• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of transbhomepageaboutsubmitalertseditorial board
Philos Trans R Soc Lond B Biol Sci. Dec 29, 2001; 356(1416): 1829–1839.
PMCID: PMC1088558

Integrating historical, clinical and molecular genetic data in order to explain the origin and virulence of the 1918 Spanish influenza virus.

Abstract

The Spanish influenza pandemic of 1918-1919 caused acute illness in 25-30% of the world's population and resulted in the death of 40 million people. The complete genomic sequence of the 1918 influenza virus will be deduced using fixed and frozen tissues of 1918 influenza victims. Sequence and phylogenetic analyses of the complete 1918 haemagglutinin (HA) and neuraminidase (NA) genes show them to be the most avian-like of mammalian sequences and support the hypothesis that the pandemic virus contained surface protein-encoding genes derived from an avian influenza strain and that the 1918 virus is very similar to the common ancestor of human and classical swine H1N1 influenza strains. Neither the 1918 HA genes nor the NA genes possessed mutations that are known to increase tissue tropicity, which accounts for the virulence of other influenza strains such as A/WSN/33 or fowl plague viruses. The complete sequence of the nonstructural (NS) gene segment of the 1918 virus was deduced and tested for the hypothesis that the enhanced virulence in 1918 could have been due to type I interferon inhibition by the NS1 protein. The results from these experiments were inconclusive. Sequence analysis of the 1918 pandemic influenza virus is allowing us to test hypotheses as to the origin and virulence of this strain. This information should help to elucidate how pandemic influenza strains emerge and what genetic features contribute to their virulence.

Full Text

The Full Text of this article is available as a PDF (196K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Basler CF, Reid AH, Dybing JK, Janczewski TA, Fanning TG, Zheng H, Salvatore M, Perdue ML, Swayne DE, García-Sastre A, et al. Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes. Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2746–2751. [PMC free article] [PubMed]
  • Brown IH, Harris PA, Alexander DJ. Serological studies of influenza viruses in pigs in Great Britain 1991-2. Epidemiol Infect. 1995 Jun;114(3):511–520. [PMC free article] [PubMed]
  • Brown IH, Harris PA, McCauley JW, Alexander DJ. Multiple genetic reassortment of avian and human influenza A viruses in European pigs, resulting in the emergence of an H1N2 virus of novel genotype. J Gen Virol. 1998 Dec;79(Pt 12):2947–2955. [PubMed]
  • Buonagurio DA, Nakada S, Parvin JD, Krystal M, Palese P, Fitch WM. Evolution of human influenza A viruses over 50 years: rapid, uniform rate of change in NS gene. Science. 1986 May 23;232(4753):980–982. [PubMed]
  • Castrucci MR, Donatelli I, Sidoli L, Barigazzi G, Kawaoka Y, Webster RG. Genetic reassortment between avian and human influenza A viruses in Italian pigs. Virology. 1993 Mar;193(1):503–506. [PubMed]
  • Claas EC, Osterhaus AD, van Beek R, De Jong JC, Rimmelzwaan GF, Senne DA, Krauss S, Shortridge KF, Webster RG. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet. 1998 Feb 14;351(9101):472–477. [PubMed]
  • Colman PM, Varghese JN, Laver WG. Structure of the catalytic and antigenic sites in influenza virus neuraminidase. Nature. 1983 May 5;303(5912):41–44. [PubMed]
  • Cox NJ, Subbarao K. Global epidemiology of influenza: past and present. Annu Rev Med. 2000;51:407–421. [PubMed]
  • DAVENPORT FM, HENNESSY AV, FRANCIS T., Jr Epidemiologic and immunologic significance of age distribution of antibody to antigenic variants of influenza virus. J Exp Med. 1953 Dec;98(6):641–656. [PMC free article] [PubMed]
  • Dowdle WR. Influenza A virus recycling revisited. Bull World Health Organ. 1999;77(10):820–828. [PMC free article] [PubMed]
  • Fanning TG, Taubenberger JK. Phylogenetically important regions of the influenza A H1 hemagglutinin protein. Virus Res. 1999 Dec 1;65(1):33–42. [PubMed]
  • Fanning TG, Reid AH, Taubenberger JK. Influenza A virus neuraminidase: regions of the protein potentially involved in virus-host interactions. Virology. 2000 Oct 25;276(2):417–423. [PubMed]
  • Fitch WM, Leiter JM, Li XQ, Palese P. Positive Darwinian evolution in human influenza A viruses. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4270–4274. [PMC free article] [PubMed]
  • Gambaryan AS, Tuzikov AB, Piskarev VE, Yamnikova SS, Lvov DK, Robertson JS, Bovin NV, Matrosovich MN. Specification of receptor-binding phenotypes of influenza virus isolates from different hosts using synthetic sialylglycopolymers: non-egg-adapted human H1 and H3 influenza A and influenza B viruses share a common high binding affinity for 6'-sialyl(N-acetyllactosamine). Virology. 1997 Jun 9;232(2):345–350. [PubMed]
  • Gammelin M, Altmüller A, Reinhardt U, Mandler J, Harley VR, Hudson PJ, Fitch WM, Scholtissek C. Phylogenetic analysis of nucleoproteins suggests that human influenza A viruses emerged from a 19th-century avian ancestor. Mol Biol Evol. 1990 Mar;7(2):194–200. [PubMed]
  • García-Sastre A, Egorov A, Matassov D, Brandt S, Levy DE, Durbin JE, Palese P, Muster T. Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology. 1998 Dec 20;252(2):324–330. [PubMed]
  • Gaydos JC, Hodder RA, Top FH, Jr, Soden VJ, Allen RG, Bartley JD, Zabkar JH, Nowosiwsky T, Russell PK. Swine influenza A at Fort Dix, New Jersey (January-February 1976). I. Case finding and clinical study of cases. J Infect Dis. 1977 Dec;136 (Suppl):S356–S362. [PubMed]
  • Gensheimer KF, Fukuda K, Brammer L, Cox N, Patriarca PA, Strikas RA. Preparing for pandemic influenza: the need for enhanced surveillance. Emerg Infect Dis. 1999 Mar-Apr;5(2):297–299. [PMC free article] [PubMed]
  • Ito T, Suzuki Y, Takada A, Kawamoto A, Otsuki K, Masuda H, Yamada M, Suzuki T, Kida H, Kawaoka Y. Differences in sialic acid-galactose linkages in the chicken egg amnion and allantois influence human influenza virus receptor specificity and variant selection. J Virol. 1997 Apr;71(4):3357–3362. [PMC free article] [PubMed]
  • Kanegae Y, Sugita S, Shortridge KF, Yoshioka Y, Nerome K. Origin and evolutionary pathways of the H1 hemagglutinin gene of avian, swine and human influenza viruses: cocirculation of two distinct lineages of swine virus. Arch Virol. 1994;134(1-2):17–28. [PubMed]
  • Katz JM, Lim W, Bridges CB, Rowe T, Hu-Primmer J, Lu X, Abernathy RA, Clarke M, Conn L, Kwong H, et al. Antibody response in individuals infected with avian influenza A (H5N1) viruses and detection of anti-H5 antibody among household and social contacts. J Infect Dis. 1999 Dec;180(6):1763–1770. [PubMed]
  • Kawaoka Y, Webster RG. Molecular mechanism of acquisition of virulence in influenza virus in nature. Microb Pathog. 1988 Nov;5(5):311–318. [PubMed]
  • Kawaoka Y, Krauss S, Webster RG. Avian-to-human transmission of the PB1 gene of influenza A viruses in the 1957 and 1968 pandemics. J Virol. 1989 Nov;63(11):4603–4608. [PMC free article] [PubMed]
  • Kilbourne ED. Influenza pandemics in perspective. JAMA. 1977 Mar 21;237(12):1225–1228. [PubMed]
  • Kupradinun S, Peanpijit P, Bhodhikosoom C, Yoshioka Y, Endo A, Nerome K. The first isolation of swine H1N1 influenza viruses from pigs in Thailand. Arch Virol. 1991;118(3-4):289–297. [PubMed]
  • Lamb RA, Lai CJ. Sequence of interrupted and uninterrupted mRNAs and cloned DNA coding for the two overlapping nonstructural proteins of influenza virus. Cell. 1980 Sep;21(2):475–485. [PubMed]
  • Li S, Schulman J, Itamura S, Palese P. Glycosylation of neuraminidase determines the neurovirulence of influenza A/WSN/33 virus. J Virol. 1993 Nov;67(11):6667–6673. [PMC free article] [PubMed]
  • Li Y, Yamakita Y, Krug RM. Regulation of a nuclear export signal by an adjacent inhibitory sequence: the effector domain of the influenza virus NS1 protein. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):4864–4869. [PMC free article] [PubMed]
  • Ludwig S, Stitz L, Planz O, Van H, Fitch WM, Scholtissek C. European swine virus as a possible source for the next influenza pandemic? Virology. 1995 Oct 1;212(2):555–561. [PubMed]
  • Masurel N. Swine influenza virus and the recycling of influenza-A viruses in man. Lancet. 1976 Jul 31;2(7979):244–247. [PubMed]
  • Matrosovich MN, Gambaryan AS, Teneberg S, Piskarev VE, Yamnikova SS, Lvov DK, Robertson JS, Karlsson KA. Avian influenza A viruses differ from human viruses by recognition of sialyloligosaccharides and gangliosides and by a higher conservation of the HA receptor-binding site. Virology. 1997 Jun 23;233(1):224–234. [PubMed]
  • Pandemic Influenza: Confronting a Re-emergent Threat. Proceedings of a meeting. Bethesda, Maryland, 11-13 December 1995. J Infect Dis. 1997 Aug;176 (Suppl 1):S1–90. [PubMed]
  • Nerome K, Ishida M, Oya A, Oda K. The possible origin H1N1 (Hsw1N1) virus in the swine population of Japan and antigenic analysis of the isolates. J Gen Virol. 1982 Sep;62(Pt 1):171–175. [PubMed]
  • O'Neill RE, Talon J, Palese P. The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins. EMBO J. 1998 Jan 2;17(1):288–296. [PMC free article] [PubMed]
  • Palese P, Compans RW. Inhibition of influenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA): mechanism of action. J Gen Virol. 1976 Oct;33(1):159–163. [PubMed]
  • Patterson KD, Pyle GF. The geography and mortality of the 1918 influenza pandemic. Bull Hist Med. 1991 Spring;65(1):4–21. [PubMed]
  • PHILIP RN, LACKMAN DB. Observations on the present distribution of influenza A/swine antibodies among Alaskan natives relative to the occurrence of influenza in 1918-1919. Am J Hyg. 1962 May;75:322–334. [PubMed]
  • Reid AH, Taubenberger JK. The 1918 flu and other influenza pandemics: "over there" and back again. Lab Invest. 1999 Feb;79(2):95–101. [PubMed]
  • Reid AH, Fanning TG, Hultin JV, Taubenberger JK. Origin and evolution of the 1918 "Spanish" influenza virus hemagglutinin gene. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1651–1656. [PMC free article] [PubMed]
  • Reid AH, Fanning TG, Janczewski TA, Taubenberger JK. Characterization of the 1918 "Spanish" influenza virus neuraminidase gene. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6785–6790. [PMC free article] [PubMed]
  • Reid AH, Taubenberger JK, Fanning TG. The 1918 Spanish influenza: integrating history and biology. Microbes Infect. 2001 Jan;3(1):81–87. [PubMed]
  • Rott R, Klenk HD, Nagai Y, Tashiro M. Influenza viruses, cell enzymes, and pathogenicity. Am J Respir Crit Care Med. 1995 Oct;152(4 Pt 2):S16–S19. [PubMed]
  • Schäfer JR, Kawaoka Y, Bean WJ, Süss J, Senne D, Webster RG. Origin of the pandemic 1957 H2 influenza A virus and the persistence of its possible progenitors in the avian reservoir. Virology. 1993 Jun;194(2):781–788. [PubMed]
  • Scholtissek C, Ludwig S, Fitch WM. Analysis of influenza A virus nucleoproteins for the assessment of molecular genetic mechanisms leading to new phylogenetic virus lineages. Arch Virol. 1993;131(3-4):237–250. [PubMed]
  • Scholtissek C, Rohde W, Von Hoyningen V, Rott R. On the origin of the human influenza virus subtypes H2N2 and H3N2. Virology. 1978 Jun 1;87(1):13–20. [PubMed]
  • Schulze IT. Effects of glycosylation on the properties and functions of influenza virus hemagglutinin. J Infect Dis. 1997 Aug;176 (Suppl 1):S24–S28. [PubMed]
  • SHOPE RE. Influenza: history, epidemiology, and speculation. Public Health Rep. 1958 Feb;73(2):165–178. [PMC free article] [PubMed]
  • Simonsen L, Clarke MJ, Schonberger LB, Arden NH, Cox NJ, Fukuda K. Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J Infect Dis. 1998 Jul;178(1):53–60. [PubMed]
  • Simonsen L, Fukuda K, Schonberger LB, Cox NJ. The impact of influenza epidemics on hospitalizations. J Infect Dis. 2000 Mar;181(3):831–837. [PubMed]
  • Subbarao K, Klimov A, Katz J, Regnery H, Lim W, Hall H, Perdue M, Swayne D, Bender C, Huang J, et al. Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science. 1998 Jan 16;279(5349):393–396. [PubMed]
  • Talon J, Horvath CM, Polley R, Basler CF, Muster T, Palese P, García-Sastre A. Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein. J Virol. 2000 Sep;74(17):7989–7996. [PMC free article] [PubMed]
  • Taubenberger JK. Influenza virus hemagglutinin cleavage into HA1, HA2: no laughing matter. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9713–9715. [PMC free article] [PubMed]
  • Taubenberger JK, Reid AH, Fanning TG. The 1918 influenza virus: A killer comes into view. Virology. 2000 Sep 1;274(2):241–245. [PubMed]
  • Taubenberger JK, Reid AH, Krafft AE, Bijwaard KE, Fanning TG. Initial genetic characterization of the 1918 "Spanish" influenza virus. Science. 1997 Mar 21;275(5307):1793–1796. [PubMed]
  • Wang X, Li M, Zheng H, Muster T, Palese P, Beg AA, García-Sastre A. Influenza A virus NS1 protein prevents activation of NF-kappaB and induction of alpha/beta interferon. J Virol. 2000 Dec;74(24):11566–11573. [PMC free article] [PubMed]
  • Webster RG, Rott R. Influenza virus A pathogenicity: the pivotal role of hemagglutinin. Cell. 1987 Aug 28;50(5):665–666. [PubMed]
  • Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y. Evolution and ecology of influenza A viruses. Microbiol Rev. 1992 Mar;56(1):152–179. [PMC free article] [PubMed]
  • Webster RG, Sharp GB, Claas EC. Interspecies transmission of influenza viruses. Am J Respir Crit Care Med. 1995 Oct;152(4 Pt 2):S25–S30. [PubMed]
  • Weis W, Brown JH, Cusack S, Paulson JC, Skehel JJ, Wiley DC. Structure of the influenza virus haemagglutinin complexed with its receptor, sialic acid. Nature. 1988 Jun 2;333(6172):426–431. [PubMed]
  • Woods GT, Schnurrenberger PR, Martin RJ, Tompkins WA. Swine influenza virus in swine and man in Illinois. J Occup Med. 1981 Apr;23(4):263–267. [PubMed]
  • Zhou NN, Senne DA, Landgraf JS, Swenson SL, Erickson G, Rossow K, Liu L, Yoon KJ, Krauss S, Webster RG. Emergence of H3N2 reassortant influenza A viruses in North American pigs. Vet Microbiol. 2000 May 22;74(1-2):47–58. [PubMed]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...