In the second half of the Twentieth 
Century, buoyed up by post-war optimism and the accelerating pace of scientific and technological advancement, many believed that the battle against bacteria and viruses was over. Even the US Surgeon General William H. Stewart remarked in 1967 "It's time to close the book on infectious diseases and pay more attention to chronic ailments such as cancer and heart disease...the war against infectious diseases has been won." 1
Some went even further: "The most likely forecast about the future of infectious disease is that it will be very dull. There may be some wholly unexpected emergence of a new and dangerous infectious disease, but nothing of the sort that has marked the past fifty years," wrote the eminent Australian virologist and Nobel Prize winner Macfarlane Burnet in a medical textbook in the early 1970s. 2
Unfortunately history has proved them both wrong. Since those bold claims were made more than twenty novel diseases, including the worst pandemic humans have ever faced, AIDS, have emerged onto the world stage and, globally, infectious diseases now account for over 25% of the fifty-seven million annual deaths worldwide 3. But what are the origins of these new threats, and what provokes their appearance in the first place?
Three factors, occurring in isolation or in combination, have emerged repeatedly as key determinants of this process: changes in host organisms, changes in the environment and changes in pathogens themselves, usually to accommodate changes in the former. 4
Human behaviour and particularly human mobility plays a key role in the emergence of new diseases. A century ago circumnavigation took more than one year; in 2005 Steve Fossett entered the record books for completing the same journey non-stop by air in just sixty seven hours. And today, even by standard commercial air travel, no major city is more than twenty-four hours from any other. Recent estimates also predict that at any given time there are more than half a million people airborne around the planet. 5 This level of population flux means that the geographical barriers faced by infectious diseases in the past have largely been removed. Journeys can be made so quickly that individuals can arrive at a destination well within the incubation period of an infectious disease thereby making outbreaks much more difficult to contain. 67
Other aspects of modern human behaviour are also facilitating the spread of novel diseases, such as needle sharing amongst drug users which can transmit HIV and HCV (hepatitis C). Modern medicine is also responsible for enabling pathogens to spread and creating microbiological niches from which novel infections may emerge. In the UK, historical use of contaminated blood products led to the infection of thousands of haemophiliacs with HIV and HCV, and some of these individuals may also be at risk of vCJD (human BSE). In the US polio vaccines prepared in the 1950s and 60s and administered to about one hundred million people world-wide were shown to be contaminated with SV40, a tumour-provoking primate polyomavirus. Large cohorts of individuals were therefore inadvertently exposed to this agent, which has subsequently been linked to an increased risk of non-Hodgkin's Lymphoma (NHL) 8.
Other aspects of medicine that may facilitate the emergence of new pathogens include organ transplantation, including experiments in xenotransplantation, and the related issue of immunosuppression. Organ transplantation into an immunocompromised host may allow tissue-resident viruses, including genomically-hosted endogenous retroviruses, to replicate unchecked which could lead to enhanced virulence or changes in host and cell tropism. It could be argued that, through its immune-disabling effects, HIV provides a very similar environment in which this can occur. 6
Environmental conditions may alter for a variety of reasons, but foremost among them is the impact of humans. The human population is currently doubling every seventy years, is set to reach nine billion by 2050, and the planet is currently sustaining the highest population density and highest population mobility that has ever existed. Not surprisingly this is applying significant pressure upon local environments. 7
Clearing of jungle and forest for settlements and housing bring people and domestic animals into contact with native fauna, facilitating the spread of infectious agents between them. Husbandry techniques, hunting, transport of animals, other forms of food and water provision such as paddy fields and reservoirs and the absence of adequate sewage treatment all provide opportunities for infectious agents to be transmitted to new hosts and for the environment to sustain new vectors. 9
On a more global scale, models predict that over the next twenty years some regions of the planet will become much drier and others much wetter owing to the secondary effects of climate change triggered by global warming. The result will be a reduction in productive land area, the creation of new niches for infectious agents and vectors in previously inhospitable environments and an even higher population density, all of which will magnify the local effects described above. 10 11
NIPAH
The impact of human environmental modification and encroachment and its ability to facilitate the transmission of infectious agents to novel hosts is elegantly showcased by the recent discovery of Nipah virus.
In late September of 1998 a novel encephalitic illness appeared abruptly in the northern part of Peninsular Malaysia. Patients affected by the mystery illness presented with abrupt-onset of a high fever, headache, prostration and neurological signs. The mortality rate was more than thirty percent.
By the following June two hundred and sixty-five cases had been reported in Malaysia and a further 11 cases in neighbouring Singapore. Significantly these latter cases were in abattoir workers who had handled imported Malaysian pig carcasses, and 93% of all the reported cases gave a history of pig contact prior to their illness. The overall mortality was high with the outbreak killing 106 people.
Initially, owing to the association with pigs, the mosquito-borne Japanese Encephalitis (JE) virus was suspected. However, the epidemiological characteristics were inconsistent with this diagnosis for several reasons: very few case patients were young children, individuals vaccinated against JE were not protected and mosquito control did not affect the disease dynamics. The link to pigs, however, was unequivocal and more than one million animals were culled, which immediately stemmed the outbreak. 13 14
The causative agent was subsequently identified as a novel Hendra-related paramyxovirus called Nipah. The virus could be cultured from the cerebrospinal fluid of affected patients and was also detectable in samples from pigs. At post-mortem both humans and pigs showed signs of visceral endovascular damage. Surprisingly, however, in pigs the agent was associated chiefly with respiratory tract involvement whilst in humans it was most manifest in the central nervous system. 12
Serological studies have subsequently identified fruit bats as the natural host and porcines are thought to act as an amplifying intermediary. Significantly, because the virus provokes a predominantly respiratory syndrome in infected pigs this facilitates transmission to humans that have close contact with symptomatic animals. 17
At present there is no evidence of direct transmission from bats to humans, suggesting that the most likely explanation for the emergence of Nipah was the construction of large numbers of piggeries in virgin Malaysian rainforest. Orchards planted nearby served to attract fruit bats to the farms, leading to the contamination of the pig-pens with bat excreta (containing Nipah) and partially-eaten pieces of fruit (potentially also containing bat saliva and hence Nipah). Pigs exposed to this material acquired and spread the infection but, unlike humans, showed only a very low level mortality.
Although Nipah has not since recurred in Malaysia, the virus has been detected elsewhere in Asia. Since 2001 there have been eight significant outbreaks in Bangladesh and neighbouring parts of India. In 2004 the WHO announced a cluster of thirty four cases and twenty six deaths and the following year, in a different part of the country (Tangail district), there were twelve deaths from a total of forty-four cases.
As yet no animal intermediates have been identified in these instances, although the presence of the virus has been confirmed in local fruit bat species and individuals involved in the Tangail outbreak had consumed date palm juice prior to becoming ill. This suggests that contamination of the fruit by infectious bat saliva, urine or faeces is a probable route through which the agent has spread to humans. However, the epidemiology of these outbreaks was also suggestive of person-to-person spread, indicating that the virus may be adapting to favour transmission between humans, probably via the aerosol route and from individuals with respiratory involvement. 15 16
KYASANUR FOREST DISEASE (KFD)
The emergence of Nipah parallels the example of the tick-borne flavivirus KFD, which was first described by Telford Work and Harold Trapido in a small forested region of southwest India in 1955. The virus came to light when scientists heard that, in that particular year, monkeys were dying in large numbers in the area, and that a number of local villagers had developed a mystery illness comprising a severe headache, chills and a high fever. The human mortality rate was about ten percent. 18
The virus was found to be carried by small forest-dwelling mammals and was spread between them by a range of tick species. Periodically, monkeys foraging on the forest floor, and human visitors to the forest, would be bitten by infected ticks and go on to develop the disease. The peaks in mortality (and in human cases) are likely to reflect environmental pressure whereby hungry foragers spend longer in the environment than normal, thereby increasing the risk of tick bites.
Following the discovery of KFD, small but consistent numbers of cases continued to be reported annually. But in 1983 there was a dramatic increase in notifications and a major epidemic involving 1500 human cases and 150 deaths. The outbreak coincided with the clearing of large tracts of the forest to build cashew nut plantations and for the grazing of cattle. 19
This has had a two-fold effect on KFD biology and epidemiology. First, clearing and farming the former forest has led to a significant increase in human presence in the area, which has in turn increased human exposure to the agent and its vectors (ticks). Second, the addition of cattle to the region has led to a relative shift in the tick population towards a larger species - Haemaphysalis spinigera - which prefer to feed on bigger animals, including humans. 19 24
As a result up to three hundred cases of KFD are now reported annually, with a mortality rate of about ten percent. An understanding of the disease has enabled control measures to be introduced including the use of insecticides to control tick populations, public information (since the majority of infections occur during the dry pre-Monsoon months January to May), and the development of a killed vaccine that can protect about seventy percent of recipients. 19
However, none of these strategies tackles the root of the problem, which is rising human population and the pressure that this applies to the local environment.
VENEZUELAN EQUINE ENCEPHALITIS (VEE)
Another example of population and economic pressure leading to the emergence and evolution of a human viral pathogen is the case of Venezuelan Equine Encephalitis (VEE), which was first identified in 1938. 22
VEE is a member of the alphavirus family and native to parts of central and South America. It produces symptoms of fever, headache, myalgia, nausea and vomiting. Some cases also develop encephalitis, coma and death.
The disease can also affect equines, amongst whom the mortality rate can be as high as eighty percent, but in humans this is variable. In three large recent epidemics between 1962 and 1995 three hundred thousand people were infected and two thousand (just below one percent) died.
The natural hosts of VEE are small rodents, and the virus is transmitted between them in a so-called "enzootic cycle" by Culex taeniopus mosquitoes which thrive in swampy wooded areas and feed predominantly on small mammals. Occasionally, however, highly viraemic "epizootic" strains of the virus emerge which enable it to be transmitted by other (usually resistant) mosquito species, which can carry the virus between larger animals such as horses and humans. This is what triggers an outbreak and molecular and serological analyses of epizootic strains and local populations seem to confirm this model.
However, in two recent VEE outbreaks in Mexico in 1993 and 1996 the circulating viral strains, though nonetheless deadly, did not produce significant viraemia in infected equines. Instead these strains bore a much closer genetic relationship to the normal enzootic rodent subtypes of the virus, suggesting that the virus had evolved a novel mode of spread.
Subsequent analysis has revealed a mutation in the viral E2 envelope glycoprotein which has allowed the agent to switch to a novel mosquito vector. University of Texas Medical Branch (UTMB) researcher Aaron Brault found that the substitution of an asparagine in place of a serine residue enables the virus to efficiently penetrate the gut wall of Oclerotatus taeniorhynchus, a much larger mosquito that prefers to feed on large mammalian hosts including horses, cattle and humans. 19 20
Ironically the reason for this vector switch can be seen from the air. Satellite and aerial photography reveal widespread deforestation close to the locations of the 1993 and 1996 Mexican outbreaks. In all a five hundred mile swathe of forest along the Pacific seaboard of Guatemala and Mexico has been cleared to make way for cattle ranching.
This has led to the loss of the Culex taeniopus habitat and created a new niche for the Ochlerotatus mosquito. Pushing the virus into this genetic corner has led to the disclosure of new mutants capable of exploiting the newly-dominant vector. According to Professor Scott Weaver, director for emerging diseases at UTMB, this is a troubling discovery because it highlights the ease with which this may happen. "This shows a virus can find a simple genetic mutation that allows it to switch to a new species of mosquito that has the capacity to infect horses and people." 23
DENGUE
The case of VEE, the evolution of which has been moulded by human environmental encroachment, parallels in some ways the emergence of dengue as a major cause of morbidity and mortality internationally.
Dengue is a flavivirus spread amongst humans by Aedes aegypti mosquitoes. The WHO estimate that there are fifty million dengue infections per year across one hundred countries with a case fatality rate of five percent. Most of these deaths are due to dengue haemorrhagic fever (DHF), which occurs when a previously-exposed individual is subsequently re-infected with a different strain of the virus.
Most infections are characterised by a short, one week, incubation period followed by high fevers, severe malaise, headache, sore throat, abdominal pain and diarrhoea with these latter symptoms most prominent in children. The illness usually lasts for about one week and cases are viraemic (infectious to mosquitoes) for between two and seven days.
Genetic analyses suggest that the agent, which exists as four serotypes (DENV 1-4), first appeared only about 1000 years ago and its emergence probably coincides with the human population reaching a sufficient threshold density to maintain transmission of the virus. 25
Before emerging in the human population dengue existed in a sylvatic cycle as an infection of non-human primates transmitted by Aedes stegomia mosquitoes. Humans were only incidental hosts infected when venturing through dengue-infected areas. 26
But the growth of human populations, the development of cities and human encroachment into virgin rainforest led to increased exposure and a greater risk of transmission of the agent to local people. At the same time urbanisation attracted novel mosquito species including the anthropophilic vector Aedes aegypti. This mosquito bites several times per day, rendering nets ineffective as a mechanism of disease prevention. It also thrives in stagnant water collecting in refuse and old tyres.
Consequently dengue moved into an "urban cycle", adapting to exploit Aedes aegypti as a vector and humans as the main host. As a result the range of dengue is now expanding and the virus is also increasingly utilising other secondary vectors such as Aedes albopictus, which inhabit additional geographies not colonised by Aedes aegypti. 27
Methods to mitigate the spread of dengue include vector control with sprays and education about careful handling of refuse to minimise breeding opportunities for mosquitoes. Tyres are a particular problem because no matter which way they are stacked they can always act as water receptacles. Stocking water-storage tanks and reservoirs with mosquito-larvae-consuming fish and small crustaceans have also been successful. At present there is no vaccine against the disease, although two candidate agents are currently undergoing trials in dengue-endemic areas, including a tetravalent agent developed by Sanofi Pasteur which has just entered clinical efficacy trials in Thailand. 28
EBOLA
Whilst dengue is an example of how pathogens may adapt to exploit an increased human population density, geography and associated mosquito species, sometimes naturally-occurring changes to the environment can catalyse the emergence of novel infections.
This is best highlighted by Ebola, which was first identified in humans in 1976 and to date has caused up to fifteen hundred human fatalities. The index case was a school teacher from the Democratic Republic of Congo (DRC) who, following a trip from his home region to a neighbouring province, presented with what at first appeared to be malaria.
The patient had a high fever, myalgia, nausea and dizziness. But quite quickly he also developed bloody diarrhoea and haematemesis, a florid rash and had signs of a profound coagulopathy. He died fourteen days later. Subsequently there were a further two hundred and eighty-four cases in Sudan and three hundred and eighteen cases in the DRC. The mortality rate was over seventy percent. 29
Scientists and doctors studying these early cases of the disease identified the causative pathogen as a filovirus. Under EM this family of thin, tubular negative-sense RNA viruses, which also includes Marburg disease virus, resemble a tangled piece of string. They are transmitted via respiratory droplets and other body fluids and are also fatal to non-human primates including chimpanzees and gorillas. So far five strains of Ebola have been recognised, Côte d'Ivoire, Sudan, Zaire, Reston and a newly-described strain, Bundibugyo. 30
However, the origins and natural hosts of the Ebola viruses remained unknown for many years and were only discovered in 2005 when Eric Leroy and his colleagues set up traps close to Ebola outbreaks amongst gorilla and chimpanzee communities. One thousand animals were analysed including birds, bats and terrestrial vertebrates and three bat species were found to be positive by PCR for Ebola sequences. 31 But how was the infection being transmitted between asymptomatic bats and other animals, including humans?
A tantalising answer to this question was announced in 2006 by UCSD researcher Sally Lahm and her colleagues. They showed that the disease frequency appears to peak at times of severe drought. The best interpretation of this finding is that environmental stress facilitates spread by driving diverse groups of animals closer together as they forage for dwindling water and food resources and this facilitates transmission. 32
At the same time the bush meat trade is a multi-million pound, multi-million tonne annual industry, and it is likely that poachers and other traders are unlikely to be deterred by the potential earnings from the sale of dead primates they discover incidentally. This is almost certainly one of the routes for the disease into humans. 33
HANTAVIRUS
A further example of the potential impact of climate change is the outbreak of hantavirus pulmonary syndrome in the USA in 1993. Initially fifteen patients in the US southwest presented to hospital with severe respiratory symptoms that began, after an incubation period of more than a month, with fevers and muscle pains. This progressed to a cough, shortness or breath and eventually respiratory failure necessitating ventilation. Eleven of those fifteen patients died. 34
Samples collected from the affected cases revealed a novel member of the negative-sense RNA Bunyavirus family, called hantavirus. 35 Environmental studies subsequently showed that the virus was naturally carried by small rodents and passed on in the animals' excreta. 36
The outbreak has been linked to the El Niño effect, which is a body of warm water that moves eastwards across the Pacific Ocean triggering secondary weather phenomena, including floods and droughts, in different geographical regions.
The 1991-2 El Niño effect provoked heavy rainfall across the southern US states. This, in turn, led to proliferation of vegetation and an explosion in the rodent population, especially of deer mice, the natural hantavirus host. As the mouse population rose the animals increased their ranges, including entering peoples' homes in order to shelter and to find food. People were exposed when they swept up the animals' droppings, aerosolising and inhaling the agent, which leads to infection. 37
The outbreak has continued since, affecting thirty-one states and causing more than 450 cases with a fatality rate is 37%. 38 A further strong El Niño event occurred in 1997-1998 and was also associated with heavy rainfall. This was followed by a fivefold increase in hantavirus cases in the US "Four Corners" region in 1999, confirming the suspected association between the two events. 39
The emergence of the hantavirus pulmonary syndrome secondary to a relatively abrupt and short-lived change in weather conditions reinforces concerns of the disease threats posed by future climate change and global warming. Changing weather patterns can clearly stimulate the transmission of novel infections to new host groups and for this reason the CDC, anticipating this threat, have already set up a dedicated unit to provide surveillance and management of these threats, and many other countries are following suit. 40
SARS
Since the majority of emerging infections are zoonoses, another way to promote the escape of a novel agent is to move animals from their native habitats. This is believed to be the mechanism underlying the appearance of SARS (severe acute respiratory syndrome) in 2002.
The disease was characterised by an abrupt-onset of respiratory symptoms, which progressed rapidly to severe respiratory compromise often requiring ventilatory support.
The disease was first detected (although not notified at the time to the international community) in China's Guandong Province in 2002 and was subsequently carried, in February 2003, to Hong Kong. Ironically, the traveller responsible for the transmission of SARS to Hong Kong was an infected physician who then passed the infection to local residents and other international travellers. 41 42
From Hong Kong it spread rapidly to thirty other countries. In total there were eight thousand confirmed cases and about eight hundred deaths before the outbreak was curtailed. 43 Molecular analyses showed that the agent responsible was a novel coronavirus distinct from the previously-described group I and II (human) and group III (avian) strains of the virus. 44 45 46
Investigations at the time of the outbreak identified infected civet cats in markets in Guandong, leading researchers to suspect that this species was the natural host. Large-scale culling of the animals was initiated, but subsequently scientists failed to find evidence of widespread infection amongst the species. The SARS-CoV was also highly pathogenic in civets, rendering them unlikely as hosts. 47
The genuine reservoir hosts were identified nearly two years later when a WHO expedition to rural China in December 2004 found the virus in three species of Rhinolophus (horseshoe bats) both by serological and PCR analysis. These insectivorous bats are often found for sale in markets across southern China, so a plausible explanation for the spread of SARS to humans is the juxtaposition of caged bats in a market close to a susceptible amplifying species, such as a civet cat. This could have established a "market cycle" allowing the virus to further "humanise" through adaptation of its surface spike protein to better engage with the human ACE2 (angio-tensin converting enzyme 2) target. 42 48 49
Thankfully, apart from small localised outbreaks in China, Taiwan and Singapore in 2004, SARS has not returned since the original 2003 epidemic. 43 However, its appearance as the "21st Century's first pandemic" 50 serves to highlight the risks of transporting animals and bringing them into dense contact with other diverse species. At the same time SARS highlights the rapidity with which an infectious agent can be transmitted globally by modern transport systems.
WEST NILE VIRUS
The risks associated with the movement of animals are also pertinent to the case of West Nile Virus (WNV), which appeared for the first time in the USA in 1999. The agent was first described in the 1930s in a febrile woman in Uganda and was subsequently identified in other parts of Africa, eastern Europe and Asia where it is chiefly an infection of birds spread by ornithophilic mosquitoes. It is a flavivirus closely related to Japanese Encephalitis and humans are an incidental host. 51 52 53
Infected cases usually present after a short incubation period (two to six days) with sudden-onset flu-like symptoms including myalgias, fever, headache and occasionally a sore throat, diarrhoea and vomiting. There may also be a rash. The case fatality rate is up to 10% with some patients developing overt encephalitis and flaccid paralysis, but the majority of cases appear to be sub-clinical. 54 55
Despite its long history WNV had never been detected in the USA, probably owing to geographical constraints on the spread of infected hosts. But in 1999 residents in New York began to report significant numbers of dead crows. At the same time 62 patients were diagnosed with an encephalitic illness subsequently confirmed as West Nile. 56
Over the next four years mosquito trapping and human serological studies tracked the spread of the agent across the USA. By 2003 almost every state had detected the virus in mosquitoes and or humans and that same year the number of cases exceeded nine thousand with nearly three hundred fatalities. 57
Subsequent investigations have revealed that the first isolation of WNV was in birds at the Bronx Zoo, leading researchers to suspect that a shipment of birds imported by air from Egypt or Israel could have triggered the outbreak. 58 At the same time the spring and early summer of 1999 were very warm and humid, which were ideal for mosquito breeding, increasing the efficiency of arbovirus spread and thereby helping the agent to "escape". 53 The virus was then carried across the continent by migrating birds, which have since been shown to demonstrate increased locomotor activity following infection. 59
On-going studies of the circulating strains of WNV have also revealed an interesting shift in the viral genotype. A single strain distinct from the original introduced form has since emerged and subsequently displaced previously-circulating strains across the US. The virus therefore appears to be undergoing adaptation to the local transmission cycles prevalent in its new geography. 60 61 62
West Nile has also been an unexpected beneficiary of the global credit crisis. In 2007 epidemiologists reported a 276% increase in the West Nile Virus notification rate in some parts of California. The same regions also reported a 300% rise in the number of home-loan defaults and repossessions, and aerial photographs of neighbourhoods with high mortgage-default rates have revealed why.
The images show large numbers of properties with neglected swimming pools that had turned green owing to lack of chemical treatment. Algal blooms like this make disused swimming pools an attractive breeding ground for mosquitoes, including the Culex species that transmit West Nile. As study author William Reisen and his colleagues point out, "The recent downturn in the housing market and increase in adjustable rate mortgages have combined to force a dramatic increase in home foreclosures and abandoned homes and produced urban landscapes dotted with an expanded number of new mosquito habitats." 63
PANDEMIC INFLUENZA
Arguably the agent causing the greatest concern at the moment is pandemic influenza, which has been defined by a US Institute of Medicine committee as "the prototype emerging infection". 64 However, the impact of "normal" seasonal human flu should also not be under-estimated. Worldwide it causes between 500,000 and 1.5 million deaths annually and in the UK is associated with an annual excess mortality of up to twelve thousand, mostly comprising elderly or otherwise vulnerable individuals. 65 66
Influenza is an orthomyxovirus and originally an infection of aquatic birds. It is believed to have made the transition to humans between six and nine thousand years ago, which coincides with increasing human urbanisation, animal husbandry and animal domestication. These practices probably provided the ecological niche that enabled 'flu, as well as a number of other infectious agents including measles and smallpox, to "jump into" and adapt to humans in the first place. 42 68
Three genera of 'flu are known and are designated A-C. A is found in avians, humans and other mammalian species including pigs, B is found mainly in humans but occasionally also in other mammals (including seals), and C causes largely trivial infections in children but can also infect other mammals. Group A 'flu viruses are further subdivided according to the species of H (haemagglutinin) and N (neuraminidase) molecules utilised on the viral surface. At present the circulating 'flu A strains are H1N1 and H3N2, although more than 16 different H types and 9 different N types have been defined; most of these, however, appear to be restricted to birds. 42 69 76
Influenza manifests within the population in two main ways: by provoking seasonal annual outbreaks or epidemics and, less commonly, global pandemics. Both of these phenomena occur as consequences of the fact that the virus uses RNA as its genetic template and the way in which this genetic material is organised.
Since RNA is single stranded, replication of the viral genome occurs with low fidelity owing to the absence of proof-reading mechanisms. This, in turn, translates into a high mutation rate which leads to progressive changes in viral antigenicity and the emergence of novel strains. This is known as genetic drift and is one of the reasons why an individual may succumb to 'flu multiple times during his or her lifetime. Antigenic drift ensures that influenza viruses continue to circulate within the population, although with generally low incidence and modest pathogenicity. 4 42
A more dramatic manifestation is antigenic shift, which is thought to underlie the production of pandemic strains of the virus that emerge when avian forms of 'flu jump the species barrier to humans. This occurs because the 'flu genome is segmented: the virion contains eight separate independently-replicating ribonucleoprotein molecules that each encoding different viral genes. 70
This means that there is the potential for human-adapted strains to exchange genomic segments with wild-type (avian or other mammalian) forms of the virus to produce genetic hybrids, termed "reassortants", which are well-adapted to replication in human cells but bear the surface characteristics of previously "unseen" strains. As herd immunity to such strains is automatically very low, or absent, the consequence is rapid spread of the novel agent and a potential pandemic. When this occurs, significant proportions of the population (exceeding 30%) may become infected over a period as short as a few months. This reassortant mechanism is thought to underlie the April 2009 emergence of H1N1 swine lineage influenza (S-LIV), and models suggest up to 32,000 cases occurred in Mexico within the space of a few weeks which led to rapid global spread and the announcement by the WHO of a level 5 (and subsequently level 6) global pandemic alert. 4 70 71 72
The genetic mixing phenomenon that leads to the emergence of novel pandemic strains could occur in two ways. Human-infecting viral strains can emerge directly from birds. Such viruses generally have a low affinity for human cell surface receptors but at sufficiently high input titres this barrier may be surmounted. The ensuing replication within the human host leads to the selection of the most human-adapted (best replicating) forms which are amplified and transmitted to other susceptible individuals. The highly-pathogenic H5N1 strain, which was first detected in Hong Kong in 1997 where it led to a number of human fatalities due to alveolar injury and respiratory failure, is thought to have emerged in this way via a direct jump from birds. Sequencing of the viral ribonucleoprotein segments has confirmed them all to be of avian origin. 75 79
An alternative mechanism for the disclosure of human-adapted strains of the virus involves an intermediate host vulnerable to and co-infected with both human and avian strains. Pigs are strong candidates and are susceptible both to avian and human influenza, making them ideal genetic mixing pots for the elaboration of hybrid viral reassortants. 42 67 70 73 75
Human cases of H5N1 are continuing to be reported from a wide region of the globe, Indonesia foremost among them. However, these cases invariably involve a history of contact with birds and onward transmission rates between humans currently remains low, probably reflecting the avian tropism of the viral haemagglutinin.
In some respects this is reassuring, but functional studies are showing that the virus may alter its haemagglutinin-binding affinity to favour the sialic acid-galactose linkage found in humans rather than birds, which could enable it to spread much more readily. This would certainly be a prerequisite for a pandemic, but may never happen. Alternatively, and perhaps more likely, H5N1 may reassort with another 'flu strain, including a contemporary human 'flu A, to yield an antigenically novel virus with enhanced human infectivity. 77 78 79 80
Regardless of the mechanism involved, prior experience with SARS, and now also H1N1 S-LIV, has shown us that modern transport facilities, particularly air travel, combined with growing world population and rising population density, facilitate the rapid global transmission of respiratory pathogens. Effective models of disease spread and strategies to mitigate transmission locally and internationally will be crucial to the control of future outbreaks. 71
The present situation with the H1N1 swine lineage influenza virus is of great concern. However, penetration and spread of the agent into the population may have been mitigated temporarily by the end of the 'flu season and the arrival of summer in the northern hemisphere, where most of the world's population live. Countries in the southern hemisphere, such as Australia, which have (at the time of writing) yet to enter their own flu seasons will therefore serve as the influenza-equivalents of caged canaries and will provide useful insights into what may subsequently occur worldwide within the next 12 months.
Indeed, analysis of previous pandemics, including the 1918 Spanish Flu, showed that under similar circumstances pandemic strains have returned during subsequent 'flu seasons to previously mildly-affected countries with more devastating effects. 74 The intervention of summer in the northern hemisphere is therefore both advantageous and disadvantageous. On the one hand this virological lull provides breathing space for the development of a vaccine, although on the other hand the H1N1 swine agent, which is currently only equivalently pathogenic to contemporary human 'flu strains, could, in the interim, acquire enhanced virulence.
As a precautionary measure many countries have stockpiled antiviral drugs including the neuraminidase inhibitors Tamiflu (oseltamivir) and Ralenza (zanamivir) . But, increasingly in recent years, viral resistance to these agents is being reported amongst existing human 'flu strains, meaning that these drugs may become unreliable as a means of defence in future. S-LIV H1N1 is currently sensitive to both agents, but circulating human H1N1 is not. 81 The development of effective vaccines therefore remains the most effective protection strategy.
However, traditional vaccine manufacturing techniques using embryonated hens' eggs may not be suitable on the grounds that they are extremely time-consuming and not all strains of the virus will grow well in eggs. Consequently governments and industry are investing heavily in novel vaccine manufacturing strategies capable of using reverse genetics to produce vaccine stocks from cell culture platforms. Research is also on-going into the development of more effective adjuncts capable of delivering simultaneous cell-mediated response against multiple strains of the virus.
CONCLUSION
The present global situation is a far cry from the suggestions of Stewart and Burnett 1 that infectious diseases are a closed book. Conservative estimates predict that the annual number of new HIV cases globally is at least three million, the majority of them in Africa, and the total number of people currently living with AIDS is over 33 million. 82
These numbers eclipse three-fold the estimated death toll from the notorious 1918 "Spanish Flu" and indicate that infectious diseases are a serious issue with international impacts. Our present lifestyles, population density and modern travel are powerful factors influencing the emergence and spread of novel disease threats.
But the most important determinant is population. The world population is currently growing at 1% per annum, which translates into a population doubling every seventy years. To be sustainable even the present population would require the resources of a second planet Earth, and this is without taking into account the likely future impacts of climate change and sea-level rise. 83
These factors will undoubtedly lead to severe environmental pressure on humans and other animals, which history has shown frequently leads to novel disease outbreaks. Therefore it is critical that the mechanisms which provoke disease emergence are appreciated and that steps are taken to minimise future risk.
However, as the examples in this essay illustrate, this much easier to say than to do and so the mainstay of our future planning must hinge on the establishment of a more environmentally sustainable future. Perhaps then, eventually, William Stewart will be right.
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