Focus: Influenza A virus

Bird Flu: The Next Pandemic?

By Kelly Grooms, B.S.
Promega Corporation

Published in January 2007


Introduction

Emergency hospital during the 1918 influenza epidemic, Camp Funston, Kansas. Courtesy of the National Museum of Health and Medicine, Armed Forces Institute of Pathology, Washington, D.C. (NCP 1603).

There are influenza outbreaks every year. Globally, these annual epidemics sicken 5–15% of the population and result in an estimated 250,000–500,000 death. Lately the term “pandemic flu” has been heard a lot. From politicians, to public health specialists, to “made for TV” movies, everyone is talking about the next pandemic. But what is a pandemic? And why are so many people talking about the next one? The word pandemic comes from the Greek words “pan” meaning all and “demos” meaning people. Thus, a pandemic is an epidemic that spreads across a large region of the world, impacting a large number of people. It is the large scope of infection that makes it different from an epidemic where the outbreak of disease is limited to a circumscribed location. There were three influenza pandemics in the twentieth century: the “Spanish influenza” pandemic occurred in 1918; the “Asian influenza” pandemic in 1957; and the “Hong Kong influenza” pandemic in 1968.   

Of the three twentieth century pandemics, the 1918 pandemic was by far the most devastating. Arguably one of the deadliest infectious disease outbreaks in human history, it was responsible for up to 50 million deaths worldwide (1). Approximately 40% of the U.S. soldiers that died in World War I died as a result influenza (2).  It is inevitable that another influenza pandemic will occur, and recent deaths caused by a highly pathogenic avian flu virus (H5N1) have increased speculation that another catastrophic flu pandemic could be on the horizon.

The Making of a New Flu Strain

Flu is caused predominantly by influenza A viruses, which are negative-stranded RNA viruses belonging to the family Orthmyxoviridae (3). They have a segmented genome that consists of eight RNA segments, which encode at least ten proteins. Two glycosylated proteins on the surface of the virus, hemagglutinin (HA) and neuraminidase (NA) can be used to subtype influenza A viruses. To date, 16 HA and 9 NA subtypes have been identified (4). All influenza A virus subtypes have been isolated from birds and are considered to have descended from an avian source (4).

The segmented genome of influenza A viruses allows them to exchange genetic material. These reassortment events occur when one host is infected with two influenza A strains. It was reassortment between an established human virus and an avian virus that resulted in the influenza strains that caused both the 1957 (H2N2) and 1968 (H3N2) pandemics.

In contrast, sequence analysis of the 1918 strain (H1N1) has shown that all eight segments were most closely related to avian viruses (5,6). This suggests that the 1918 pandemic was caused by virus of novel origin that infected humans and then adapted to spread person to person (5).  A novel origin of the virus could partly explain the virulence of the 1918 pandemic, since people would not have been exposed to any segment of the 1918 virus and would have had no immunity. However, to establish that no segments of the 1918 strain were previously circulating in the human population would require archival samples of pre-1918 virus, and none have been found to date.

Asian Bird Flu: Could it Become the Next Pandemic?

Recently, another avian influenza virus has begun infecting people on a limited basis.

First isolated in 1996 in China, the “Asian Bird Flu”, or H5N1 influenza, is a highly pathogenic avian influenza strain.  Reports of H5N1 poultry outbreaks have continued to increase and it now appears to be endemic in avian hosts in Asia (7).  H5N1 can kill wild water fowl, which has long been considered a disease-free natural reservoir, and has become progressively more deadly for mammals (8). Through infection in migratory birds, the H5N1 virus is progressing westward across Europe (9). In 2005, H5N1 variants with an increased virulence in experimentally infected chicken and mice were isolated from dead migratory birds in Qinghai Lake in China, which is a breeding center for migratory birds from southeast Asia, Siberia, Australia and New Zealand (10).

Although rare, human infection with H5N1 influenza has resulted in an unusually high fatality rate. As of November 2006, the World Health Organization reported 258 laboratory-confirmed cases of H5N1 influenza in humans. Out of these, 154 (59.7%) were fatal (11).

The genetic evidence that suggests the 1918 pandemic strain arose from an avian influenza strain that adapted to humans combined with the emergence of a new avain influenza strain with a high mortality rate in humans is causing concern that another catastrophic pandemic could be coming. The last step would be for a H5N1 strain to adapt so that it is easily transmitted from person to person. Although there has been one report of person-to-person infection with H5N1 influenza (12), the virus does not yet spread efficiently in humans.

Predicting a Pandemic

It is impossible to know if the current H5N1 will ever adapt to humans in such a way that it could easily be spread from person to person. However, there is evidence that mutations that enhance viral polymerase activity may help avian influenza viruses adapt to humans (13).  By comparing the three avain virus polymerase genes PA, PB1 and PB2 with the human influenza A polymerase genes, Taubenberger, J. et al. identified four amino acids of PB, one of PB1 and five of PB2 that are found in human influenza (including the 1918 virus) but not typically found in avian viruses (14).

When the genetic sequences of two H5N1 strains (the 1997 Hong Kong H5N1 and the 2004 Vietnam H5N1) were analyzed, several human isolates of these viruses contained one of the five amino acid changes in PB2 that Tauberger,  et al. (14) identified as being significant for the infection of humans by the 1918 virus. This suggests that several more genetic changes would be necessary before the H5N1 virus could spread efficiently from person to person (6).  Samples of virus are isolated in most reported cases of bird-to-human transmission, and monitoring the sequences of viruses isolated in these instances could help predict the emergence of potential pandemic strains before large spread infection occurs.

Conclusion

Influenza A viruses cause seasonal outbreaks of disease every year. Occasionally, a new strain emerges as a result of reassortment between human and avian influenza viruses. These reassorted viruses can result in pandemic influenza outbreaks such those that occurred in 1957 and 1968.  Recent evidence suggests that avian influenza viruses might also adapt to become highly infectious in people without reassorting with a human viral strain. The devastating pandemic of 1918 is believed to have been caused by an avian virus that successfully adapted to humans. Sequence analysis of different influenza strains have identified several amino acid changes in the three avian influenza polymerase genes that may be critical for the virus to successfully adapt to humans.

The highly pathogenic avian influenza virus H5N1 has become widespread in both domestic fowl and wild birds in Asia, and the sporadic number of human cases is increasing. These facts, taken with sequence analysis that showed some H5N1 isolates contained sequence changes thought to be critical for full adaptation to humans, has health officials concerned that another pandemic strain could be emerging. Although the H5N1 virus may never develop the ability to spread efficiently enough to trigger a pandemic, the 1918 pandemic teaches us that it should be closely watched. And perhaps the 1918 virus left behind just enough clues that we can identify the next strain before it triggers a pandemic.

References

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