![3DDown](3D"http://vir.sgmjournals.org/icons/fig-down.gif")
).
The 1918 influenza pandemic fits the classic pattern of =
influenza=20
epidemiology in many ways. It occurred 28 years after =
the=20
previous pandemic of 1890 and emerged globally with explosive =
suddenness in September 1918 after a limited wave earlier in=20
the year. Most communities experienced morbidity of 25=A8C40 =
% and=20
the vast majority of cases were self-limiting. Age-specific =
morbidity=20
was also similar to other pandemics, with children under=20
15 years of age experiencing the highest rates of =
infection=20
(Jordan, 1927). Clinically, the 1918 pandemic presented the =
same=20
symptoms and course as influenza of other years and, =
pathologically,=20
the disease was similar to other pandemics in that damage was =
confined largely to the respiratory tract (Wolbach, 1919; Winternitz et al., 1920). However, the 1918 pandemic differed from =
other=20
pandemics in a few key respects. First, while the clinical =
course in=20
the majority of cases was mild, a substantially higher =
percentage of=20
cases developed severe pneumonic complications. As a result, =
the case=20
mortality rate in the USA averaged 2=A1=A45 %, several times =
higher than=20
the contemporary average. Also, mortality during the 1918 =
pandemic=20
was concentrated in an unusually young age group (Linder =
& Grove,=20
1943; Marks & Beatty, 1976; Rosenau & Last, 1980). People under the age of 65 accounted for =
more than 99=20
% of excess influenza-related deaths in 1918. In 1957 and =
1968,=20
people under 65 accounted for only 36 and 48 % of excess =
deaths due=20
to influenza (Simonsen et al., 1998). The age group affected most severely by the 1918 =
pandemic=20
was between 20 and 40 years and this group accounted for =
almost half of influenza deaths during the pandemic.
Until recently, the 1918 pandemic strain was not available for=20
study, since influenza viruses were not isolated and cultured =
until the 1930s. By then, 15 years of circulation in =
humans=20
had altered significantly the antigenicity of the circulating =
H1 haemagglutinin (HA), as assessed serologically (Shope, 1936; Taubenberger et al., 2001), and only indirect analyses of the 1918 =
strain could=20
be performed. Recently, extraction of RNA from fixed and =
frozen lung=20
tissues from victims of the 1918 pandemic has allowed the =
sequencing=20
of the 1918 influenza virus genome (Taubenberger et =
al.,=20
1997). Four of eight gene segments have been =
sequenced (Reid=20
et al., 1999, 2000, 2002; Basler et al., 2001). This work has two principal goals: to determine =
the=20
genetic contribution to the virulence of the 1918 influenza =
and to=20
determine the origin of the pandemic virus. Understanding the =
basis=20
of the virulence of the 1918 strain could help in the =
development of=20
influenza treatment and prevention, while knowing where and =
how the=20
strain developed could help direct surveillance and =
prevention=20
efforts.
![3D""](3D"http://vir.sgmjournals.org/icons/toc/rarrow.gif"=20) |
=20
Influenza A virus biology and ecology =
|
TOP
ABSTRACT
![](3D"http://vir.sgmjournals.org/icons/toc/uarrow.gif"=20) INTRODUCTION
![](3D"http://vir.sgmjournals.org/icons/toc/dot.gif") Influenza A virus biology...
![](3D"http://vir.sgmjournals.org/icons/toc/darrow.gif"=20) The 1957 and 1968...
Origin of the 1918...
Involvement of an intermediate...
CONCLUSION
REFERENCES
|
I=
nfluenza=20
A viruses are negative-stranded RNA viruses of the family=20
Orthomyxoviridae (Lamb & Krug, 2001; Wright & Webster, 2001). Their segmented genome consists of eight RNA =
segments=20
encoding at least ten proteins. Two glycosylated proteins on =
the=20
surface of the virus, HA and NA (neuraminidase), are involved =
in=20
virus attachment and release from host cells. They are also =
the=20
primary target of the immune system in humans and swine. Two=20
nonstructural proteins, NS1 and NS2 (also called NEP), are =
involved=20
in regulating numerous aspects of the virus life cycle. Three =
proteins, PA, PB1 and PB2, are responsible for virus =
replication,=20
while the nucleoprotein, NP, is the nucleocapsid structural =
protein.=20
Finally, two membrane proteins, M1 and M2, are involved in =
nuclear=20
export and pH maintenance, respectively, among other =
activities (Lamb=20
& Krug, 2001; Wright & Webster, 2001). Influenza A virus is capable of considerable =
genetic=20
variability. Its polymerases' lack of proofreading capability =
results=20
in a high mutation rate and the organization of the genome =
into=20
segments allows reassortment as an important mechanism for =
generating=20
diverse strains. Co-infection of one host with two strains =
can result=20
in novel, reassortant strains, because progeny viruses can be =
formed=20
with some gene segments from one strain and some from the =
other.=20
Pandemic influenza results when an influenza virus strain =
emerges=20
with an HA protein to which few people have prior immunity=20
(Kilbourne, 1977). It is thought that the source of HA genes new to =
humans=20
is the extensive pool of influenza viruses that infect wild=20
birds (Wright & Webster, 2001). Periodically, genetic material from avian =
strains is=20
transferred to strains infectious to humans by reassortment. =
Of the=20
15 HA subtypes found in birds (H1=A8CH15), only three (H1, H2 =
and H3)=20
are known to have caused pandemics in man (Kilbourne, 1997). Recently, wholly avian H5N1 and H9N2 =
viruses (without=20
reassortment) caused illness in a limited number of people in =
China=20
(Lin et al., 2000; Hatta & Kawaoka, 2002). Avian and human HAs differ in their ability =
to bind=20
to different forms of sialic acids and avian HAs bind poorly =
to the=20
sialic acid receptors prevalent in the human respiratory =
tract.=20
These different receptor affinities act as a barrier to=20
cross-species infection. Before a virus with an avian HA can=20
replicate and spread efficiently in humans, some adaptation =
of the HA=20
binding affinity is necessary. It is not known currently =
whether=20
the HA subtypes that have become established in human strains =
were able to adapt more easily than other subtypes or whether =
all 15 avian subtypes pose a similar risk of =
reassortment.=20
Since pigs can be infected with both avian and human strains, =
and=20
various reassortants have been isolated from pigs, they have =
been=20
proposed as an intermediary in the generation of reassortant =
pandemic=20
strains (Ludwig et al., 1995). In 1979, an avian influenza A virus began =
infecting=20
swine in Northern Europe, thereby establishing a stable virus =
lineage=20
(Ludwig et al., 1995). Since that time, there has been evidence of =
reassortment between the new swine lineage and human strains=20
circulating currently. Viruses have been detected in swine in =
which=20
the avian-derived H1 and N1 have been replaced by =
reassortment with=20
the H3 and N2 HA and NA segments circulating concurrently in =
humans=20
(Castrucci et al., 1993; Claas et al., 1994; Marozin et al., 2002). However, reassortant strains with the =
avian-derived=20
H1 and N1 along with human-adapted core protein segments have =
not=20
been found. Such reassortant strains would be antigentically =
novel=20
and probably capable of effective replication in humans and,=20
therefore, would have substantial pandemic potential. =
Similarly, a=20
number of triple reassortant strains, which include gene =
segments of=20
swine, human and avian origin, have been isolated recently =
from=20
pigs in the USA. Several reassortant viruses bearing human HA =
and NA segments have been isolated from swine but, as yet, no =
viruses with swine or avian surface proteins and human =
internal=20
protein segments have been detected (Zhou et al., =
2000; Marozin et al., 2002; Olsen, 2002).
Until recently, it was thought that reassortment between avian =
and=20
human strains would be unlikely to take place in humans =
because there=20
was no evidence that humans could be infected by a wholly =
avian=20
influenza virus. However, in 1997, 18 people were infected =
with avian=20
H5N1 influenza viruses in Hong Kong and six died of =
complications=20
after infection (Claas et al., 1998; Subbarao et al., 1998). Although these viruses were very poorly=20
transmissible, if at all (Katz et al., 1999), their detection indicates that humans can =
be infected=20
with wholly avian influenza virus strains. Therefore, it may =
not be=20
necessary to invoke swine as the intermediary in the =
formation of a=20
pandemic strain (Scholtissek, 1995), since reassortment could take place directly =
in=20
humans (Young & Palese, 1979; Palese & Young, 1982).
While reassortment appears to be a critical event for the =
production=20
of a pandemic virus, a significant amount of data exists to=20
suggest that influenza viruses must also acquire specific =
adaptations=20
to spread and replicate efficiently in a new host. In =
addition=20
to the adaptation of the HA protein to host cell receptors,=20
other viral proteins must be able to interact with each other =
and various host cell proteins. Unfortunately, little is =
known=20
about which specific genetic features of influenza viruses =
contribute=20
to the emergence of a virulent pandemic strain. Virulence is=20
complex and involves a number of features, including host =
adaptation,=20
transmissibility, tissue tropism and virus replication =
efficiency.=20
The genetic basis for each of these features is not =
characterized=20
fully yet but is most likely polygenic in nature (Kilbourne,=20
1977).
|
The=20
1957 and 1968 influenza virus pandemic strains =
|
TOP
ABSTRACT
INTRODUCTION
Influenza A virus biology...
The 1957 and 1968...
Origin of the 1918...
Involvement of an intermediate...
CONCLUSION
REFERENCES
|
P=
rior to=20
recent work on the 1918 virus, only two pandemic influenza =
virus=20
strains were available for molecular genetic analysis, the =
H2N2=20
strain from 1957 and the H3N2 strain from 1968. The 1957 =
pandemic=20
resulted from the emergence of a reassortant influenza virus =
in which=20
both the HA and NA segments had been replaced by gene =
segments=20
related closely to avian strains (Scholtissek et al., =
1978a; Schafer et al., 1993; Webster et al., 1995). The 1968 pandemic followed with the =
emergence of a=20
strain in which the H2 subtype HA gene segment was replaced =
with an=20
avian-derived H3 HA gene segment (Scholtissek et al., =
1978a; Webster et al., 1995), while retaining the N2 gene segment derived in =
1957.=20
More recently, it was shown that the PB1 gene segment was =
replaced=20
in both the 1957 and 1968 pandemics, also with a likely avian =
derivation in both cases (Kawaoka et al., 1989). The remaining five gene segments: PA, PB2, =
NP, M and=20
NS, were all preserved from the H1N1 strains circulating =
prior to=20
1957. These segments were likely the direct descendants of =
the gene=20
segments present in the 1918 virus.
A pandemic virus faces the twin challenges of being =
antigenically=20
=A1=AEnew=A1=AF to its host, while being supremely well =
adapted to it.=20
This challenge was met in 1957 and 1968 by reassortment: =
combining=20
surface proteins novel to humans with human-adapted internal =
proteins=20
(with the intriguing exception of PB1). The 1968 viral HA =
appears to=20
have had an avian origin (Fang et al., 1981; Bean et al., 1992). Sequencing of an avian H3 HA gene=20
(A/duck/Ukraine/1/63) isolated in 1963 demonstrated its close =
molecular similarity to the HA gene of A/Aichi/2/68, the =
latter=20
being an example of the 1968 pandemic virus. For example, =
1605=20
of 1765 nucleotides (90=A1=A49 %) are identical between the =
two=20
viruses, while 542 of 566 amino acids (95=A1=A48 %) are =
identical=20
(Fang et al., 1981). In addition, of the approximately =
40 amino acid=20
residues involved in antigenic recognition, only four =
residues differ=20
between A/duck/Ukraine/1/63 and A/Aichi/2/68. For comparison, =
there=20
are 14 amino acid differences in antigenic residues =
between=20
A/duck/Ukraine/1/63 and A/Victoria/3/75, a human virus =
isolated only=20
7 years after the A/Aichi/2/68 virus (Fang et =
al., 1981). Also, phylogenetic analyses support =
strongly the=20
avian origin of the 1968 pandemic HA gene (Bean et =
al., 1992).
Like the 1968 H3 pandemic strain, the HA of the 1957 pandemic =
is=20
closely related also to avian H2 sequences. When the 1957 H2=20
sequences are compared as a group to avian HA sequences, only =
four=20
amino acids differ consistently between the human and avian =
groups=20
[N92![3D"-]()
" =
src=3D"http://vir.sgmjournals.org/math/rarr.gif"=20
border=3D0>D, T114![3D"-]()
"=20
src=3D"http://vir.sgmjournals.org/math/rarr.gif" border=3D0>K, =
K156" src=3D"http://vir.sgmjournals.org/math/rarr.gif" border=3D0>E =
and=20
I214![3D"-]()
" =
src=3D"http://vir.sgmjournals.org/math/rarr.gif"=20
border=3D0>T; H3 subtype sequence numbering (Winter et =
al.,=20
1981)]. Residue 226, which is Q in all avian =
sequences and L=20
in most human sequences, is likely also to reflect a =
consistent=20
difference between human and avian strains, since it is =
critical to=20
improving the H2 binding affinity for receptors on human =
cells.=20
Approximately 40 amino acids have been identified as =
being=20
involved in antibody binding in the H3 molecule (Wiley et =
al.,=20
1981) and studies indicate that the H2 subtype has =
a similar=20
antigenic structure (Tsuchiya et al., 2001). Only one of the five amino acids differing =
between=20
avian and early human isolates is in an antigenic site, =
suggesting=20
that there had been little or no antigenic drift pressure on=20
the H2 molecule before it emerged in a pandemic strain. =
Phylogenetic=20
analyses (Schafer et al., 1993) indicate that the gene was acquired from an =
avian=20
source shortly before 1957. It appears that the avian source =
was=20
Eurasian, since the pandemic viral sequences resembled =
Eurasian avian=20
sequences much more closely than they resembled North =
American avian=20
sequences.
The 1957 pandemic strain also acquired a novel N2-subtype NA,=20
replacing the N1 of the previous strain. The sequence of the=20
new NA was related very closely to avian N2 sequences, with=20
only six amino acids differing consistently from avian =
sequences.=20
Thirty-four amino acids have been identified as potentially=20
antigenic residues on the N2 protein (Martinez et al., =
1983); none of the six differences are in these =
antigenic=20
sites, suggesting that the protein had not been under =
selective=20
antigenic pressure in humans before the pandemic. The avian =
sequence=20
related most closely to the 1957 sequences is=20
A/chicken/Korea/MS96/96, which differs at over 20 amino =
acids.=20
There are no full-length N2 sequences from wild birds in the=20
published databases but it seems likely that the recent avian =
origin=20
of the 1957 N2 will be confirmed by further sequencing of =
wild avian=20
strains.
The hypothesis that reassortment between avian and human strains =
is the likely mechanism for the generation of new pandemic =
strains=20
has become well accepted. During a recent outbreak of highly=20
pathogenic avian influenza in The Netherlands, efforts were=20
made to minimize the possibility of simultaneous infection =
with=20
human and avian influenza, especially when the virus began by =
causing conjunctivitis in humans. Those involved in the =
culling=20
process were vaccinated against circulating human strains and =
discouraged from contact with sick birds when suffering =
flu-like=20
symptoms in an effort to minimize the possibility of an =
individual=20
being infected simultaneously with human and avian strains =
(ProMED=20
Mail, 2003). Given that the 1957 and 1968 pandemic strains may =
well have originated in just such a dual infection, these =
precautions=20
seem appropriate. It is possible, though, that reassortment =
is=20
not the only route to a pandemic. In 1947, drift in the prevailing =
H1=20
strain resulted in vaccine failure and outbreaks of influenza =
on a=20
pandemic scale (Kilbourne, 1997). In 1977, an H1N1 virus re-emerged, having =
been absent=20
since 1957, but failed either to cause a pandemic or to =
replace the=20
prevailing H3N2 subtype (Nakajima et al., 1978).
|
Origin=20
of the 1918 HA gene |
TOP
ABSTRACT
INTRODUCTION
Influenza A virus biology...
The 1957 and 1968...
Origin of the 1918...
Involvement of an intermediate...
CONCLUSION
REFERENCES
|
T=
he=20
genetic sequences encoding the HA1 domains of five 1918 =
influenza=20
virus strains have been determined. Two of the strains came =
from=20
American soldiers who died on 26 September 1918: one in Camp =
Upton=20
(New York, USA) and one in Fort Jackson (South Carolina, =
USA). The=20
third came from an Inuit woman who died in mid-November 1918 =
in a=20
remote village on the Seward Peninsula of Alaska (USA). Two=20
nucleotide differences were found among these three strains, =
one of=20
which resulted in an amino acid substitution in the =
receptor-binding=20
site (Taubenberger et al., 1997; Reid et al., 1999). The fourth and fifth strains came from =
influenza=20
victims treated at the Royal London Hospital in London (UK) =
and who=20
died of pneumonia on 13 November 1918 and 15 February 1919,=20
respectively (Reid et al., 2003). The five sequences differ from each other =
by only one=20
to three nucleotides. Our results show that strains separated =
by over=20
7500 miles (Brevig Mission, Alaska, USA to London, UK) =
and by=20
several months (26 September 1918 to 15 February 1919) share =
a=20
sequence identity of 99 %.
There is reason to question whether the 1918 pandemic strain=20
originated in a simple reassortment immediately before the =
pandemic.=20
Extensive phylogenetic analyses of the HA gene segment, in=20
particular, are difficult to reconcile with the hypothesis of =
direct=20
avian origin (Reid et al., 1999). The sequence of the 1918 HA, although it is =
related=20
more closely to avian strains than subsequent mammalian H1 =
sequences,=20
has many more differences from avian sequences than the 1957 =
and 1968=20
HA sequences. If it should prove true that the 1918 pandemic =
strain=20
acquired a novel HA via a different mechanism than subsequent =
pandemics, this could have important public health =
implications. An=20
alternate origin could even have contributed to the =
exceptional=20
virulence of the 1918 pandemic strain. Despite the current =
lack of=20
influenza virus samples from before 1918, several indirect=20
experimental approaches have been explored to test the =
hypothesis of=20
an alternative origin of the 1918 influenza virus =
strain.
The sequence of the 1918 HA is related most closely to =
A/sw/Iowa/30,=20
the first influenza virus isolated from swine (Reid et =
al.,=20
1999). The similarity suggests that the human pandemic =
influenza=20
virus became established in swine, in which it changed very=20
slowly over the next 12 years. Unlike the 1957 and 1968=20
pandemic HAs, phylogenetic analyses do not place the 1918 =
sequence=20
in the avian clade. However, the 1918 pandemic sequence is =
related=20
more closely to avian H1s than to any other mammalian H1s and =
has many avian features. Of the 41 amino acids that have =
been shown to be targets of the immune system and subject to=20
antigenic drift pressure in humans, 37 match the avian =
consensus=20
sequence, suggesting that there was little immunologic =
pressure=20
on the HA protein before the autumn of 1918 (Reid et al., =
1999; Brownlee & Fodor, 2001). Another mechanism by which influenza =
viruses evade=20
the human immune system is the acquisition of glycosylation =
sites to=20
mask antigenic epitopes. Modern human H1N1s have up to five=20
glycosylation sites in addition to the four found in all =
avian=20
strains. The 1918 virus has only the four conserved avian =
sites.=20
The H1 receptor-binding site apparently required little change=20
from the avian-adapted receptor-binding site configuration =
[with=20
a preference for ![3D{alpha}=20](3D"http://vir.sgmjournals.org/math/agr.gif")
(2,3) =
sialic acids]=20
to that of swine H1s [which can bind both (2,3) and =
(2,6)=20
sialic acids] (Matrosovich et al., 1997). The receptor-binding residues of the 1918 HA =
differs=20
by as little as one amino acid (E190![3D"-]()
"=20
src=3D"http://vir.sgmjournals.org/math/rarr.gif" border=3D0>D) from the =
avian=20
consensus.
In spite of the many ways in which the 1918 HA resembles avian=20
viruses, phylogenetic analyses always place the 1918 HA with=20
the mammalian viruses and not with the avian viruses (Reid =
et=20
al., 1999). Both the 1957 and 1968 pandemic strains appear to =
have resulted from reassortments of a human-adapted influenza =
virus strain with HA genes from a Eurasian avian lineage =
strain=20
(Scholtissek et al., 1978b; Bean et al., 1992; Schafer et al., 1993). In contrast, the 1918 HA is much less avian-like =
and,=20
while probably novel to humans in 1918, does not appear to =
have=20
been derived directly from an avian strain (Taubenberger =
et=20
al., 2001). Table 1 presents the number of amino acid differences =
between=20
pandemic viruses and the consensus HA sequences of both North =
American and Eurasian birds. The numbers demonstrate that the =
HA=20
genes of the pandemic viruses of 1968 and 1957 are more =
Eurasian=20
avian-like (seven and five differences) than North American=20
avian-like (13 and 19 differences). In contrast, the 1918 =
pandemic=20
virus HA gene appears much less avian than either the 1968 or =
1957=20
viruses and has no clear affinity with either North American =
or=20
Eurasian avian viruses (Table 1). A similar situation can be demonstrated =
with the NA=20
genes of the 1918 and 1957 strains.
View =
this=20
table:
[in=20
this window]
[in a new window]
|
Table 1. Number of amino acid =
differences=20
between pandemic HA and the avian subtype consensus =
sequences
=
| |
=
;
The=20
1918 HA sequence suggests two contradictory explanations of =
its=20
origin: either the HA spent some length of time in an =
intermediate=20
host where it accumulated many changes from the original =
avian=20
sequence or the 1918 HA came directly from an avian virus =
with a=20
sequence markedly different from the H1 sequences available =
currently=20
(Reid et al., 1999). One possibility is that avian sequences =
might have=20
drifted substantially in the 80 years since the 1918 =
pandemic.=20
To assess this possibility, our laboratory, in collaboration =
with J.=20
Dean (Museum of Natural History, Smithsonian Institution, =
Washington,=20
USA) and R. D. Slemons (Ohio State University, Ohio, USA), =
was able=20
to identify an H1 avian influenza A virus strain from a Brant =
Goose=20
collected in 1917 and stored in the collections of the =
Smithsonian=20
Institution. The H1 sequence obtained is related closely to =
modern=20
avian North American H1 strains (Fig. 1), suggesting that there has been little drift =
in avian=20
sequences over the past 80 years (Fanning et al., =
2002). Thus, the possibility that the 1918 virus =
came=20
directly from the ancestor of an avian H1 strain known =
currently is=20
remote.
View =
larger=20
version (25K):
[in=20
this window]
[in a new window]
|
Fig. 1. Phylogenetic tree =
showing H1=20
sequences, including the 1918 pandemic strains and the 1917 =
Brant=20
goose (arrows) (Fanning et al., 2002).
=
| |
=
;
However,=20
there remains the possibility that H1-subtype HAs may exist =
in an=20
avian host that has not been identified yet or that more =
sequence=20
variation would be found within the H1 subtype upon more =
extensive=20
sampling. Currently, the influenza virus sequence database =
contains=20
only 14 avian H1 sequences, of which only nine are =
full-length=20
sequences. Five of the 14 sequences are from turkeys or =
chickens and=20
eight are from ducks. Comparison of these sequences shows =
that the=20
two sequences related most closely (A/goose/Hong Kong/8/76 =
and=20
A/chicken/Hong Kong/14/76) are 99=A1=A46 % identical at the =
nucleotide=20
level. The most distantly related (A/duck/Alberta/35/76 and=20
A/turkey/Germany/2482/90) are 85=A1=A42 % identical. Within =
the Eurasian=20
group of avian viruses, sequence similarity ranges from 88 to =
99=A1=A46=20
%. The North American viruses are more homogeneous, with=20
similarities ranging from 95=A1=A47 to 98=A1=A43 %. The 1918 =
pandemic=20
strain is equally distant =A8C between 74=A1=A45 and =
77=A1=A46 % identity =A8C=20
from all the avian H1s. Extensive sequencing of wild bird H1 =
strains=20
may identify a strain more similar to the 1918 HA. =
|
=20
Involvement of an intermediate host in 1918? =
|
TOP
ABSTRACT
INTRODUCTION
Influenza A virus biology...
The 1957 and 1968...
Origin of the 1918...
Involvement of an intermediate...
CONCLUSION
REFERENCES
|
I=
t may be=20
that no avian H1 will be found resembling the 1918 strain =
because, in=20
fact, the HA did not reassort directly from a bird strain. In =
this=20
case, an intermediate host must be identified. A possibility =
that has=20
been widely suggested is the pig (Webster et al., =
1992). Known to be susceptible to a wide range of both =
human=20
and avian viruses and long-lived enough to exert some =
positive immune=20
selection on the HA gene, swine could well have served as an=20
intermediate host between birds and humans in 1918 (Alexander =
&=20
Brown, 2000).
Indeed, during the 1918 pandemic, simultaneous outbreaks of=20
influenza were seen in humans and swine. Interestingly, swine =
influenza was first recognized as a clinical entity in that=20
species in the autumn of 1918 (Koen, 1919) concurrently with the spread of the second =
wave of the=20
pandemic in humans (Dorset et al., 1922). Investigators were impressed by the clinical =
and=20
pathological similarities between human and swine influenza =
in 1918=20
(Koen, 1919; Murray & Biester, 1930). An extensive review by the veterinarian W. =
W. Dimoch=20
of the diseases of swine published in August 1918 makes no =
mention of=20
any swine disease resembling influenza (Dimoch, 1918). Thus, contemporary investigators were =
convinced that=20
influenza virus had not circulated as an epizootic disease in =
swine=20
before 1918 and that the virus spread from humans to pigs =
because of=20
the appearance of illness in pigs after the first wave of the =
1918=20
influenza in humans (Shope, 1936).
Thereafter, the disease became widespread among swine herds =
in the=20
Midwest USA. The epizootic of 1919=A8C1920 was as extensive =
as that in=20
1918=A8C1919. The disease then appeared among swine in the =
Midwest every=20
year, leading to R. E. Shope's isolation of the first =
influenza virus=20
in 1930, A/swine/Iowa/30 (Shope & Lewis, 1931), 3 years before the isolation of the =
first human=20
influenza virus, A/WS/33, by W. Smith, C. Andrewes and P. =
Laidlaw=20
(Smith et al., 1933). Classical swine viruses have continued to =
circulate=20
not only in North American pigs but also in swine populations =
in=20
Europe and Asia (Nerome et al., 1982; Kupradinun et al., 1991; Brown et al., 1997).
During the fall and winter of 1918=A8C1919, severe =
influenza-like=20
disease outbreaks were noted not only in swine in the USA but =
also in Europe and China (Koen, 1919; Chun, 1919; Beveridge, 1977). The classical swine H1N1 lineage became endemic in =
swine=20
herds in the USA and there are good data to support the =
global=20
circulation of the 1918 influenza virus in pigs concurrently=20
with its circulation in humans. Since 1918, there have been=20
many examples of both H1N1 and H3N2 human influenza A virus=20
strains becoming established in swine (Castrucci et al., =
1993; Brown et al., 1998; Zhou et al., 2000). Unfortunately for the argument that swine =
might have=20
served as the intermediate between avian and humans in 1918, =
swine=20
influenza virus strains have been isolated only sporadically =
from=20
humans (Gaydos et al., 1977; Woods et al., 1981; Rimmelzwaan et al., 2001). It seems probable that at least during the =
height of=20
the 1918 pandemic, the direction of transmission was from =
humans to=20
pigs. However, is it possible that before the pandemic, the=20
originally avian HA was gradually adapting into a swine =
influenza=20
virus strain?
Interestingly, an avian H1N1 lineage has become established =
in=20
European swine in the last 20 years, providing a model =
for the=20
evolution of avian viruses in pigs. As noted earlier, the =
1918 HA1=20
sequence had many more amino acid differences from avian =
sequences=20
than did the 1957 and 1968 pandemic strains but very few of =
these=20
change were in antigenic sites, suggesting that the 1918 HA =
had not=20
been subjected to significant selective pressure before =
emerging as a=20
pandemic. In phylogenetic analyses, the 1918 HA is always =
placed in=20
the mammalian clade. It would be interesting to note whether, =
at some=20
point in the evolution of an avian H1N1 lineage in European =
pigs, a=20
similar degree of divergence from the avian clade would be =
found. The=20
earliest avian-like H1N1 strains were isolated from swine in=20
Northern Europe in 1979 and 1980. A/swine/Arnsberg/6554/79 =
has=20
12 amino acid differences from the avian consensus =
sequence and=20
A/Swine/Netherlands/3/80 has seven differences. In both =
cases, three=20
of the differences are in antigenic sites. In contrast, the =
1918 HA=20
has 28 amino acid differences from the avian consensus =
sequence,=20
of which four are in antigenic sites. The latest avian-like =
H1N1=20
isolated from swine in Europe from which sequence is =
available,=20
A/swine/Belgium/117/96, has 17 differences from the avian =
consensus=20
sequence, of which five are in antigenic sites. Furthermore,=20
phylogenetic analyses place even A/swine/Belgium/117/96 in =
the avian=20
clade. Thus, it appears that even 20 years of evolution =
in swine=20
has not resulted in the number of changes from the avian=20
consensus sequence exhibited by the 1918 pandemic =
strain.
|
=20
CONCLUSION |
TOP
ABSTRACT
INTRODUCTION
Influenza A virus biology...
The 1957 and 1968...
Origin of the 1918...
Involvement of an =
intermediate...
CONCLUSION
REFERENCES
|
U=
nderstanding=20
the origin of the 1918 pandemic influenza virus strain is not =
a=20
question of idle historical curiosity. Given the speed with =
which a=20
new pandemic could spread in the modern world, the emergence =
of a=20
strain as virulent as that of 1918 would be devastating. =
Current=20
surveillance efforts focused on rapid identification of novel =
strains=20
in humans as well as efforts to minimize the possibility of=20
cross-infection between species are aimed at detecting and =
preventing=20
a new pandemic. However, it is important to recognize that =
the=20
mechanisms by which pandemic strains originate have not been=20
explained yet. It seems likely that the 1957 and 1968 =
pandemic=20
strains originated in the reassortment of avian and human =
strains.=20
However, the actual circumstances and time-course of these=20
reassortment events were not detected at the time and, =
therefore, it=20
is unclear how long it would take such a reassorted strain to =
develop=20
into a pandemic. The 1918 pandemic strain is even more =
puzzling=20
because its HA sequence is neither consistent with direct=20
reassortment with a known avian H1 strain nor with adaptation =
in=20
swine. Sequencing of more avian H1 strains and research into=20
alternative intermediate hosts than swine, such as poultry or =
horses,=20
may shed further light on the origins of the 1918 pandemic. =
Until its=20
origins are understood better, detection and prevention =
efforts=20
may overlook the beginning of the next pandemic.
|
=20
ACKNOWLEDGEMENTS |
This =
work was=20
supported in part by grants from the NIH and by the =
intramural funds=20
of the Armed Forces Institute of Pathology. The opinions or=20
assertions contained herein are the private views of the =
authors and=20
are not to be construed as official or as reflecting the =
views of the=20
Department of the Army or Department of Defense. This is a US =
government work; there are no restrictions on its use. =
|
=20
REFERENCES |
TOP
ABSTRACT
INTRODUCTION
Influenza A virus biology...
The 1957 and 1968...
Origin of the 1918...
Involvement of an intermediate...
CONCLUSION
REFERENCES
|
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