Radzioch D, et al. NF-kappa B-mediated MyoD decay during muscle wasting requires nitric oxide synthase mRNA stabilization, HuR protein, and nitric oxide release. Mol Cell Biol. 2005;/25:/6533 45.
    • 37. Figueras M, Busquets S, Carbo N, Almendro V, Argiles JM, Lopez-Soriano FJ. Cancer cachexia results in an increase in TNF-alpha receptor gene expression in both skeletal muscle and adipose tissue. Int J Oncol. 2005;/27:/855 60.
    • 38. Suematsu N, Tsutsui H, Wen J, Kang D, Ikeuchi M, Ide T. Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation. 2003;/107:/1418 23.
    • 39. Bourraindeloup M, Adamy C, Candiani G, Cailleret M, Bourin MC, Badoual T, et al. N-acetylcysteine treatment normalizes serum tumor necrosis factor-alpha level and hinders the progression of cardiac injury in hypertensive rats. Circulation. 2004;/110:/2003 9.
    • 40. Cailleret M, Amadou A, Andrieu-Abadie N, Nawrocki A, Adamy C, Ait-Mamar B, et al. N-acetylcysteine prevents the deleterious effect of tumor necrosis factor-(alpha) on calcium transients and contraction in adult rat cardiomyocytes. Circulation. 2004;/109:/406 11.
    • 41. Sihvola RK, Koskinen PK, Pulkkinen VP, Tikkanen JM, Lemstrom KB. Inhibition of tumor necrosis factor-alpha attenuates myocardial remodeling in rat cardiac allografts. J Heart Lung Transplant. 2006;/25:/569 78.
    • 42. Pandey M, Loskutoff DJ, Samad F. Molecular mechanisms of tumor necrosis factor-alpha-mediated plasminogen activator inhibitor-1 expression in adipocytes. FASEB J. 2005;/ 19:/1317 9.
    • 43. Neels JG, Pandey M, Hotamisligil GS, Samad F. Autoamplification of tumor necrosis factor-alpha: a potential mechanism for the maintenance of elevated tumor necrosis factor-alpha in male but not female obese mice. Am J Pathol. 2006;/168:/435 44.
    • 44. Nystr o¨m T, Nygren A, Sj o¨holm A. Increased levels of tumour necrosis factor-alpha (TNF-alpha) in patients with Type II diabetes mellitus after myocardial infarction are related to endothelial dysfunction. Clin Sci (Lond). 2006;/ 110:/673 81.
    • 45. Zhang C, Hein TW, Wang W, Ren Y, Shipley RD, Kuo L. Activation of JNK and xanthine oxidase by TNF-alpha impairs nitric oxide-mediated dilation of coronary arterioles. Mol Cell Cardiol. 2006;/40:/247 57.
    • 46. Sorkin LS, Xiao WH, Wagner R, Myers RR. Tumour necrosis factor-alpha induces ectopic activity in nociceptive primary afferent fibres. Neuroscience. 1997;/81:/255 62.
    • 47. Junger H, Sorkin LS. Nociceptive and inflammatory effects of subcutaneous TNFalpha. Pain. 2000;/85:/145 51.
    • 48. Zhang JM, Li H, Liu B, Brull SJ. Acute topical application of tumor necrosis factor alpha evokes protein kinase A-dependent responses in rat sensory neurons. J Neurophysiol. 2002;/ 88:/1387 92.
    • 49. Chatterjee S. Sphingolipids in atherosclerosis and vascular biology. Arterioscler Thromb Vasc Biol. 1998;/18:/1523 33.
    • 50. Corda S, Laplace C, Vicaut E, Duranteau J. Rapid reactive oxygen species production by mitochondria in endothelial cells exposed to tumor necrosis factor-alpha is mediated by ceramide. Am J Respir Cell Mol Biol. 2001;/24:/762 8.
    • 51. Martin SF, Williams N, Chatterjee S. Lactosylceramide is required in apoptosis induced by N-Smase. Glycoconj J. 2006;/23:/147 57.
    • 52. Garcia-Ruiz C, Colell A, Mari M, Morales A, FernandezCheca JC. Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. Role of mitochondrial glutathione. J Biol Chem. 1997;/272:/11369 77.
    • 53. Gudz TI, Tserng KY, Hoppel CL. Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide. J Biol Chem. 1997;/272:/24154 8.
    • 54. Garcia-Ruiz C, Colell A, Morales A, Kaplowitz N, Fernandez-Checa JC. Role of oxidative stress generated from the mitochondrial electron transport chain and mitochondrial glutathione status in loss of mitochondrial function and activation of transcription factor nuclear factor-kappa B: studies with isolated mitochondria and rat hepatocytes. Mol Pharmacol. 1995;/48:/825 34.
    • 55. Rahman I, Gilmour PS, Jimenez LA, MacNee W. Oxidative stress and TNF-alpha induce histone acetylation and NFkappaB/AP-1 activation in alveolar epithelial cells: potential mechanism in gene transcription in lung inflammation. Mol Cell Biochem. 2002;/234 235(1 2):/239 48.
    • 56. Moodie FM, Marwick JA, Anderson CS, Szulakowski P, Biswas SK, Bauter MR, et al. Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells. FASEB J. 2004;/18:/1897 9.
    • 57. Nimmerjahn F, Dudziak D, Dirmeier U, Hobom G, Riedel A, Schlee M, et al. Active NF-kappaB signalling is a prerequisite for influenza virus infection. J Gen Virol. 2004;/85:/2347 56.
    • 58. Wurzer WJ, Ehrhardt C, Pleschka S, Berberich-Siebelt F, Wolff T, Walczak H, et al. NF-kappaB-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas/FasL is crucial for efficient influenza virus propagation. J Biol Chem. 2004;/279:/30931 7.
    • 59. Goldfeld AE, Doyle C, Maniatis T. Human tumor necrosis factor alpha gene regulation by virus and lipopolysaccharide. Proc Natl Acad Sci U S A. 1990;/87:/9769 73.
    • 60. Yao J, Mackman N, Edgington TS, Fan ST. Lipopolysaccharide induction of the tumor necrosis factor-alpha promoter in human monocytic cells. Regulation by Egr-1, c-Jun, and NF-kappaB transcription factors. J Biol Chem. 1997;/272:/17795 801.
    • 61. Steer JH, Kroeger KM, Abraham LJ, Joyce DA. Glucocorticoids suppress tumor necrosis factor-alpha expression by human monocytic THP-1 cells by suppressing transactivation through adjacent NF-kappa B and c-Jun-activating transcription factor-2 binding sites in the promoter. J Biol Chem. 2000;/275:/18432 40.
    • 62. Christophersen OA, Haug A. Possible roles of oxidative stress, local circulatory failure and nutrition factors in the pathogenesis of hypervirulent influenza: implications for therapy and global emergency preparedness. Microb Ecol Health Dis. 2005;/17:/189 99.
    • 63. Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, et al. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet. 2002;/ 360:/1831 7.
    • 64. Chan MC, Cheung CY, Chui WH, Tsao SW, Nicholls JM, Chan YO, et al. Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir Res. 2005;/6:/ 135.
    • 65. Lee DC, Cheung CY, Law AH, Mok CK, Peiris M, Lau AS. p38 mitogen-activated protein kinase-dependent hyperinduction of tumor necrosis factor alpha expression in response to avian influenza virus H5N1. J Virol. 2005;/79:/ 10147 54.
    • 66. Lipatov AS, Andreansky S, Webby RJ, Hulse DJ, Rehg JE, Krauss S, et al. Pathogenesis of Hong Kong H5N1 influenza virus NS gene reassortants in mice: the role of cytokines and B- and T-cell responses. J Gen Virol. 2005;/86:/1121 30.
    • 67. Shinya K, Hamm S, Hatta M, Ito H, Ito T, Kawaoka Y. PB2 amino acid at position 627 affects replicative efficiency, but not cell tropism, of Hong Kong H5N1 influenza A viruses in mice. Virology. 2004;/320:/258 66.
    • 68. Salomon R, Franks J, Govorkova EA, Ilyushina NA, Yen HL, Hulse-Post DJ, et al. The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04. J Exp Med. 2006;/203:/689 97.
    • 69. Gambaryan A, Webster R, Matrosovich M. Differences between influenza virus receptors on target cells of duck and chicken. Arch Virol. 2002;/147:/1197 208.
    • 70. Gambarian AS, Iamnikova SS, L'vov DK, Robertson JS, Webster RG, Matrosovich MN. [Differences in receptor specificity between the influenza A viruses isolated from the duck, chicken, and human.] Mol Biol (Mosk) 2002;36:542 9 (in Russian).
    • 71. Shinya K, Ebina M, Shinya Y, Ono M, Kasai N, Kawaoka Y. Influenza virus receptors in the human airway. Avian and human influenza viruses seem to target different regions of a patient's respiratory tract. Nature. 2006;/440:/435 6.
    • 72. Seo SH, Webster RG. Cross-reactive, cell-mediated immunity and protection of chickens from lethal H5N1 influenza virus infection in Hong Kong poultry markets. J Virol. 2001;/ 75:/2516 25.
    • 73. Seo SH, Peiris M, Webster RG. Protective cross-reactive cellular immunity to lethal A/Goose/Guangdong/1/96-like H5N1 influenza virus is correlated with the proportion of pulmonary CD8 T cells expressing gamma interferon. J Virol. 2002;/76:/4886 90.
    • 74. Mamelund S-E. Spanish influenza mortality of ethnic minorities in Norway 1918 1919. Eur J Population. 2003;/ 19:/83 102.
    • 75. Mamelund S-E. Spanish Influenza and beyond: the case of Norway. Dr polit. thesis. Department of Economics, University of Oslo, 2004.
    • 76. Crosby A. America's forgotten pandemic. The influenza of 1918. Cambridge, UK: Cambridge University Press; 1989.
    • 77. Johnson NP, Mueller J. Updating the accounts: global mortality of the 1918 1920 ''Spanish'' influenza pandemic. Bull Hist Med. 2002;/76:/105 15.
    • 78. Oxford JS, Sefton A, Jackson R, Innes W, Daniels RS, Johnson NP. World War I may have allowed the emergence of ''Spanish'' influenza. Lancet Infect Dis. 2002;/2:/111 4.
    • 79. Oxford JS. The so-called Great Spanish Influenza Pandemic of 1918 may have originated in France in 1916. Philos Trans R Soc Lond B Biol Sci. 2001;/356:/1857 9.
    • 80. Oxford JS, Lambkin R, Sefton A, Daniels R, Elliot A, Brown R, et al. A hypothesis: the conjunction of soldiers, gas, pigs, ducks, geese and horses in northern France during the Great War provided the conditions for the emergence of the ''Spanish'' influenza pandemic of 1918 1919. Vaccine. 2005;/23:/940 5.
    • 81. Horimoto T, Kawaoka Y. Pandemic threat posed by avian influenza A viruses. Clin Microbiol Rev. 2001;/14:/129 49.
    • 82. Lahariya C, Sharma AK, Pradhan SK. Avian flu and possible human pandemic. Indian Pediatr. 2006;/43:/317 25.
    • 83. WHO home page about influenza: Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO [updated 23 May 2006].
    • 84. MacKenzie D. The bird flu threat. New Scientist 2006;7 January:i viii.
    • 85. Wasson JT. Meteorites. Their record of early solar-system history. New York: WH Freeman and Company; 1985.
    • 86. Turco RP, Toon OB, Park C, Whitten RC, Pollack JB, Noerdlinger P. Tunguska meteor fall of 1908: effects on stratospheric ozone. Science. 1981;/214:/19 23.
    • 87. Sephton MA. Organic compounds in carbonaceous meteorites. Nat Prod Rep. 2002;/19:/292 311.
    • 88. Llorca J. Organic matter in meteorites. Int Microbiol. 2004;/ 7:/239 48.
    • 89. Pizzarello S. The chemistry of life's origin: a carbonaceous meteorite perspective. Acc Chem Res. 2006;/39:/231 7.
    • 90. Matthews CN, Ludicky R. Hydrogen cyanide polymers on comets. Adv Space Res. 1992;/12:/21 32.
    • 91. Irvine WM, Bockelee-Morvan D, Lis DC, Matthews HE, Biver N, Crovisier J, et al. Spectroscopic evidence for interstellar ices in comet Hyakutake. Nature. 1996;/383:/ 418 20.
    • 92. Irvine WM, Dickens JE, Lovell AJ, Schloerb FP, Senay M, Bergin EA, et al. The HNC/HCN ratio in comets. Earth Moon Planets. 1997;/78:/29 35.
    • 93. Meier R, Owen TC. Cometary deuterium. Space Sci Rev. 1999;/1 2:/33 43.
    • 94. Hesstvedt E, Isaksen ISA. On NO2 absorption of solar radiation and its role in the heat budget of the lower atmosphere. Institute Report Series. Institute of Geophysics, University of Oslo, No. 6, May 1974.
    • 95. WHO home page about influenza: Fact sheet.
    • 96. Anati E. Esodo Tra Mito E Storia. Archeologia, esegesi a geografica storica. [Exodus between myth and history. Archaeology, exegesis and historical geography.] Capo di Ponte, Italy: Edizioni del Centro, 1997 (in Italian).
    • 97. Anati E. The riddle of Mount Sinai. Archaeological discoveries at Har Karkom. Capo di Ponte, Italy: Edizioni del Centro; 2001.
    • 98. Gibbons A. How the Akkadian empire was hung out to dry. Science. 1993;/261:/985.
    • 99. Weiss H, Courty M-A, Wetterstrom W, Guichard F, Senior L, Meadow R, et al. The genesis and collapse of Third Millennium North Mesopotamian civilization. Science. 1993;/261:/995 1004.
    • 100. Hassan FA. The collapse of the Old Kingdom: low floods, famines, and anarchy. Catastrophes and recoveries in the Holocene, 29 August 2 September 2002. Department of Geography & Earth Sciences, Brunel University, Uxbridge, UK (abstract).
    • 101. Andersen BG, Borns HW Jr. The Ice Age World. Oslo: Scandinavian University Press; 1994.
    • 102. Trump DH. The prehistory of the Mediterranean. Harmondsworth, UK: Penguin Books, 1981 (first published by Allan Lane 1980).
    • 103. Edwards IES. The pyramids of Egypt. Harmondsworth, UK: Penguin Books, reprinted 1982 (first published 1947).
    • 104. Covensky M. The ancient Near Eastern tradition. New York: Harper & Row; 1966.
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