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dcyphr | Cross-Species Virus Transmission and the Emergence of New Epidemic Diseases

Introduction

Viruses from wildlife hosts have caused emerging high-impact diseases such as severe acute respiratory syndrome (SARS), Ebola, and influenza which are major threats to public health. The emergence of these diseases occurred when an animal virus switched host into humans and was transmitted within human populations. The importance of this host switching is shown by recent, highly infectious strains of H5N1 influenza A, which spilled over from birds and caused hundreds of cases and some deaths. The emergence of influenza A should be a cause for alarm because of its potential to have efficient and pathogenic transmission between humans. Fortunately, host transfers usually only cause single infections or limited outbreaks.

There are three stages in successful host switching: (1) initial single infection with no human-to-transmission, (2) spillovers that cause local epidemics (outbreaks), and (3) epidemic or endemic human-to-human transmission. There are many variables that determine the success of host switching including the type and intensity of contact between the animal and the human, barriers to infection in the host, viral factors that allow efficient infection, and how well the virus spreads in human populations.

Sources of New Epidemic Viruses in Humans and Other Animals

The major sources of new human viral diseases come from animal viruses. It is likely we only know a small fraction of the viruses infecting animals. The risks of these viruses staying unrecognized are evident in the emergence of SARS coronavirus (CoV), hantaviruses, Ebola and Marburg viruses, Nipah virus, Hendra virus, and HIV, all of which resulted from host switches of established animal viruses.

HIV/AIDS is an important, recent example of emerging viral disease from host switching. After switching from primates to humans 70 years ago, HIV has infected hundreds of millions of people. Even after better understanding of the virus and the development of effective antiretroviral therapies, millions of new infections still occur each year. Another recent example of host switching is the coronavirus causing SARS, which infected thousands of people in 2002 and 2003 and causing hundreds of deaths and economic disruption. Other viruses such as measles and smallpox may have emerged from host switching events in prehistoric times. These examples make it important that we understand how viruses enter and spread in new hosts.

Environmental and Demographic Barriers to Host Switching

Exposures between animals and humans are an important step in host switching events, and some events may be prevented by limiting these exposures. For example, HIV has transferred to humans multiple times since 1920. A major barrier to establish host switching events in recent decades is likely the limited opportunity for primates to come into contact with humans followed by enough human-to-human contact to establish transmission. In other cases, host switching is prevented by the requirement for multiple, complex adaptive changes in the virus itself.

Ecology and Contact with Alternative Hosts

Contact between animals and humans is affected by geographical, ecological, and behavioral separation. Factors that affect the geographical distribution of animals (e.g, wildlife trade, introduction of domestic species) or that decrease behavioral separation (e.g, bush meat hunting) promote viral emergence. Changes in social and demographic factors (e.g population expansion, traveling), human behavior (IV drug use, sexual practices, farming practices) and the environment (deforestation, agricultural expansion) also affect viral emergence.

Human population density is important in the establishment of transmission and epidemic potential of viruses. Human trade and travel patterns have been examined to characterize the spread of disease vectors such as mosquitos and of pathogens like SARS. In H5N1, they have been examined to predict spread of the disease through trade and bird migration. Patterns in human contact and density are important for disease emergence. 

Intermediate hosts between humans and animals may also play a critical role in disease emergence. For example, the emergence of Nipah virus in Malaysia was facilitated by pig farming. Fruit bats are the original source of Nipah virus. Planting of fruit orchards around pig farms attracted bats, allowing host switching of the virus from bats to pigs. This example shows how man made ecological changes can increase viral emergence. Similarly, SARS CoV originated in bats but infected humans through civet cats and other farmed animals.

Host Barriers to Virus Transfer

To infect a host, a virus must be able to efficiently infect appropriate cells. This process is restricted at many levels, including receptor binding, entry or fusion, trafficking in the cell, and viral genome replication and expression. Multiple host barriers require multiple changes in the virus, making host switching more difficult. Other factors preventing host switching are antiviral responses and other responses that restrict infection.

The Role of Host Genetic Separation

Spillover/epidemic infections have occurred between both closely and distantly related hosts. While evolutionary relatedness may be a factor in host switching, the rate and intensity of contact between animals and humans may be more critical. Host switches between closely related species may be limited by similar immune responses to the same pathogens, or by innate immune resistance.

Host Tissue Specificity and External Barriers in Alternative Hosts

The first level of protection against viruses occurs at the level of viral entry into the skin or mucosal surfaces, or in blood, lymphatic circulation, or tissues. Defenses include physical barriers to entry as well as host factors that bind to viruses and prevent infection.

Receptor Binding

Receptor binding by viruses is a critical role in host switching. For example, SARS-CoV derived from bats interact differently with angiotensin-converting enzyme 2 receptors of humans and carnivore hosts. Gaining the ability to bind to new receptors allows infection of new hosts, but can be a complex process requiring multiple changes in the virus.

Intracellular Host Range Restrictions

Prevention of host switching can also occur after receptor binding in viral infection cycles. For example, there are several intracellular mechanisms that restrict cell infection by retroviruses, such as deaminases and TRIM5a protein which block infection into the next cell. 

Interferons, which are part of the immune response, protect cells against viruses and are often host-specific.

Viral proteins involved in replication of viruses may show host-specific activities, and there is often a requirement for a particular combination of these proteins. Other viruses are restricted at the level of genome replication or gene expression.

The Existing Host Range of a Virus as a Factor in Host Switching

Since the initial infection of humans is a key part of viral emergence, the existing range of hosts a virus can infect may influence its ability to establish infection in a new host. Viruses that infect many different hosts may increase likelihood of host switching since they can already exploit host mechanisms to infect and replicate. Viruses that infect only one or a few related hosts are more restricted by different receptors and replication mechanisms. However, both of these kinds of viruses have successfully switched hosts.

Viral Evolutionary Mechanisms Leading to Emergence

Evolutionary changes are not always required for viruses to switch hosts. However, some cases of emergence require evolution of the virus for efficient infection and transmission in the new host. The evolution of viruses to adapt to new host is not well-understood. Genetic variation is important, as the greater the rate of variation the more a virus can better adapt to a new host. RNA viruses have error-prone replication mechanisms, short replication times, and large virus populations. In contrast, DNA viruses are less variable.

Viral Fitness Trade-Offs

Mutations that benefit the virus in humans may reduce viral fitness in its original host. The nature of these fitness trade-offs and how they affect host switching is an important, but unresolved area of study. After host-switching, a combination of genetic drift and selection determine mutations that remain long-term. However, only a small proportion of viruses will exhibit increased fitness after host switching.

Mode of Virus Transmission

An important constraint of host switching is the mode of virus transmission. For example, insect vectors that feed on mammals can create cross-species viral exposures. However, levels of variation in viruses transmitted in this way are relatively constrained compared to other mechanisms. This is because viruses need to balance fitness in at least three hosts: the donor and recipient hosts, and the vector. Host switching of viruses that spread by droplet, sexual fluids, and fecal-oral routes have adaptational challenges due to host differences and variation in environmental exposure.

Recombination and Reassortment in Viral Evolution Leading to Host Switching

For many viruses, genetic recombination allows the gaining of multiple genetic changes in a single step, producing advantageous genotypes. The potential for recombination differs between RNA and DNA viruses. 

Many recombinations or reassortments are likely to decrease fitness. However, they may be important for incremental adaptation after host switching has occurred.

Are Viral Intermediates with Lower Fitness Involved in Host Switching?

The process of host switching is rarely observed directly, but can be inferred by comparing the genomes of viral ancestors in donor hosts with viruses in recipient hosts. If several changes are required for host switching, intermediate viruses would likely be less fit in donor or recipient hosts than ancestors. Crossing this evolutionary “low-fitness valley” can be a key step for host switching, and may explain the rarity of host switching. After host switching, if the virus spreads with a reproductive number greater than 1, it could increase its fitness through mutations and become an epidemic. 

Early detection of viruses that do not spread efficiently could provide opportunity for epidemic control. For example, the early SARS CoV virus was inefficiently transmitted by most infected people, and early recognition of the outbreak and implementation of control measures allowed the epidemic to be stopped before the virus was fully established in human hosts. How viruses gain the ability to spread efficiently is poorly understood.

During early stages of an outbreak, “superspreading” events may play a critical role in the establishment of a virus in humans after it has host switched.

Posttransfer Adaptation

For many host-switching viruses, full adaptation to the new host can take months or years to complete.

Summary and Implications for Prediction and Control

Much progress has been made in identifying factors that control or influence virus host switching. Studies point to common pathways of host switching and suggest preventive strategies. With better information about the origins of emerging viruses, it may be possible to identify and control emergent viruses in their original hosts. For arboviruses (viruses with a mosquito vector), vector control can limit host switching. Public health measures, such as health monitoring and quarantine, are also effective in limiting the spread of epidemics. Other strategies include reducing human-related change in infectious disease “hot spots,” as well as culling or vaccinating reservoir animals. Vaccination has been successful in raccoons/foxes in the U.S to control rabies, and wild dog rabies has been controlled in Kenya and Tanzania by vaccinating domestic dogs.

New, rapidly spreading viruses can become impossible to control after a certain number of infections. Coordinated, strategic planning is critical for the confrontation of new viruses early after emergence. National and international planning is also critical.

Strategies for control should include improved surveillance of regions of high likelihood of host switching events, improved detection of pathogens in reservoirs or early in outbreaks, research to clarify events that promote emergence, and modified forms of quarantine and other control measures. Human disease surveillance should be coupled with veterinary and wild-animal infection surveillance. Vaccine strategies could be used in some control programs, but presents difficulties due to the slow rate of vaccine development and approval. Antiviral drugs could also be used, but also present difficulties due to cost, logistic problems, and side effects.

The emergence of new viral diseases by animal-to-human host switching will continue to be a major source of new infectious diseases. A better understanding of variables that contribute to such emergences are important for public health.