Host Species Barriers to Influenza Virus Infections

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http://www.sciencemag.org/cgi/content/full/312/5772/394

<table border="0" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td align="left">Science 21 April 2006:
Vol. 312. no. 5772, pp. 394 - 397
DOI: 10.1126/science.1122818
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<!-- BEGIN: legacy HTML content --> <!--RESUMEHIGHLIGHT--> Host Species Barriers to Influenza Virus Infections



<nobr>Thijs Kuiken,¹^*</nobr> <nobr>Edward C. Holmes,²</nobr> <nobr>John McCauley,³</nobr> <nobr>Guus F. Rimmelzwaan,¹</nobr> <nobr>Catherine S. Williams,²</nobr> <nobr>Bryan T. Grenfell²^,4</nobr> Most emerging infectious diseases in humans originate from animalreservoirs; to contain and eradicate these diseases we needto understand how and why some pathogens become capable of crossinghost species barriers. Influenza virus illustrates the interactionof factors that limit the transmission and subsequent establishmentof an infection in a novel host species. Influenza species barrierscan be categorized into virus-host interactions occurring withinindividuals and host-host interactions, either within or betweenspecies, that affect transmission between individuals. Viralevolution can help surmount species barriers, principally byaffecting virus-host interactions; however, evolving the capabilityfor sustained transmission in a new host species representsa major adaptive challenge because the number of mutations requiredis often large.
¹ Department of Virology, Erasmus Medical Center, 3015 GE Rotterdam, Netherlands.
² Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University, University Park, PA 16802, USA.
³ Institute for Animal Health, Compton Laboratory, Compton, Newbury, Berkshire RG20 7NN, UK.
⁴ Fogarty International Center, National Institutes of Health, Bethesda, MD 20892, USA.
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^* To whom correspondence should be addressed. E-mail: t.kuiken@erasmusmc.nl<script type="text/javascript"><!-- var u = "t.kuiken", d = "erasmusmc.nl"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></script>
The highly pathogenic avian influenza H5N1 virus is just oneexample of a zoonotic pathogen capable of transmission fromanimal reservoir species to humans (1). If we are to containand eradicate such emerging infectious diseases (EIDs), we needto understand how and why some pathogens become capable of infectingand being maintained in novel host species. Here, we reviewthe interaction of factors that collectively limit the transmissionof an infection from a donor host species to a recipient speciesand that constitute the host species barrier. We discuss thesefactors specifically as they apply to influenza, but the underlyingprinciples apply to any EID.
The host species barrier is not a simple concept; the likelihoodof a virus becoming endemic in a new host species depends onthe interaction of three sets of processes (Fig. 1): interspecificinteractions between hosts of the donor and recipient species,host-virus interactions within individual hosts of the recipientspecies, and host-host interactions within the recipient species.For any type of species transfer, there must be sufficient contactbetween donor and recipient species and enough compatibilitybetween the virus and the new host to allow replication andthe possibility of transmission to other members of the recipientspecies. If this transmission can occur, the contact networkstructure of the recipient species, together with variationsin transmission through this network, are critical in determiningwhether the virus will persist or die out. As the history ofinfluenza pandemics and epidemics illustrates, viral evolutioncan help considerably in lowering the species barrier. However,we argue below that the relative rarity of successful speciesjumps testifies to the complex adaptations often required toachieve sustained transmission in a new species. We also reviewthe components and evolutionary dynamics of the species barrieras they apply to influenza and then suggest areas for futurework.
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<center><table cellpadding="0" cellspacing="0" width="95%"><tbody><tr bgcolor="#e1e1e1"><td><table cellpadding="2" cellspacing="2"> <tbody><tr bgcolor="#e1e1e1"><td align="center" bgcolor="#ffffff" valign="top"> </td><td align="left" valign="top"> Fig. 1. Schematic illustrating phases in overcoming species barriers. (A) Interspecific host-host contact must allow transmission of virus from donor species to recipient species. (B) Virus-host interactions within an individual of recipient species affect the likelihood of the virus replicating and being shed sufficiently to infect another individual of recipient species. (C) Intraspecific host-host contact in recipient species must allow viral spread (R₀ > 1) in the presence of any preexisting immunity. Superspreader events (red asterisk) early in the transmission chain can help this process. (D) The pathogen must persist in the recipient species population even during epidemic troughs (after most susceptible individuals have had the disease) so that subsequent epidemics can be seeded: If few susceptibles are left, the virus may (stochastically) go extinct in epidemic troughs. Viral variation and evolution can aid invasion and persistence, particularly by affecting host-virus interactions. <nobr>[View Larger Version of this Image (13K GIF file)]</nobr> </td></tr></tbody></table> </td></tr></tbody></table></center>

The Virus-Host Interaction: Within-Host Barriers
Cell entry-exit and receptor biology. For a virus shed by onehost to infect another, it must breach entry barriers (e.g.,mucus, alveolar macrophages, and epithelium) and find its wayto tissues in which it can replicate. For example, chimpanzeesare relatively resistant to experimental respiratory exposureto human influenza viruses, possibly because their respiratorytract secretions contain mucins that can specifically bind virusesbefore they reach airway epithelial cells (2). Once in appropriatetissues, a virus must attach to and enter cells before it canreplicate. The specificity of receptor molecules governs virusentry into cells (3). For example, hemagglutinin molecules onthe viral coats of avian influenza viruses preferentially bindto one form of molecule in the host cell membrane [sialic acid(SA)--2,3-Gal?terminated saccharides], whereas the hemagglutininson human influenza viruses prefer another (SA--2,6-Gal?terminatedsaccharides) (4). This difference, together with the predominanceof SA--2,6-Gal?terminated saccharides in the human trachea,may explain why replication of avian influenza viruses in humansgenerally tends to be restricted (5). The rare occurrences offatal pneumonia in humans infected with the current H5N1 virusfrom Asia (6) and the H7N7 virus from the Netherlands in 2003(7) are likely due to the ability of these viruses to attachto and replicate in lower respiratory tract cells, which dohave SA--2,3-Gal?terminated saccharides (8, 9).
Replication and spread within tissues. Once it has entered acell of the new host, the virus must successfully co-opt hostcell processes to replicate there. Many avian influenza virusescan infect mouse cells but cannot replicate, frequently becauseamino acid residue 627 of the PB2 protein of the viral polymerasediffers between avian and mammalian influenza viruses. In theavian virus, this residue is usually glutamic acid, whereasin mammalian influenza virus it is lysine (4), suggesting thatPB2 residue 627 might be important in determining species range.In experimentally infected mice, a glutamic acid?to?lysinemutation at this position in the PB2 protein of H5N1 virus resultsin increased virulence and the ability to invade extrarespiratoryorgans (10). It is notable that both H5N1 virus from human patientsin Asia (10) and H7N7 virus from a fatal human case in the Netherlands(7) possess a lysine at this site, suggesting rapid evolutionwithin humans of a virus originating in poultry. Strikingly,though, and worryingly, lysine is the PB2 residue in H5N1 virusesisolated from wild waterfowl in mid-2005 from Qinghai Lake,in China (11, 12).
If a virus does succeed in replicating, it needs to be releasedfrom the host cell to infect more cells or be shed from thehost. In influenza, progeny virus particles are bound to hostcell sialosaccharides by their hemagglutinin. Viral neuraminidasecleaves these sialosaccharides, thus releasing newly producedvirus from the cell surface. Like the respective hemagglutinins,neuraminidases from avian influenza viruses have a preferencefor SA--2,3-Gal?terminated saccharides, whereas thosefrom many human influenza viruses prefer SA--2,6-Gal?terminatedsaccharides (4). Interestingly, the H2N2 virus that caused the1957 pandemic initially retained a binding preference for "avian"SA--2,3-Gal?terminated sialosaccharides but switched affinityto "human" SA--2,6-Gal?terminated saccharides during subsequentinfluenza seasons in the human population (13).
Even if progeny virus exits one host cell, host innate immuneresponses may hinder infection of other cells. Interferons mayinduce uninfected cells to enter an antiviral state that inhibitsviral replication (4). To counter host responses, influenzavirus has developed strategies for evading innate immunity:The viral NS1 polypeptide acts as an antagonist of interferoninduction in infected cells by sequestration of double-strandedRNA or suppression of host posttranscriptional processing ofmRNAs (4). NS1 also may help influenza viruses to replicatein interferon-treated cultured cells, as has been reported forH5N1 virus isolates from 1997 (14); whether currently isolatedH5N1 viruses have retained this property remains to be determined.
Sometimes infection is restricted to particular tissues; inother cases, it can be systemic. For influenza virus to spreadfrom the respiratory tract to other susceptible tissues, itneeds to enter the lymph and/or blood system, be successfullytransported, and exit at tissue-blood junctions (15). In poultry,whether infection is localized or systemic depends on the aminoacid sequence at the cleavage site of the precursor hemagglutinin.This cleavage is required for the hemagglutinin to become fullyfunctional. Low pathogenicity influenza viruses require extracellularproteases limited to the respiratory and gastrointestinal tractsto cleave the precursor hemagglutinin, whereas highly pathogenicavian influenza viruses have changes in the cleavage site thatallow the precursor hemagglutinin to be processed by ubiquitousintracellular proteases, resulting in fatal systemic infection(4). In mammals, the viral factors determining systemic infectionare less clear, although cleavability of the precursor hemagglutininplays an important role (10).
From their sites of replication, viruses need ultimately tobe transmitted to new hosts. In general, dissemination of progenyviruses from the infected host occurs through shedding in respiratory,enteric, or urogenital secretions. Human influenza virus replicatesmainly in the upper respiratory tract and is usually readilytransmitted via droplets formed during coughing or sneezing(16). By contrast, the H5N1 influenza virus typically infectshuman cells in the lower respiratory tract (8, 9) and so maybe less easily shed from the infected patient; this may partlyexplain why so far there has been little human-to-human transmissionobserved.

Host-Host Interactions: Cross-Species Contacts
Human population growth and consumption patterns are now reducingthe magnitude of many geographical, environmental, or behavioralbarriers that limit contact and potential virus transmissionbetween donor and recipient species. The spread of viral diseasesthrough international travel and trade is a major concern, althoughnatural modes of spread can be important too. H5N1 virus wasspread from Southeast Asia to Western Europe in 2005 and 2006,most likely by a combination of migratory wild birds (11, 12)and trade in poultry and poultry products. Even when donor andrecipient species live in the same area, spread of infectionfrom the one to the other can be hampered by differences inhabitat use or by environmental barriers. The massive increasein poultry production in Southeast Asia has certainly reducedsome of the obstacles to interspecific transmission of avianinfluenza virus. Increasing numbers of poultry are kept in closeproximity to wild waterfowl (17) and are brought into contactwith other species at live animal markets (18). Even if twohost species share the same geographical area and habitat, hostbehavior may limit pathogen transmission by, for instance, restrictinginfective contacts. Conversely, certain behaviors can predisposehosts to increased pathogen exposure. For example, consumptionof raw poultry products resulted in fatal H5N1 virus infectionin both humans and felids (19, 20), and racing greyhounds mayhave contracted equine influenza virus A/H3N8 after being fedmeat from infected horses (21).

Host-Host Interactions: Intraspecific Contacts in the Recipient Population
Assuming that a virus can be transmitted between individualsof the recipient host species, persistence of infection thendepends on how it is spread through the host's contact network,and successful invasion depends on the network structure andthe likelihood of particular individuals in the network transmittingthe virus. The basic reproduction ratio of infection, R₀, representsthe number of secondary cases produced when an infected individualis introduced into a well-mixed local population of wholly susceptibleindividuals (22, 23). It is well established that, as the proportionof susceptibles in the population, s, drops (as individualsbecome infected, then recover), the number of secondary casesper infection, R, also drops: R = sR₀. If R < 1, as is currentlythe case for H5N1 virus in humans, an infection will not causea major epidemic. But if R is even modestly greater than unity,a novel infection may spread locally, with potential for furtherspread in the absence of control (24).
For some novel infections that jump the species barriers, thereis no preexisting immunity; however, preexisting immune protectioncan sometimes reduce the number of susceptibles, and hence R.For instance, humans who had previously encountered an influenzavirus with the N2 neuraminidase may have been partially protectedin the 1968 H3N2 pandemic that followed the global circulationof H2N2 viruses (25). There is also indirect evidence of short-termimmunity between subtypes of influenza viruses (24, 26), whichcould play a role in the early spread of pandemics (24). Inaddition, cross-reactive T cells also may contribute to heterosubtypicimmunity to influenza and reduce viral shedding (27).
The biological characteristics and evolutionary potential ofthe invading virus can also affect the longer term persistenceof the infection. Acute immunizing infections are typified byinitial steep increases in the number of infected individuals.This type of epidemic depletes the supply of susceptibles, leadingto deep epidemic troughs (Fig. 1D) when local stochastic extinctionof infection is possible, especially after a major epidemictypical of an invasion of a new host species. This effect createsa barrier to sustained transmission that applies especiallyto infections with strong, stable immunity, such as morbilliviruses(28); however, it is less of a handicap to infections such asinfluenza, in which the viruses can evolve quickly to overcomeprevailing herd immunity (29). Teasing out what combinationof immune escape and spatial dynamics allows interpandemic influenzato persist, despite its short infectious period and stronglyseasonal transmission, is an important area for future work(29).
Overall, the likelihood of an EID persisting in a new speciesdepends in a complex way on the population sizes and the degreesof mixing of donor and recipient host species as well as thevalues of R₀ in each (30). At every geographical level, whetherlocal, regional, or global, the rate and the pattern of diseasespread depend on the spatial distribution and mixing of thehost population. Long-range spatial spread is in general facilitatedby high infectivity, a long infectious period, and (at leastin human influenza) a period of transmission before symptomsbecome apparent and quarantine measures can be taken. This contrastswith severe acute respiratory syndrome (SARS), in which theperiod of infectiousness begins with the onset of symptoms,allowing quarantine measures to be taken before maximum infectiousnessis attained (31). The fate of an epidemic can also depend stronglyon heterogeneities in R₀, particularly on the role of "superspreaders"early in the epidemic (32). For example, some superspreaderindividuals may be more infective per contact for some reason;other superspreaders may not have higher per-contact transmission,but have many more contacts and therefore greatly multiply therate of spread (22). If superspreaders become infected earlyin an outbreak, the epidemic is more likely to take off, whichcan have substantial implications for disease control (32).

The Role of Pathogen Evolution
In evolutionary terms and from the perspective of the pathogen,the host species barrier for infection can be thought of asa fitness valley lying between two distinct fitness peaks representingdonor and recipient hosts, respectively (Fig. 2). The more mutationsrequired for a virus to move between these peaks, the deeperthe valley and the less likely that this can occur in a singlestep, particularly if adaptation involves changes at multipleloci, as in the case of avian influenza virus transmitting inhuman populations (33). Such a model has two important implicationsfor our understanding of viral disease emergence.
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<center><table cellpadding="0" cellspacing="0" width="95%"><tbody><tr bgcolor="#e1e1e1"><td><table cellpadding="2" cellspacing="2"> <tbody><tr bgcolor="#e1e1e1"><td align="center" bgcolor="#ffffff" valign="top"> </td><td align="left" valign="top"> Fig. 2. Evolutionary models for the cross-species transmission of pathogens. (A) The donor and recipient species represent two distinct fitness peaks separated by a steep fitness valley. Multiple adaptive mutations (solid circles) are therefore required for the virus to successfully establish onward transmission in the recipient host species. (B) The donor and recipient species are separated by a far shallower fitness valley. This facilitates successful cross-species transmission because only a small number of advantageous mutations are required. (C) When multiple mutations are required for a virus to adapt to a new host, these may evolve progressively in the recipient species. However, this necessarily requires some onward transmission. (D) It is also possible that many of the mutations required to allow adaptation to a new host species were preexisting in the donor species and transmitted simultaneously. This will accelerate successful viral emergence. <nobr>[View Larger Version of this Image (22K GIF file)]</nobr> </td></tr></tbody></table> </td></tr></tbody></table></center>
 First, the effective rate of virus adaptation is not simplydetermined by the overall rate at which mutations arise, butby the fitness of these mutations, particularly the proportionthat are advantageous in multiple hosts. Hence, although RNAviruses often show prodigious levels of genetic variation, reflectingtheir high rates of mutation and immense intrahost populationsizes (34), a large proportion of the mutations that arise withinan individual viral population will be deleterious or slightlyso (35). As a case in point, vector-borne RNA viruses seem tobe characterized by a particularly high proportion of deleteriousmutations because of the fitness trade-offs that are inherentin replication in hosts as distant as mammals and arthropods(36) and that thereby constitute a major constraint on theiradaptability (23). Further, there is growing evidence that mutations,both advantageous and deleterious, often show complex epistaticinteractions, which can also have major effects on the rateand the progress of adaptation (37).
Second, the critical parameters determining when successfulonward transmission will occur include not only the time ittakes to optimize fitness (R₀ > 1) in the new host species(38) but also the probability that the recipient populationis exposed to a viral strain that, by chance, already harborsseveral mutations required for successful onward transmission.For example, of the myriad influenza viruses produced by faultyreplication within an individual, some, by chance, may possessthose mutations that affect the receptor binding site to altersialic acid binding capacity. This was highlighted recently(January 2006) in samples from a patient infected with H5N1virus in Turkey. This individual had a mixed population of viruses,some of which expressed hemagglutinin with an amino acid sequenceassociated with an increased affinity for SA--2,6-Gal?terminatedsaccharides. Because intrahost genetic diversity has rarelybeen examined in RNA viruses, it is unclear how much adaptivelyimportant genetic variation rests within hosts.
Reassortment and recombination further complicate the picture.These processes will allow some viruses to acquire many of thekey adaptive mutations in a single step and hence make a majorjump in fitness space. However, whereas reassortment may allowviruses to traverse the adaptive landscape faster than throughmutation alone, the optimal epistatic interactions among genesare likely to be broken by reassortment, and most reassortments,like most point mutations, are also expected to be largely deleterious.

Future Research Needs
Although there is a vast body of literature on influenza, onlya few studies consider the barriers for influenza viruses tocross from one species to another. There are several importantquestions in this area that need to be addressed. Which geneticchanges would allow the currently circulating H5N1 virus toacquire the characteristic to spread efficiently among humans?Such a study would require a combination of reverse geneticsto generate potential virus candidates and a suitable animalmodel to simulate human-to-human transmission. If such a viruswere to evolve, which factors at the population level wouldallow it to cause a pandemic? Investigating this requires epidemiologicalmodels that take into account not only the properties of thedonor and recipient populations but also the characteristicsof the newly emerged virus. What is the within-host diversityof influenza viruses, and does it include mutants that are ableto replicate in a new host species? The current status of viralgenome sequencing makes such studies possible, although studiesof intrahost viral diversity are notable for their rarity. Wehave a detailed understanding of the replication cycle of influenzavirus in a cell culture system, but what, at the tissue andorgan level in vivo, are the barriers that limit human influenzavirus to the respiratory tract while allowing H5N1 virus tocause systemic disease? To understand this requires a multidisciplinaryapproach based on a combination of laboratory investigationand human clinical studies. Apart from the specific applicationto influenza virus, answering these questions will also resultin a better understanding of the general principles that preventviruses from jumping the species barrier.

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Re: Host Species Barriers to Influenza Virus Infections

Figure 1



Fig. 1. Schematic illustrating phases in overcoming species barriers. (A) Interspecific host-host contact must allow transmission of virus from donor species to recipient species. (B) Virus-host interactions within an individual of recipient species affect the likelihood of the virus replicating and being shed sufficiently to infect another individual of recipient species. (C) Intraspecific host-host contact in recipient species must allow viral spread (R₀ > 1) in the presence of any preexisting immunity. Superspreader events (red asterisk) early in the transmission chain can help this process. (D) The pathogen must persist in the recipient species population even during epidemic troughs (after most susceptible individuals have had the disease) so that subsequent epidemics can be seeded: If few susceptibles are left, the virus may (stochastically) go extinct in epidemic troughs. Viral variation and evolution can aid invasion and persistence, particularly by affecting host-virus interactions. <nobr>[View Larger Version of this Image (64K JPEG file)]</nobr>

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Re: Host Species Barriers to Influenza Virus Infections

Figure 2



Fig. 2. Evolutionary models for the cross-species transmission of pathogens. (A) The donor and recipient species represent two distinct fitness peaks separated by a steep fitness valley. Multiple adaptive mutations (solid circles) are therefore required for the virus to successfully establish onward transmission in the recipient host species. (B) The donor and recipient species are separated by a far shallower fitness valley. This facilitates successful cross-species transmission because only a small number of advantageous mutations are required. (C) When multiple mutations are required for a virus to adapt to a new host, these may evolve progressively in the recipient species. However, this necessarily requires some onward transmission. (D) It is also possible that many of the mutations required to allow adaptation to a new host species were preexisting in the donor species and transmitted simultaneously. This will accelerate successful viral emergence. <nobr>[View Larger Version of this Image (123K JPEG file)]</nobr>

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