A brief guide to emerging viruses (Part 2)

Colin R. Howard

Royal Veterinary College, University of London,London NW1 0TU,UK

4 Why are diseases “emerging”?

Public health is influenced by the interactions between social conditions, the environment as much as it is by the evolution of pathogens. Changes in the natural environment are playing an ever-increasing role in determining disease patterns. Today’s increasingly variable climate is accelerating this rate of change, often compounded by economic instability, the ravages of war, and natural disasters. Acting together, these factors are the prime contributors to the global emergence, resurgence and redistribution of infectious disease. Nearly all of this increase has occurred between 1910-1945 and since 1976: indeed the rate of warming is now at an unprecedented level.

4.1 Ease of air travel

Over 100 million journeys are now made by air each year and it is feasible for a passenger to visit three or more continents in as many days. Thus the frequency of air travel between countries is a major factor to be acknowledged in containing emerging disease outbreaks. Hufnagel (2004) has produced a mathematical model that simulates accurately the spread of SARS virus in 2003 from China to 17 nations that experienced 4 or more cases. Once the statistical information is available, the model can be used to predict those regions most at risk in the event of any future SARS epidemic. Were a vaccine available, the model predicts a rapid response would be required to prevent the need for global vaccination. For many originating cities, the initial spread of virus could be quickly contained with only a third of the population immunised, assuming an index case makes a single journey by air. However, 75% would need to be immunised should such a passenger make two journeys, and were the passenger to make three journeys then the whole population would need to be vaccinated. Thus the message from the studies is clear: air travel represents a major risk factor for the global spread of a new infectious agent, and that controlling its spread may require the political will to stop air travel between certain cities and countries.

It is not only humans that travel: Inter-national Air Transport Association (IATA) estimates that around 80 000 wild-caught animals are air freighted each year, many being placed in holding facilities whilst in transit that are close to populated areas. Even mosquitoes may be carried. One school of thought is that the West Nile virus (WNV) entered the USA as a result of an infected mosquito surviving the air journey from the Middle East to New York City.

4.2 Human migration

The last decade has seen an unprecedented four-fold increase in human migration. Religious persecution and political conflicts have over the centuries provided major impetus for people to migrate, but environmental disasters and economic imbalance between developing and developed nations are additional reasons. Such movements are vastly facilitated by the ease of air travel, whereas a hundred years ago migration often entailed a long sea journey of days or weeks, ample time for infected individuals to display symptoms or succumb to illness. An estimated 100 million people have been uprooted across 36 countries as a result of military conflicts and the bigotry of despots and other unelected political leaders (US Commission for Refugees: world Refugee Survey, 200, Washington, Immigration and Refugee Services of America). Shifting population groups take with them distant cultural and health beliefs that impact upon the public health structures within which they become adsorbed.

Urbanisation is a major contributory factor in disease emergence and evolution. The last 50 years has seen a dramatic movement of peoples away from rural areas into the cities, with present estimates around 75% of the global population now living in urban areas. Even in less developed regions of the world, this figure now approaches 40%. As a benchmark, in 1990 there were just five cities in the world with populations in excess of 10 million. At the turn of the century, this had risen dramatically to 19, with 11 of these mega cities being in Asia.

As the majority of emerging diseases are zoonoses, it could be argued that increased dwelling in conurbations would lessen rather than increase the probability of an individual coming into contact with an existing or newly emergent pathogen. However, this argument ignores the almost limitless capacity for pathogens to adapt in the face of changing behaviour of either host or animal reservoir, especially viruses. Dengue is a particular example of a virus that no longer needs an animal reservoir. Childhood diseases, such as measles, have long been considered as originating in domesticated animals but evolved independently of animal hosts once humans collectivised into townships. There are obvious hurdles for any disease to surmount in order to adapt to new animal reservoirs that live in close proximity to urban areas. Evidence that cross species transmission is taking place is clearly seen among the hantaviruses where host switching has occurred, thus extending the range of these viruses and giving greater potential for changes in virulence.

4.3 The changing environment

The environment in which we live is changing on an unprecedented scale. Climate change needs to be distinguished from climate variation: change is where there is statistically significant variation from either the mean state over a prolonged period of time. Approximately 25% of the Earth’s rain forest has been cleared in the last 50 years. The systematic and ruthless deforestation of Amazonas and parts of Southeast Asia is having a profound effect on local ecosystems, particularly by constraining the range of natural predators which in turn are instrumental in keeping rodents, insects and other potential carriers of infectious disease under control. The reduction in biological diversity can trigger the invasion and spread of opportunistic species, heralding the emergence of disease.

Greenhouse gases such as CO2have increased by 20% over the last two centuries. The net result of the greenhouse effect is to increase the surface temperature by 0.4-0.6 degree Celsius. This apparently trivial increase is an indicator of profound climate change: global warming is linked to the melting of the polar caps and a continuous shift in weather patterns. The result is either floods or sustained droughts. These events are the direct result of increased air temperatures at altitudes of 10-25 000 feet above the Earth’s surface, particularly in the Southern Hemisphere. The most notable manifestations have been the increasing climatic conditions initiated by changes in sea surface temperatures in the Pacific, known as the El Nio Southern Oscillation (ENSO). For example, in the summer of 1990 the surface of the ocean turned warmer, initiating an El Nio event, which in turn led to a period of prolonged drought in many regions of the Americas. A sudden reversal in sea temperature in the summer of 1995 resulted in heavy rainfalls, especially in Columbia, resulting in resurgence of mosquito-borne diseases such as dengue and equine encephalitis.

Diseases dependent upon mosquito populations and rodent reservoirs are particularly affected. Outbreaks of Bolivian haemorrhagic fever in Bolivia and hantavirus pulmonary syndrome (HPS) in the USA have been unequivocally associated with abnormal periods of drought or rainfall, leading to unusually rapid increases in rodent numbers. This in turn increases considerably the risk of human exposure to any pathogens they may carry as well as stimulate such pathogens to undergo mutational adaptations to the changing ecosystems. Importantly, improved techniques and heightened awareness are altering our perception as to the distribution of zoonotic diseases in animal reservoirs, and their potential to initiate further epidemics in humans. To some extent, the emergence of viral diseases — particularly the viral haemorrhagic fevers — are warning signs that serious perturbations of our ecosystems are taking place.

The relationship between a virus and its arthropod vector is more than just regarding the insect acting as a mechanical vehicle for transferring virus from one host to another. A well-established biological relationship evolves in a way that the vector plays a major role in the evolution of the virus and adaptation of the virus to a changing ecology. Present thinking is that viruses evolve to the point where there is a steady state relationship between virus and vector, and virus and host. Any perturbation in the vector, host or viral genome thus would imbalance this equilibrium, leading to the emergence (or re-emergence) of disease.

Vector-borne diseases are judged as highly sensitive to climate conditions, although the evidence for climate change and altered epidemiology of vector-borne disease is generally regarded as particularly sensitive to temperature. In particular, even a small extension to a transmission season may have a disproportionate effect as transmission rates raise exponentially rather than linearly as the transmission season progresses. Climate change can also bring about altered vector distributions if suitable areas for expansion become newly available. Again, the effect may be disproportional, particularly if the vector transmits disease to human or animal populations without pre-existing levels of acquired immunity with the result those clinical cases are more numerous and potentially more severe. Computer modelling thus shows that increased temperature favours the spread of vector-borne diseases to higher elevations and to more temperate latitudes.Aedesaegypti, a major vector of dengue, is limited to distribution by the 10 ℃ winter isotherm but this is shifting, thus threatening an expansion of disease ever northward, and particularly threatening the southern states of the USA.

Global warming continues to re-shape the environment and habitats of humans and wildlife. The most potent of these is the so-called “ENSO” centred on an irregular pattern of atmospheric and oceanic current conditions along the Pacific seaboard of South America. These trigger aberrant weather patterns ranging from extreme arid periods to abnormal rainfall, the latter resulting in floods and explosive increases in arthropod and rodent populations. Thus the risk of vector-borne disease and zoonoses are exacerbated, particularly in areas where the medical infrastructure is fragile even in times of stability. The emergence of HPS in 1993 has been linked to such oscillations, although fortunately in a region with strong public health infrastructure.

Both mosquito and rodent numbers are affected by oscillations in climate. The relentless change inflicted by humans on habitats in the name of progress has had a marked effect on rodent habitats. Over the last 50 years, nearly a quarter of the world’s forests have disappeared to make way for intensive agriculture, mining, roads and other artefacts of human existence. Murine species are more resistant and adaptable than most. Whilst other rodent genera have declined, murine rodents have thrived, especially in peri-urban areas. This resilience is immediately evident by casual observation from the platforms of any subway system in any major capital city of Europe. What this means is that, although species diversity has become less with fewer genera represented, those remaining have thrived; in most instances these are murine rodents, the type most likely to harbour animal and human disease.

The influence of climate changes on wild rodent populations can be considerable. Fluctuations in population sizes occur in regular cycles, particularly in arid and semi-arid zones where small climate changes can bring about significant fluctuations in food quality and quantity. The extent of such variations is magnified when there are abnormal weather patterns. The sudden expansion in number of deer mice that immediately preceded the 1993 Four Corners outbreak has been blamed on abnormal rainfall resulting from changes in the El Nio system described above. The emergence of BHF in the Beni region of Northeast Bolivia in the 1960’s was linked to a sudden rise in the numbers ofCalomyscallosusthat followed an abnormally dry period, this exacerbated by a drop in the number of feral cats as a result of the widespread use of DDT.

Of all the member species of the mammalian order Rodentia, it is members of the family Muridae that has been most successful and are to be found in almost all habitats. This family has species that are the natural hosts of almost all arenaviruses and hantaviruses. Importantly, these species are susceptible to climate and ecological change, resulting in variable population numbers. Of all species of mammals, rodents are among the most adaptable to comparatively sudden changes in climate and environmental conditions. Murine species are particularly adaptable. Although species diversity is becoming less, murine rodents have continued to thrive. Among the fastest reproducing mammals, field voles can have over 15 broods per year, each with an average of six pups. Rodents thrive on contaminated food and water, and are excellent swimmers. That rodents constitute an important part of the Earth’s biomass is manifested by estimates of rodents consuming at least a fifth of the world’s output of grain.

Murine rodents can be found in most habitats, representing the natural hosts of most arenaviruses and hantaviruses so far identified. Evolving in the Old World, murines are a comparatively recent introduction into the New World, most probably via the Bering land isthmus some 20-30 million years ago. It is among species of the family Muridae that reservoir hosts of aenaviruses and hantaviruses are to be found.

Small climate changes can bring about considerable fluctuations in population size, inhabiting desert and semi-desert areas, particularly in food quantity and quality. A prolonged drought in the early 1990’s reduced the population of murine predators, such as snakes, coyotes and birds of prey. The drought came to an end in 1993 with heavy rainfall resulting in a massive increase in grasshopper numbers and pinon nuts, major food sources for feral rodents such as deer mice. The culmination of climatic swings, decrease in the numbers of predators and a sudden abundance in food resulted in an explosive, 10-fold increase in rodent populations. Many other instances of disease emergence followed this particular oscillation. A hitherto unknown arenavirus — at first mistaken for dengue fever — emerged in Venezuela, and BHF returned to this South American country in 1994.

It has been predicted by the International Panel on Climate Change that the average global temperature will increase by up to 6.2 ℃ over the next 20 to 30 years. The effect of this temperature rise will be felt mostly in the higher latitudes during the winter months, and that such rise will be most noticeable during the night. Rainfall patterns are also predicted to change, accompanied by more severe weather events.

Climate change can have substantial effects on animal populations, especially small mammals whose reproductive capacity can adjust rapidly to changing levels of food supply. As we shall see later, this occurred most noticeably in the outbreak of hantaviruses in the USA during 1993 following an abnormal increase in rainfall in the south western states of New Mexico and Arizona. Vector-borne diseases are also strongly affected by climate change. Insects are cold-blooded and thus respond quickly to changes in ambient temperature, many surviving desiccation over long periods of time. In times of abnormal rainfall, aquatic sites for breeding multiply many fold, thus adult insect numbers increase dramatically. Extreme weather events spread insect vectors more widely, thus transmitted diseases can enter areas not previously endemic for particular vector-borne diseases. If predictions of temperature increases for nighttimes are correct, the risk of enhanced transmission rates will be increased for those diseases depending upon transmission by blood sucking vectors that are active during dusk and darkness.

4.4 Increase in temperature

• Increased metabolic rate leading to increased rate of blood feeding in turn increases chance of disease transmission.

• Extension of geographical range of vectors into new breeding areas.

• Seasonal vector activity becomes extended as winters decrease in severity, particularly in higher latitudes.

• Over-wintering of larvae becomes easier and less subject to temperature lowering.

• Pathogen replication increases thus leading to opportunities for transmission much earlier in the vector life cycle.

• An increase in the number of insect species capable of transmitting disease.

This last point is exemplified by West Nile Virus entering the USA in 1999. Over a period of five years the virus has adapted to the extent that over 20 arthropod vectors now are able to transmit a virus that was previously unknown in North America.

The overall effect of climate change is one of increased rate of transmission of disease with a concomitant enhanced risk of exposure among humans with little or no pre-existing immunity to any particular infection.

4.5 Intervention and changes in clinical practice

Increasing use of antibiotics, blood and blood products as well as transplantation have all contributed to disease emergence. Blood-borne viruses such as hepatitis C virus have been spread as a result of contaminated sharps and surgical equipment. Reducing the risk of blood-borne diseases has led the effort to increase dramatically the technology for accurate, specific and rapid diagnostic assays. Unfortunately these efforts have not been applied so easily to veterinary and animal disease diagnosis, partly because of economics — especially in farm animal medicine — and partly due to lack of public investment.

Transplantation is now also perceived as being associated with risk of disease transmission. A notable example is LCM virus, for many years not regarded as a significant human pathogen despite it being the prototype member of the arenaviridae family. It is becoming apparent that there are significant numbers of other diseases closely related to viruses found in animals but yet to be associated with human diseases. There is the potential for major health risks among patients such as transplant recipients being subjected to immunosuppressive therapy.

A further significant area yet to be fully investigated concerns the susceptibility of older individuals to new emerging agents. Among developed societies there is a rapidly increasing percentage of the population above the age of 50. These cohorts are known to be at heightened risk to many enteric infectious agents, e.g. hepatitis A virus.

4.6 Adaptability and pathogen evolution

RNA viral genomes exhibit much higher nucleotide substitution rates, which in turn permit more rapid adaptation to increasing levels of host immunity, altered dynamics in animal reservoir populations, and vector competence. The reason why RNA viruses adjust rapidly is that infected cells lack the capacity to repair errors during translation of viral RNA into mRNA and/or errors introduced during genome replication. This is in marked contrast to DNA viruses where any errors are corrected by host cell proof-reading enzymes.

Adaptability is further enhanced among RNA viruses with segmented genomes. Thus reassortment can occur between physically separate gene segments if a host cell is infected simultaneously with two phenotypically distinct viruses. This is particularly important among influenza viruses where both point mutations (leading to antigenic drift) and reassortment (leading to a major change in antigenicity known as antigenic shift) can result in new viruses with significant alterations in both species specificity and pathogenicity. Reassortment is increasingly recognised among other viruses with segmented genomes within the family bunyaviridae, for example Garissa virus isolated from Africa.

Of those viruses exhibiting a broad range of host specificity, where known this is accompanied by conserved amino acid sequences in domains responsible for interacting with host cell receptors.