Ecology Ecology of Emerging Zoonotic Viruses
by
Vincent Munster, Seth Judson, Michael Letko
  • LAST MODIFIED: 22 February 2018
  • DOI: 10.1093/obo/9780199830060-0195

Introduction

As an emerging and evolving discipline, viral ecology has yet to be as thoroughly defined as other fields of ecology. This remains an ambitious task since viruses are able to infect all domains of life, creating many possibilities for interactions between hosts, viruses, and their physical surroundings. Understanding archaeal and bacterial viruses has been important for developing fundamental principles in molecular ecology, for example determining how bacteriophages influence bacterial genetics through introducing foreign DNA via transduction. However, much recent interest in viral ecology has been in regards to the viruses of eukaryotes, especially in relation to emerging infectious diseases. As zoonotic viruses such as ebolaviruses or influenza viruses infect new species, including humans, more research studies seek to uncover the complex ecologies of zoonotic viruses. This annotated bibliography focuses on the ecology of emerging zoonotic viruses to highlight specific principles in viral ecology. Examining the ecologies of zoonotic viruses allows virus ecologists to study the interactions of viruses with their environment, between their hosts, and molecularly within their hosts. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

General Overviews

While the topic of viral ecology is extensive, Hurst 2000 broadly summarizes viral ecology in bacteria, archaea, and eukaryotes. Another book, Weitz 2016, highlights the quantitative methods and theory used in multiple aspects of viral ecology. Many other resources approach viral ecology from the perspective of zoonotic viruses. This is in part due to the fact that emerging zoonotic viruses significantly contribute to human diseases, as shown by Jones, et al. 2008. While recent efforts in viral ecology have focused on identifying “the next big one,” the next virus to emerge and cause an epidemic or pandemic, such as Ebola virus or HIV, research, such as Drosten 2013, have recognized that there is a gap between virus surveillance (identifying new viruses and hosts) and prediction. Understanding viral ecology can help fill this gap. While the ecologies of many viruses have been studied, Lloyd-Smith, et al. 2011 noted that there are a few viruses such as rabies virus and influenza A virus that have been studied more than others. Due to recent identification of bats as the reservoir hosts for emerging viruses with high outbreak potential such as: Ebola virus, Marburg virus, severe acute respiratory syndrome coronavirus (SARS-CoV), Nipah virus, and Hendra virus, the interest in the ecology of bat-borne viruses has increased tremendously. Multiple hypotheses about how bats are able to maintain and transmit viruses have been recently developed, as reviewed by Plowright, et al. 2015, and much remains to be discovered in this topic of viral ecology, as discussed by Hayman, et al. 2012. Thus studying the ecology of viruses in bats, primates, rodents, and other animals that spill over into humans and domestic species reveals principles in viral ecology and areas for future research.

  • Drosten, C. 2013. Virus ecology: A gap between detection and prediction. Emerging Microbes & Infections 2.5: e31.

    DOI: 10.1038/emi.2013.25Save Citation »Export Citation »

    This review summarizes key principles in viral ecology and identifies gaps in the discipline, specifically moving beyond identifying new viruses and reservoirs to understanding fundamental properties of viral ecology to enable prediction.

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  • Hayman, D. T. S., R. A. Bowen, P. M. Cryan, et al. 2012. Ecology of zoonotic infectious diseases in bats: Current knowledge and future directions. Zoonoses and Public Health 1–20.

    DOI: 10.1111/zph.12000Save Citation »Export Citation »

    This review summarizes both the pathogen and host ecology of viruses in bats, identifying key principles in infection dynamics.

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  • Hurst, C. J., ed. 2000. Viral ecology. San Diego, CA: Academic Press.

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    This is one of the few books on the subject of viral ecology, covering how viruses interact with most forms of life.

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  • Jones, K. E., N. G. Patel, M. A. Levy, et al. 2008. Global trends in emerging infectious diseases. Nature 451.7181: 990–993.

    DOI: 10.1038/nature06536Save Citation »Export Citation »

    An influential analysis that has been cited over twenty-four hundred times and is well known for estimating that approximately two-thirds of all emerging infectious diseases are zoonotic, many of which are viral diseases.

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  • Lloyd-Smith, J. O., D. George, K. M. Pepin, et al. 2011. Epidemic dynamics at the human-animal interface. Science 362.2009: 1362–1367.

    DOI: 10.1126/science.1177345Save Citation »Export Citation »

    A review of trends in modeling pathogens (especially viruses) and their ecological dynamics. It highlights the need for studying the complex life cycles and host-pathogen interactions of emerging viruses.

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  • Plowright, R. K., P. Eby, P. J. Hudson, et al. 2015. Ecological dynamics of emerging bat virus spillover. Proceedings. Biological Sciences/The Royal Society 282.1798: 2014–2124.

    DOI: 10.1098/rspb.2014.2124Save Citation »Export Citation »

    A review of the temporal and spatial ecology of viral spillover from bats, using Hendra virus as an example.

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  • Weitz, J. S. 2016. Quantitative viral ecology: Dynamics of viruses and their microbial hosts. Princeton, NJ: Princeton Univ. Press.

    DOI: 10.1515/9781400873968Save Citation »Export Citation »

    This book contains theoretical principles of viral ecology as well as methods used for modeling the ecological dynamics of viruses.

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Environmental and Anthropogenic Determinants

As zoonotic viruses have emerged in different populations and species, researchers have sought to understand the large-scale factors that influence viral ecology. Environmental factors such as seasonality, climate, and habitat all influence the reservoir and secondary hosts of viruses, creating opportunities for viral persistence and cross-species transmission. Understanding these factors helps us determine spatial and temporal relationships in epidemic and endemic diseases. One of the most notable examples of the relationship between the environmental factors and viral disease emergence has been determined studying hantaviruses. The association between increased cases of hantavirus pulmonary syndrome during El Niño–southern oscillation (ENSO) events, as described by Engelthaler, et al. 1999 and Hjelle and Glass 2000, allowed researchers to determine underlying relationships between precipitation and rodent reservoir hosts that led to the emergence of a hantavirus, Sin Nombre virus, in humans. As novel viruses continue to emerge, researchers seek to unravel the biotic and abiotic factors that influence viral ecology. Understanding these factors could enable researchers to generate better predictions about where and when viruses might emerge. While there is much uncertainty regarding the role of the environment in bat-borne and other mammalian viruses, strong predictions have been made for arthropod vector-borne viruses. For example, a prediction for Rift Valley fever virus by Anyamba, et al. 2009, was able to forecast Rift Valley fever outbreaks in East Africa two to six weeks before they occurred. Advances in obtaining environmental and climatic data via remote sensing, as reviewed by Kalluri, et al. 2007, have dramatically improved researchers’ abilities to ascertain environmental factors of viral ecology and forecast disease emergence. Changes in the ecology of reservoir species can have a great impact on the spread of associated pathogens. Human activities, such as deforestation and urbanization, have likely contributed to the emergence of Henipa viruses and Ebola virus during the West African outbreak of 2014–2015. Anthropogenic climate changes, as reviewed by Patz, et al. 2005, have altered transmission patterns of viruses by changing or expanding the range of insects and arthropods that tranmist disease. Ali, et al. 2017 indicates that the recent emergence of Zika virus in the Americas was partially attributed to anthropogenic factors such as climate variation, land use change, poverty, and human movement. Research by Pulliam, et al. 2012 suggests that anthropogenic landscape changes altered fruit bat migratory behavior due to resource supplementation by alternative food sources facilitated by close contact with agricultural amplifying hosts and thereby increasing the risk of zoonotic transmission. Heesterbeek, et al. 2015 provides an overview of the challenges in disease modeling to understand the parameters under which viruses emerge, including population growth, increased urbanization and land changes, greater travel, and increased livestock production.

  • Ali, S., O. Gugliemini, S. Harber, et al. 2017. Environmental and social change drive: The explosive emergence of Zika virus in the Americas. PLoS Negl Trop Dis 11.2: e0005135.

    DOI: 10.1371/journal.pntd.0005135Save Citation »Export Citation »

    This paper reviews the current hypotheses and preliminary evidence for the environmental and social changes that were the underlying cause of the ZIKV epidemic.

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  • Anyamba, A., J. -P. Chretien, J. Small, et al. 2009. Prediction of a Rift Valley fever outbreak. Proceedings of the National Academy of Sciences 106.3: 955–959.

    DOI: 10.1073/pnas.0806490106Save Citation »Export Citation »

    The authors created a predictive model for Rift Valley fever virus using climate data obtained by remote sensing.

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  • Engelthaler, D. M., D. G. Mosley, J. E. Cheek, et al. 1999. Climatic and environmental patterns associated with hantavirus pulmonary syndrome, Four Corners region, United States. Emerging Infectious Diseases 5.1: 87–94.

    DOI: 10.3201/eid0501.990110Save Citation »Export Citation »

    A study of environmental associations between epidemic and endemic cases of hantavirus pulmonary syndrome in the Four Corners region.

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  • Heesterbeek, H., R. M. Anderson, V. Andreasen, et al. 2015. Modeling infectious disease dynamics in the complex landscape of global health. Science 347.6227: aaa4339.

    DOI: 10.1126/science.aaa4339Save Citation »Export Citation »

    This review provides an overview of modeling approaches to understand epidemiological patterns of diseases emerging, including anthropogenic factors such as increased human connectivity and human behavior.

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  • Hjelle, B., and G. E. Glass. 2000. Outbreak of hantavirus infection in the Four Corners region of the United States in the wake of the 1997–1998 El Niño-southern oscillation. The Journal of Infectious Diseases 181.5: 1569–1573.

    DOI: 10.1086/315467Save Citation »Export Citation »

    An examination of the relationships between ENSO events and hantavirus cases in the Four Corners region.

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  • Kalluri, S., P. Gilruth, D. Rogers, and M. Szczur. 2007. Surveillance of arthropod vector-borne infectious diseases using remote sensing techniques: A review. PLoS Pathogens 3.10: 1361–1371.

    DOI: 10.1371/journal.ppat.0030116Save Citation »Export Citation »

    A review of remote sensing techniques used to determine relationships in emerging arthropod viruses.

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  • Patz, J. A., D. Campbell-Lendrum, T. Holloway, and J. A. Foley. 2005. Impact of regional climate change on human health. Nature 438.7066: 310–317.

    DOI: 10.1038/nature04188Save Citation »Export Citation »

    A review on the impact of climate change on human health, with multiple examples of emerging viruses such as dengue.

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  • Pulliam, J. R., J. H. Epstein, J. Dushoff, et al. 2012. Agricultural intensification, priming for persistence and the emergence of Nipah virus: A lethal bat-borne zoonosis. Journal of the Royal Society Interface 9.66: 89–101.

    DOI: 10.1098/rsif.2011.0223Save Citation »Export Citation »

    Analyses of anthropogenic changes underlying Nipah virus emergence.

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Virus Stability and Persistence

The environment also influences the ecology of viruses outside of their hosts. The stability of viruses on surfaces, in liquids, or in aerosols, is an important determinant of transmission. Many emerging zoonotic viruses can be transmitted via contact with contaminated surfaces (fomite transmission), small or large aerosol droplets, bodily fluids, or water. While there are general relationships in virus stability and persistence, these factors must be considered individually for each virus. For example, Sobsey and Meschke 2003 reviewed the environmental stabilities of multiple viruses and found that while non-enveloped viruses tend to be more stable in liquids than enveloped viruses, there are exceptions to this relationship. Factors such as medium, temperature, pH, and humidity all influence the stabilities of different viruses. The discipline of environmental virology studies these relationships. Environmental virology contributes to the understanding of viral ecology by determining how viruses are transmitted in different environments. Bosch, et al. 2003 reviews the history of environmental virology and the properties of emerging pathogenic viruses in the environment. While many abiotic factors influence viral persistence, Stallknecht, et al. 1990 also found that factors such as host origin influence the stability of influenza viruses in water. For highly pathogenic viruses, biosafety level 3 and 4 laboratories enable researchers to study how viruses persist in different environments while controlling different variables. For example, Sagripanti, et al. 2010 studied the stabilities of various viruses on different surfaces and in the dark. Studies such as these will be necessary to determine the properties of emerging viruses. Understanding the properties of stability and persistence can then further knowledge about how these viruses spread between hosts.

  • Bosch, A., R. M. Pintó, and F. X. Abad. 2003. Survival and transport of enteric viruses in the environment. Viruses in Foods (January 1956): 151–188.

    DOI: 10.1007/0-387-29251-9_6Save Citation »Export Citation »

    A chapter on the study of environmental virology and the factors influencing persistence.

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  • Sagripanti, J. L., A. M. Rom, and L. E. Holland. 2010. Persistence in darkness of virulent alphaviruses, Ebola virus, and Lassa virus deposited on solid surfaces. Archives of Virology 155:2035–2039.

    DOI: 10.1007/s00705-010-0791-0Save Citation »Export Citation »

    A comparative study of how different surfaces and darkness influence the stabilities of highly pathogenic viruses.

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  • Sobsey, M. D., and J. S. Meschke. 2003. Virus survival in the environment with special attention to survival in sewage droplets and other environmental media of fecal or respiratory origin. Report for the World Health Organization. Geneva, Switzerland: WHO.

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    A review of the abiotic factors influencing virus survival and persistence. It emphasizes that one must be careful in generalizing about enveloped and non-enveloped viruses.

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  • Stallknecht, D. E., S. M. Shane, M. T. Kearney, and P. J. Zwank. 1990. Persistence of avian influenza viruses in water. Avian Diseases 34.2: 406.

    DOI: 10.2307/1591428Save Citation »Export Citation »

    One of the early studies on the persistence of avian influenza viruses in water. It finds that abiotic factors, virus strain, and host origin influence environmental persistence.

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Ecology of Viruses between Hosts

How viruses persist within a host population, spread between host species, and amplify are all key aspects of viral ecology. Viruses have varying degrees of host specificity, meaning that some viruses are able to infect and persist in multiple host species while others are more limited. Viruses also vary in their infectiousness (how readily they cause disease) and contagiousness (how quickly they are transmitted between hosts). Drosten 2013 reviewed this equilibrium between infectiousness and contagiousness and how it influences viral ecology. Viruses that are highly infectious may kill their host before transmission occurs, whereas some viruses that are highly contagious may not cause severe disease. The between-host ecologies of viruses have been studied in many systems. Recent research has focused on the ecology of viruses between bats and other species because of the number of emerging bat-borne viruses, such as ebolaviruses, henipaviruses, and coronaviruses. Researchers have studied the evolutionary constraints of emerging bat-borne viruses. Streicker, et al. 2010 found that the phylogeny of host bat species strongly influenced which rabies viruses could cross species. Others have studied the influence of population size on virus maintenance. Drexler, et al. 2011 determined how emerging viruses amplify within a bat colony depending on the host population. Another area of interest has been the temporal relationships in viral ecology. The periodic birthing and breeding patterns of certain bats have been associated with emergence of different viruses. For example, Hayman 2015 modeled how the biannual birthing of African fruit bats enable filoviruses, such as Ebola virus, to persist within bat populations. Lastly, spatial relationships in the ecology of viruses have also been examined. Maganga, et al. 2014 found associations between the size and shape of bat species’ host ranges and their diversity of viruses. Therefore, evolutionary, temporal, and spatial patterns all influence the ecology of viruses between hosts and must be investigated as key relationships in viral ecology.

  • Drexler, J. F., V. M. Corman, T. Wegner, et al. 2011. Amplification of emerging viruses in a bat colony. Emerging Infectious Diseases 17.3: 449–456.

    DOI: 10.3201/eid1703.100526Save Citation »Export Citation »

    A long-term study of the prevalence of viruses within a bat colony that found a correlation between virus and bat population dynamics.

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  • Drosten, C. 2013. Virus ecology: A gap between detection and prediction. Emerging Microbes & Infections 2.5: e31.

    DOI: 10.1038/emi.2013.25Save Citation »Export Citation »

    This review highlights the principle of how viruses vary with infectivity and transmission, which influence how viruses are maintained in a population.

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  • Hayman, D. T. S. 2015. Biannual birth pulses allow filoviruses to persist in bat populations. Proceedings of the Royal Society of London B: Biological Sciences 282.1803.

    DOI: 10.1098/rspb.2014.2591Save Citation »Export Citation »

    An analysis of the relationship between the biannual birthing periods of bats and the maintenance of viruses within the population.

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  • Maganga, G. D., M. Bourgarel, P. Vallo, et al. 2014. Bat distribution size or shape as determinant of viral richness in African bats. PLoS ONE 9.6.

    DOI: 10.1371/journal.pone.0100172Save Citation »Export Citation »

    A study on the association between bat species’ host ranges and the prevalence of viruses within bat species, indicating that geographic fragmentation may influence viral diversity within bats.

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  • Streicker, D. G., A. S. Turmelle, M. J. Vonhof, I. V. Kuzmin, G. F. McCracken, and C. E. Rupprecht. 2010. Host phylogeny constrains cross-species emergence and establishment of rabies virus in bats. Science 329.5992: 676–679.

    DOI: 10.1126/science.1188836Save Citation »Export Citation »

    The researchers found that the evolutionary distance between bat host species may be the most important factor in determining which rabies viruses can cross species.

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Viral-Host Coevolution and the Molecular Biology of Species Barriers

Viruses must be adapted to their hosts in order to replicate and transmit. As reviewed by Howard and Fletcher 2012, adaptations to the host species are required at all steps of the viral life cycle, including cell binding and entry, recruitment of host factors essential for replication, suppression of antiviral host factors, assembly and egress from the cell. Viral infections can have a deleterious effect on host fitness, and thus exert a positive selective pressure on various host factors to disfavor viral replication. This host-evolution, in turn, applies a positive selective pressure back on the virus to further adapt to the newly emerging genetic changes within the host. Therefore, viruses and their hosts are in a constant arms race, leading to their co-evolution. Brockhurst and Koskella 2013 provides a detailed review on experimental studies that directly observe coevolution in the laboratory. These experiments, often performed with bacteria and phage host systems, are providing the first empirical tests of longstanding coevolutionary ideas, including the influential Red Queen hypothesis. Mismatches in crucial viral-host interactions can form species barriers to cross-species transmission if a virus is unable to exploit the host cell machinery in a novel species. Research from numerous groups, reviewed in Daugherty and Malik 2012, has demonstrated various molecular mechanisms that drive viral host coevolution. Virus adaptations to host selective pressures have recently been observed and extensively characterized under experimental laboratory conditions. An overview of the various types of experimental, forced viral-adaptation studies was reviewed in Sawyer and Elde 2012. Viruses have an increased chance of cross-species transmission between species that are similar at the genetic level. Longdon, et al. 2014 closely reviews how host adaptation can facilitate cross-species viral replication. The transmission of viruses from animals to the humans, as in the case of Ebola virus, Marburg virus, SARS-CoV, MERS-CoV, Nipah virus, Hendra virus, HIV, Zika virus, and influenza A virus, has spurred interest in attempting to predict the next potential pandemic zoonotic event. At the same time, scientists have only begun to appreciate the complex nature of virus-host genetic interactions that help govern cross-species transmission. Pepin, et al. 2010 discusses the challenges in predicting novel zoonotic events with the limited knowledge currently available, and further outlines the types of experimental studies needed to increase predictive power. While our understanding of the molecular determinants for zoonosis is increasing, more work is needed in this area in order to make stronger predictions for future emerging infectious diseases.

  • Brockhurst, M. A., and B. Koskella. 2013. Experimental coevolution of species interactions. Trends in Ecology & Evolution 28.6: 367–375.

    DOI: 10.1016/j.tree.2013.02.009Save Citation »Export Citation »

    In this review, the authors provide a synthesis of current experimental studies providing insights in coevolutionary processes.

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  • Daugherty, M. D, and H. S. Malik. 2012. Rules of engagement: Molecular insights from host-virus arms races. The Annual Review of Genetics 46:677–700.

    DOI: 10.1146/annurev-genet-110711-155522Save Citation »Export Citation »

    A review on how viral-host interactions coevolve under positive selective pressures. The authors discuss how studying signatures of positive selection in host innate-immunity genes can lead to identifying interacting surfaces with viral antagonists.

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  • Howard C. R, and N. F. Fletcher. 2012. Emerging virus diseases: Can we ever expect the unexpected? Emerging Microbes and Infections 12:e46.

    DOI: 10.1038/emi.2012.47Save Citation »Export Citation »

    Pages 6–9 of this review provide a broad overview of the various types of barriers viruses must overcome in order to transmit between species. Multiple examples from diverse viruses are provided.

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  • Longdon, B., M. A. Brockhurst, C. A. Russell, J. J. Welch, and F. M. Jiggins. 2014. The evolution and genetics of virus host shifts. PLoS Pathogens 10.11: e1004395.

    DOI: 10.1371/journal.ppat.1004395Save Citation »Export Citation »

    This review summarizes how viruses adapt to genetic barriers in their hosts and how these adaptations can facilitate zoonotic transmission. The authors frame different viral adaptations within an evolutionary scale and discuss the challenges to predicting novel cross-species transmission events.

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  • Pepin, K. M, S. Lass, J. R. Pulliam, A. F. Read, and J. O. Lloyd-Smith. 2010. Identifying genetic markers of adaptation for surveillance of viral host jumps. Nature Reviews Microbiology 8.11: 802–813.

    DOI: 10.1038/nrmicro2440Save Citation »Export Citation »

    This review highlights the difficulty in predicting novel zoonotic transmission solely from host and viral genetic data. The authors discuss the types of studies necessary to advance the field and refer to recent insights gained from studying the mechanisms behind viral zoonotic transmission events.

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  • Sawyer, S. L, and N. C. Elde. 2012. A cross-species view on viruses. Current Opinion in Virology 2.5: 561–568.

    DOI: 10.1016/j.coviro.2012.07.003Save Citation »Export Citation »

    In this review on forced viral adaptation studies, the authors discuss the various ways virus-host coevolution has been examined experimentally.

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Viral Transmission and Entry––Receptor Adaptation

The first step in which a virus must be adapted to its host is at the level of cell entry. Incompatibility with a host receptor can completely block infection of a noncognate host species, as in the case of hepatitis C virus (HCV), which infects humans but fails to infect mice. Ploss, et al. 2009 discovered that HCV is only compatible with the human version of the cell surface protein, occludin, but not the murine version. Introduction of human occludin in mice allowed for their infection, and lead to a new small animal model for HCV infection. Partial incompatibility with a host receptor can also influence viral entry efficiency. Without a complete block to viral entry, a virus can still enter the cell, replicate, and further adapt to the host receptor increasing viral spread. This type of cross-species adaptation in viral glycoproteins has been observed for several viruses including SARS-CoV by Li 2013., parvoviruses by Allison, et al. 2014, and avian influenza A virus by Moncla, et al. 2016. Ng, et al. 2015 demonstrated that species variation in the receptor for Zaire Ebola virus can be overcome by introducing a single amino acid change in the viral glycoprotein. While this mutation was artificial, this work highlighted the adaptation potential of the Zaire Ebola virus glycoprotein.

  • Allison, A. B, D. J. Kohler, A. Ortega, et al. 2014. Host-specific parvovirus evolution in nature is recapitulated by in vitro adaptation to different carnivore species. PLoS Pathogens 10.11: e1004475.

    DOI: 10.1371/journal.ppat.1004475Save Citation »Export Citation »

    This study demonstrates how parvoviruses can adapt to more efficiently enter cells from diverse species. The researchers passage different parvoviruses in different species’ cell lines and the adaptive mutations are characterized. In general, all of the viruses acquired mutations in their capsid proteins, which allowed more efficient use of the host receptor.

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  • Li, F. 2013. Receptor recognition and cross-species infections of SARS coronavirus. Antiviral Research 100.1: 246–254.

    DOI: 10.1016/j.antiviral.2013.08.014Save Citation »Export Citation »

    This review thoroughly examines the genetic changes in the SARS coronavirus spike protein as the virus transmitted between species and within humans. The author gives detailed structural explanations behind each amino acid change, citing recent co-crystal structures of the SARS spike protein and the host-cell receptor, ACE2.

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  • Moncla, L. H., G. Zhong, C. W. Nelson, et al. 2016. Selective bottlenecks shape evolutionary pathways taken during mammalian adaptation of a 1918-like avian influenza virus. Cell Host & Microbe 19.2: 169–180.

    DOI: 10.1016/j.chom.2016.01.011Save Citation »Export Citation »

    Using deep sequencing analysis on samples from a previous study, the authors trace the emergence of a set of mutations in avian influenza hemagglutinin during infection of a mammalian host (ferret). The findings reveal how some HA mutations are transient and influence the ability of the virus to gain further adaptations in order to replicate to high titers in mammals and transmit by aerosol.

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  • Ng, M, E. Ndungo, M. E. Kaczmarek, et al. 2015. Filovirus receptor NPC1 contributes to species-specific patterns of ebolavirus susceptibility in bats. eLife 4. pii: e11785.

    DOI: 10.7554/eLife.11785Save Citation »Export Citation »

    This study demonstrates that Zaire Ebola virus has reduced entry in cells from Eidolon helvum bats compared to other bat species. The authors attribute this cell entry impairment to a single amino acid change in Eidolon helvum NPC1 and further demonstrate a single amino acid change in Ebolavirus GP can overcome this difference.

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  • Ploss, A, M. J. Evans, V. A. Gaysinskaya, et al. 2009. Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 457.7231: 882–886.

    DOI: 10.1038/nature07684Save Citation »Export Citation »

    This landmark study demonstrates that occludin is a key species barrier preventing mice from infection by hepatitis C virus. The authors show that expression of human occludin in mice allows for viral entry.

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Viral Replication––Adaptation to Innate Host Defenses and Dependency Factors

After entering the cell, a virus must circumvent the various host defense systems that can halt viral replication. The best studied host defense is the interferon response, which recognizes aberrant molecular features common among intracellular pathogens, shuts down crucial host-cell machinery required for viral replication and activates the immune system. Katze, et al. 2002 reviews the interferon pathway and provides examples of different strategies taken by viruses to evade this system. As shown by Valmas and Basler 2011 for Marburg virus, species variation in the interferon system can severely inhibit viral replication in non-cognate species, and apply a selective pressure for species-specific viral adaptation. More recently, researchers have identified additional antiviral host proteins, termed “restriction factors,” that are constitutively expressed and interfere with specific classes of viruses. Initial examples of restriction factors were discovered in the early 2000s for retroviruses, namely HIV, and are reviewed by Duggal and Emerman 2012. As many restriction factors are expressed independent of the interferon system, they require specialized viral strategies for evasion. Often, these strategies involve the use of nonstructural, “accessory” genes in the viral genome. Hatziioannou, et al. 2014 demonstrated that replacing the viral infectivity factor (VIF) protein in HIV with the VIF protein from Simian immunodeficiency virus (SIV) allowed for HIV replication in macaques. In addition to generating a new animal model of HIV disease progression, this study underscored the importance of species variation in restriction factors and subsequent species-specific viral adaptation. Beyond retroviruses, species-specific adaptation to restriction factors has also been observed for avian influenza A virus by Riegger, et al. 2015 and for poxviruses by Elde, et al. 2012. Concomitant with evasion of host defenses, viruses must also hijack the necessary host cell machinery in order to replicate the viral genome. Again, species variation in this machinery can thwart viral replication in non-cognate species, as shown by Mänz, et al. 2013 and for the avian influenza viral polymerase complex and by Lou, et al. 2016 for herpes simplex 1 virus incompatibility with host DNA repair machinery. Taken together, all of these studies shed light on the various intracellular challenges viruses face in the course of replication. Species variation in any of the host cell defense mechanisms or machinery required for viral replication can impose strong species barriers to zoonotic transmission.

  • Duggal, N. K., and M. Emerman. 2012. Evolutionary conflicts between viruses and restriction factors shape immunity. Nature Reviews Immunology 12.10: 687–695.

    DOI: 10.1038/nri3295Save Citation »Export Citation »

    This review provides an overview of all the known host factors that can restrict the replication of retroviruses and how retroviruses counteract these proteins. These host factors are under constant positive selection from retroviruses and therefore vary between species, generating multiple, strong species barriers to retroviral zoonosis.

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  • Elde, N. C., S. J. Child, M. T. Eickbush, et al. 2012. Poxviruses deploy genomic accordions to adapt rapidly against host antiviral defenses. Cell 50.4: 831–841.

    DOI: 10.1016/j.cell.2012.05.049Save Citation »Export Citation »

    RNA viruses have considerably higher mutations rates compared to DNA viruses. The authors of this study passaged vaccinia virus, a bovine poxvirus, in human cells and observed a gene amplification event allowed the viral protein to overwhelm a host antiviral host protein, despite their relatively low affinity. This remarkable finding demonstrates how even viruses with a low mutation rate can rapidly change to selective pressures across species.

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  • Hatziioannou, T, G. Q. Del Prete, B. F. Keele, et al. 2014. HIV-1-induced AIDS in monkeys. Science 344.6190: 1401–1405.

    DOI: 10.1126/science.1250761Save Citation »Export Citation »

    The authors demonstrate how the knowledge of species barriers and restriction factors can be exploited to generate novel animal models of viral pathogenesis. In this study, HIV-1, which does not induce acquired immunodeficiency syndrome (AIDS) in non-human primates, was minimally modified to counteract an antiviral protein in macaques. The resulting modified HIV-1 was then capable of replicating and inducing AIDS in a macaque model.

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  • Katze, M. G., Y. He, and M. Gale Jr. 2002. Viruses and interferon: A fight for supremacy. Nature Reviews Immunology 2.9: 675–687.

    DOI: 10.1038/nri888Save Citation »Export Citation »

    The authors provide a broad overview of how several clinically relevant viruses evade the host cell interferon system.

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  • Lou, D. I, E. T. Kim, N. R. Meyerson, et al. 2016. An intrinsically disordered region of the DNA repair protein Nbs1 is a species-specific barrier to herpes simplex virus 1 in primates. Cell Host & Microbe 20.2: 178–188.

    DOI: 10.1016/j.chom.2016.07.003Save Citation »Export Citation »

    The authors of this study demonstrate that species-specific variation in the DNA repair enzyme, Nbs1, can restrict replication of Herpes simplex 1 virus (HSV-1). Thus, HSV-1 can only transmit between certain primate species and humans.

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  • Mänz, B, M. Schwemmle, and L. Brunotte. 2013. Adaptation of avian influenza A virus polymerase in mammals to overcome the host species barrier. Journal of Virology 87.13: 7200–7209.

    DOI: 10.1128/JVI.00980-13Save Citation »Export Citation »

    This review discusses the species-specific adaptations in influenza A virus polymerase that help facilitate cross species transmission from birds to humans.

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  • Riegger, D, R. Hai, D. Dornfeld, et al. 2015. The nucleoprotein of newly emerged H7N9 influenza A virus harbors a unique motif conferring resistance to antiviral human MxA. Journal of Virology 89.4: 2241–2252.

    DOI: 10.1128/JVI.02406-14Save Citation »Export Citation »

    This study describes a mutation found in the nucleoprotein of an isolate of avian influenza A virus that confers resistance to the antiviral human MxA protein. The decreased sensitivity to this human restriction factor allows for more efficient viral replication in human cells.

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  • Valmas, C., and C. F. Basler. 2011. Marburg virus VP40 antagonizes interferon signaling in a species-specific manner. Journal of Virology 85.9: 4309–4317.

    DOI: 10.1128/JVI.02575-10Save Citation »Export Citation »

    This study characterizes mutations acquired in the VP40 protein of Marburg virus after mouse-adaptation. The authors show that two amino acid changes are required to effectively inhibit interferon signaling in murine cells.

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Viral Assembly and Egress––Adaptations Necessary for Spread within the Host

The final step of viral replication in the host involves assembly of nascent viral particles and egress from the cell. Species barriers at this stage of the viral life cycle have only recently begun to be appreciated. Walter, et al. 2016 characterized a sequence in the p7 protein of hepatitis C virus (HCV) that facilitated viral assembly. Replacing this sequence with an analogous fragment from nonprimate hepacivirus (NPHV) prevented virion assembly in human cells. While a detailed mechanistic understanding for this observation has yet to be elucidated, this study clearly demonstrated that viruses must be adapted to their hosts at the level of viral assembly. The earliest example of a cellular protein that could disrupt viral egress was described for HIV-1 by Neil, et al. 2008. In this landmark paper, the authors identified a transmembrane host protein called tetherin, that is expressed on the cell surface and prevents the release of newly formed viral particles. A follow up study, McNatt, et al. 2009, demonstrated that HIV-1 fails to counteract tetherin from different species. Additionally, Pardieu, et al. 2010 showed species-specific restriction and counteraction of tetherin for Kaposi’s sarcoma herpes virus. Thus, tetherin represents the first-described species barrier at the level of viral egress. Later work from Sauter, et al. 2009 showed that lentiviruses from other host species counteract tetherin differently from HIV-1. This work provided compelling evidence for how these different strategies may have influenced the ability of these viruses to transmit and spread within the human population. Since these early studies were published, tetherin has been shown to have antiviral activity against a diverse range of enveloped viruses including filoviruses, arenaviruses, paramyxoviruses, gamma-herpes viruses, and rhabdoviruses (reviewed in Le Tortorec, et al. 2011). Collectively, these studies underscore the importance in pursuing additional species-barriers, throughout the viral lifecycle.

  • Le Tortorec, A., S. Willey, and S. J. Neil. 2011. Antiviral inhibition of enveloped virus release by tetherin/BST-2: Action and counteraction. Viruses 3.5: 520–540.

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    This review provides a broad summary of the mechanistic details of tetherin restriction and counteraction by various viruses.

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  • McNatt, M. W., T. Zang, T. Hatziioannou, et al. 2009. Species-specific activity of HIV-1 Vpu and positive selection of tetherin transmembrane domain variants. PLoS Pathogens 5.2: e1000300.

    DOI: 10.1371/journal.ppat.1000300Save Citation »Export Citation »

    This study demonstrates that HIV-1 fails to counteract tetherin proteins from different species.

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  • Neil, S J., T. Zang, and P. D. Bieniasz. 2008. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451.7177: 425–430.

    DOI: 10.1038/nature06553Save Citation »Export Citation »

    The authors identify tetherin: an interferon-induced protein that can retain enveloped viruses like HIV-1 on the cell surface, preventing their release. The researchers then demonstrate how HIV-1 evades this host protein with the viral Vpu protein, leading to shedding of the virus from the cell surface.

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  • Pardieu, C., R. Vigan, S. J. Wilson, et al. 2010. The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin. PLoS Pathogens 6.4: e1000843.

    DOI: 10.1371/journal.ppat.1000843Save Citation »Export Citation »

    This paper demonstrates that Kaposi’s sarcoma herpes virus fails to counteract tetherin from rhesus macaques.

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  • Sauter, D., M. Schindler, A. Specht, et al. 2009. Tetherin-driven adaptation of Vpu and Nef function and the evolution of pandemic and nonpandemic HIV-1 strains. Cell Host & Microbe 6.5: 409–421.

    DOI: 10.1016/j.chom.2009.10.004Save Citation »Export Citation »

    This work shows how different lentiviruses have evolved different strategies to overcome tetherin-mediated restriction, in a species-specific manner. The authors further show how tetherin can pose a species barrier to viruses from non-cognate species.

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  • Walter, S, A. Bollenbach, J. Doerrbecker, et al. 2016. Ion channel function and cross-species determinants in viral assembly of nonprimate hepacivirus p7. Journal of Virology 90.10: 5075–5089.

    DOI: 10.1128/JVI.00132-16Save Citation »Export Citation »

    The p7 protein of hepaciviruses has been shown to be essential for viral assembly. In this study, the authors generate chimeric p7 proteins between human hepatitis C virus (HCV) and equine nonprimate hepacivirus (NPHV) to demonstrate species-specific determinants essential for viral assembly in human cells.

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