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CORD-19:113f9670b9a495a6352bc03bf2d923e60fa41b7d JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
T1 0-31 Sentence denotes A cross-species view on viruses
T2 33-41 Sentence denotes Abstract
T3 42-194 Sentence denotes We describe the creative ways that virologists are leveraging experimental cross-species infections to study the interactions between viruses and hosts.
T4 195-345 Sentence denotes While viruses are usually well adapted to their hosts, cross-species approaches involve pairing viruses with species that they don't naturally infect.
T5 346-460 Sentence denotes These cross-species infections pit viruses against animals, cell lines, or even single genes from foreign species.
T6 461-657 Sentence denotes We highlight examples where cross-species infections have yielded insights into mechanisms of host innate immunity, viral countermeasures, and the evolutionary interplay between viruses and hosts.
T7 659-868 Sentence denotes Model organisms have been critically important in biomedical research, and are particularly useful for studying conserved biological processes and pathways that operate by similar rules across diverse species.
T8 869-992 Sentence denotes Indeed, our understanding of viral pathogenesis in humans has greatly benefited from research conducted in model organisms.
T9 993-1201 Sentence denotes However, the dynamic interplay between hosts and viruses in nature ( Figure 1 ) is difficult to recapitulate in laboratory-based studies that employ a single viral clone infecting an isogenic host population.
T10 1202-1333 Sentence denotes First, in the process of virus host-switching, a virus of one species evolves the ability to infect and spread in a second species.
T11 1334-1488 Sentence denotes In this process, genetic differences between these species, not genetic similarities, are what dictate the evolutionary adaptations required by the virus.
T12 1489-1614 Sentence denotes Second, viruses and the host genes that encode defenses against them are known to be exceptional for their genetic diversity.
T13 1615-1808 Sentence denotes Therefore, the results of experiments using clonal hosts and clonal viruses in the laboratory may not always reveal the spectrum of possible host-virus interactions that truly exists in nature.
T14 1809-2018 Sentence denotes Third, in studies of viruses infecting their natural host species, including cell lines derived from those species, host defense mechanisms can be masked because the viruses have already evolved to evade them.
T15 2019-2157 Sentence denotes In all of these instances, experiments conducted in non-host species (referred to here as heterologous species) can be highly informative.
T16 2158-2390 Sentence denotes Here we consider both the strengths and limitations of approaches involving infections of heterologous animals, heterologous cell lines, and even cell lines differing only by the expression of single genes from heterologous species.
T17 2391-2557 Sentence denotes We also highlight examples where these types of approaches have revealed the evolutionary dynamics driving counter-evolution and adaptation between viruses and hosts.
T18 2558-2685 Sentence denotes In the 1970's and 1980's, scientists developed techniques for introducing and expressing foreign genes in mammalian cell lines.
T19 2686-2782 Sentence denotes It is now common to express a gene from one species in a cell line derived from another species.
T20 2783-2899 Sentence denotes The usefulness of this approach in virology has been well demonstrated in studies of retroviral restriction factors.
T21 2900-3013 Sentence denotes For decades retrovirologists have documented tissue and species tropism of mammalian retroviruses, including HIV.
T22 3014-3238 Sentence denotes Studies on the genetic underpinnings of these patterns ultimately revealed an impressive landscape of host innate immunity genes, including the restriction factor genes APOBEC3G, TRIM5, Tetherin, and SAMHD1 [1] [2] [3] [4] .
T23 3239-3366 Sentence denotes In some cases, comparisons of cell lines derived from susceptible and resistant human tissues were used to isolate these genes.
T24 3367-3539 Sentence denotes Notably, the identification of the TRIM5α restriction factor instead resulted from comparing cell lines derived from susceptible and resistant primate species (Figure 2A ).
T25 3540-3765 Sentence denotes In this case, researchers took advantage of the fact that some rhesus macaque cells are highly resistant to HIV-1 infection, isolating a cDNA from these cells that conveyed HIV-1 resistance when expressed in human cells [5] .
T26 3766-3958 Sentence denotes After its discovery, sequence comparisons of different nonhuman primate TRIM5α orthologs were exploited to quickly map the genetic determinants of virus recognition ( Figure 2B ) [6] [7] [8] .
T27 3959-4187 Sentence denotes Analyses of the molecular evolution of the TRIM5 gene aided in these studies [6] , as signatures of recurrent positive selection often accumulate in the exact regions of host genes that modulate host-virus interactions [9, 10] .
T28 4188-4423 Sentence denotes Several nonhuman primate species were found to encode unique variants of TRIM5α resulting from gene fusion events, constituting novel restriction factors with different viral specificities when expressed in human cells [11] [12] [13] .
T29 4424-4585 Sentence denotes A human-monkey chimera of TRIM5, as well as natural primate orthologs with strong activity against HIV, are now being developed for human gene therapy [14, 15] .
T30 4586-4771 Sentence denotes It is important to recognize that this potent anti-retroviral gene is constitutively expressed in many human cell types, yet lies silent because HIV has evolved to escape its detection.
T31 4772-4937 Sentence denotes The powerful antiviral activity of TRIM5α was only revealed when HIV was paired with cells of a heterologous host species to which the virus is not yet well adapted.
T32 4938-5152 Sentence denotes Removing HIV from the context of the human genetic landscape uncovered how exquisitely vulnerable HIV is to naturally existing host factors that may ultimately prove vital to eradicating this deadly human pathogen.
T33 5153-5368 Sentence denotes After many similar studies, we now appreciate that it is common for the interactions between host innate immunity proteins and viruses to be highly species-specific [6, [16] [17] [18] [19] [20] [21] [22] [23] [24] .
T34 5369-5534 Sentence denotes For instance, the NS1B protein of influenza B binds and antagonizes the interferon-induced ISG15 protein of humans and other primates, but not of mice or dogs [25] .
T35 5535-5657 Sentence denotes This potentially contributes to the narrow host range of influenza B viruses, which have only been found to infect humans.
T36 5658-5766 Sentence denotes Heterologous gene studies performed in tissue culture have also motivated live animal studies in some cases.
T37 5767-5924 Sentence denotes For instance, the evolution of viral escape was observed in monkeys encoding restrictive alleles at the APOBEC3G and TRIM5 restriction factor loci [23, 26] .
T38 5925-6208 Sentence denotes An intriguing new twist on this heterologous gene approach is to resurrect extinct forms of host genes, including both ancient cell surface receptors and ancient restriction factors, and to test their activity when paired against viruses in the context of modern cells [24, 27, 28] .
T39 6209-6375 Sentence denotes In these studies, functional differences between extinct and modern genes reveal the evolutionary pathways by which hosts adapted to their viral challenges over time.
T40 6376-6594 Sentence denotes In summary, the approach of studying single genes from heterologous or extinct species provides unique insight into host innate immunity, viral escape, and the evolutionary events that are driven by these interactions.
T41 6595-6748 Sentence denotes Virologists often hunt for particular cell lines that are highly permissive for the replication of a certain virus in order to recover high viral titers.
T42 6749-6922 Sentence denotes These cell lines may be derived from species other than the one from which the virus was isolated or from tissues other than the ones in which the virus normally replicates.
T43 6923-7124 Sentence denotes For instance, human influenza virus is commonly grown in MDCK (dog kidney) and MDBK (bovine kidney) cells because these cell lines are more permissive for flu replication than other lines ( Figure 3 ).
T44 7125-7352 Sentence denotes It is important to consider that, by ignoring other less permissive cell lines, we may be casting aside opportunities to discover new restriction factors and other cellular factors of importance to particular viral life cycles.
T45 7353-7484 Sentence denotes It is also common to use heterologous cell lines to attenuate viruses, sometimes for the purpose of creating vaccine strains [29] .
T46 7485-7663 Sentence denotes During the process of attenuation, viruses undergo selection for increased fitness in cells of the new host species, at the expense of viral fitness in the original host species.
T47 7664-7844 Sentence denotes Critical genetic differences between the two species, as well as the context of the infection (i.e. cell lines from a particular tissue vs. whole organisms) drive viral adaptation.
T48 7845-8035 Sentence denotes For example, vaccinia virus, which is presumed to have arisen from cows and/or horses, was passaged nearly 600 times in chicken cells to create an attenuated strain used to vaccinate humans.
T49 8036-8127 Sentence denotes The genome of this strain contains several large deletions and hundreds of mutations [30] .
T50 8128-8312 Sentence denotes All major deletions accumulated in the distal regions of the vaccinia genome, which is enriched for genes involved in counteracting specific host defenses, including adaptive immunity.
T51 8313-8468 Sentence denotes Losses of these regions imply a considerable fitness cost to maintaining anti-host proteins that are expendable for efficient replication in chicken cells.
T52 8469-8614 Sentence denotes The acquired point mutations may also reflect adaptations specific to the innate immune defenses of chickens, but this has not been demonstrated.
T53 8615-8778 Sentence denotes The growing field of experimental evolution has the potential to help us understand the adaptive processes that viruses undergo when they acclimate to novel hosts.
T54 8779-9029 Sentence denotes These approaches involve serial passage of a virus through a novel host, and are especially effective when viral aliquots are collected and catalogued throughout the course of the adaptation process [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] .
T55 9030-9140 Sentence denotes In some cases, more specific mechanistic insights have been gained from infections of heterologous cell lines.
T56 9141-9289 Sentence denotes For example, the interferon-induced gene product Protein Kinase R (PKR) limits viral replication by blocking global protein translation in the cell.
T57 9290-9459 Sentence denotes To circumvent this immune strategy, many viruses encode antagonists of PKR, including herpes simplex viruses, influenza viruses, poxviruses, and cytomegaloviruses [41] .
T58 9460-9725 Sentence denotes Infections in diverse primate cell lines were used to demonstrate that two of these viral antagonists, TRS1 of cytomegalovirus and K3L of vaccinia virus, each have substantially different specificities for inhibiting the PKR proteins of different species [18, 42] .
T59 9726-9903 Sentence denotes The authors of these studies proposed that constant evolutionary struggle between viral antagonists and host defenses uniquely shaped these interactions in each primate species.
T60 9904-10124 Sentence denotes In this case, selection has tailored more than just interaction affinities between viral antagonists and PKR, as the variants of TRS1 from human and Old World monkey cytomegaloviruses inhibit PKR by different mechanisms.
T61 10125-10250 Sentence denotes Therefore, a cross-species viewpoint can help reveal key functional differences in how viruses adapt to defeat host immunity.
T62 10251-10331 Sentence denotes In nature, new diseases arise when existing viruses adapt to infect new species.
T63 10332-10478 Sentence denotes In most known cases this involves the viral genome acquiring a series of mutations that ultimately makes it more fit in the new host ( Figure 4 ).
T64 10479-10604 Sentence denotes Cross-species infections of live animals in laboratory settings can be useful for understanding virus evolution in new hosts.
T65 10605-10769 Sentence denotes A compelling example is the recent adaptation of H5N1 avian influenza to ferrets, the most common animal model system for studying influenza transmission in humans.
T66 10770-10914 Sentence denotes H5N1 is an avian flu virus that is highly lethal to chicken flocks, and has also been infecting humans through zoonotic transmission since 1997.
T67 10915-11030 Sentence denotes The well-publicized anxiety around H5N1 avian flu stems from its extremely high case fatality rate in humans [43] .
T68 11031-11258 Sentence denotes H5N1 does not yet transmit efficiently from human to human via aerosolization and respiratory inhalation, which is taken to mean that the virus requires additional mutational changes before epidemic spread in humans can result.
T69 11259-11464 Sentence denotes In line with this hypothesis, three recent studies identified small combinations of viral mutations that result in respiratory transmission of this virus between ferrets in neighboring cages [40, 44, 45] .
T70 11465-11512 Sentence denotes Some uncertainties about these studies persist.
T71 11513-11653 Sentence denotes For instance, past transmission studies in ferrets have not always been accurate in predicting transmission or pathogenesis in humans [46] .
T72 11654-11792 Sentence denotes However, this work illustrates how crossspecies infections of animals may reveal exactly how viruses adapt to new hosts, including humans.
T73 11793-11894 Sentence denotes The implications of intra-species genetic diversity can also be studied with experimental approaches.
T74 11895-12010 Sentence denotes For example, the MHC loci are some of the most genetically diverse loci in human and other mammalian genomes [47] .
T75 12011-12219 Sentence denotes A recent study reported experimental evolution of Friend virus by serial passage through three different mouse strains that are genetically identical except at their major histocompatibility (MHC) loci [48] .
T76 12220-12431 Sentence denotes The study demonstrated an important role for specific host MHC genotypes in the evolutionary trajectory of the virus by showing that viral fitness was improved in mice with MHC genotypes "familiar" to the virus.
T77 12432-12595 Sentence denotes This experiment nicely illustrates a central tenet of the Red Queen hypothesis [49] , namely that unique host genotypes exert unique selective pressure on viruses.
T78 12596-12827 Sentence denotes The same concept has also been demonstrated in primates, where retroviruses have been shown to take specific and reproducible evolutionary trajectories depending on the particular restriction factor alleles of their host [23, 26] .
T79 12828-13026 Sentence denotes Thus, viruses evolve in response to local host genotypes but, by doing so, exert selective pressure on host populations to continually diversify allelic repertoires at loci involved in host defense.
T80 13027-13106 Sentence denotes In this way, the evolution of host and virus populations are intimately linked.
T81 13107-13309 Sentence denotes Further studies exploiting genetic differences between closely related strains and species holds great promise for revealing the fundamental rules that govern co-evolution in host and virus populations.
T82 13310-13382 Sentence denotes Virus evolution during host switching can also be monitored in the wild.
T83 13383-13576 Sentence denotes An interesting and often-cited case involves the repeated release of the myxoma poxvirus in Europe and Australia as a form of biological control over invasive European rabbit populations [50] .
T84 13577-13708 Sentence denotes Historically, this virus was known to cause mild disease in South American rabbits, but was found to be lethal to European rabbits.
T85 13709-13826 Sentence denotes However, after release into European rabbit populations, the emergence of less virulent viral forms quickly followed.
T86 13827-13989 Sentence denotes Attenuation of viral pathogenicity resulted in increased rabbit survival times, which may have optimized viral transmission to new rabbits through insect vectors.
T87 13990-14129 Sentence denotes Rabbit populations also adapted to widespread exposure to myxoma virus, but not to the level observed in rabbit species from South America.
T88 14130-14263 Sentence denotes While this is as an illustrious example of host-virus co-evolution, the mutations underlying adaptation have not yet been identified.
T89 14264-14531 Sentence denotes It will be challenging to determine which specific mutational changes conveyed the observed fitness improvements, as a majority of the mutations that accumulated in host and virus genomes are predicted to have been evolutionarily neutral or even slightly deleterious.
T90 14532-14754 Sentence denotes This limitation pertains to most experiments that involve sampling from infection dynamics unfolding in nature, and can be especially vexing in highly heterogeneous virus populations and for protocols with sparse sampling.
T91 14755-15009 Sentence denotes On the other hand, the genetic basis of adaptation in both host and virus genomes has been successfully described in another major model for host-switching of viruses in nature: the emergence of carnivore parvoviruses in dogs in the 1970's [27, 51, 52] .
T92 15010-15209 Sentence denotes Future studies may reveal the molecular details of the cross-species transmission of myxoma virus and the host-virus genetic conflict that unfolded in the context of this ecologically complex system.
T93 15210-15458 Sentence denotes By pairing viruses with heterologous host species at the level of organisms, cell lines, and single genes, species-specific differences are leveraged to provide insight into the struggle for survival that exists between viruses and hosts [53, 54] .
T94 15459-15720 Sentence denotes In turn, mechanistic studies of host-virus interactions benefit from this evolution-based perspective, as observations of positive selection and species-specific mutational patterns can be used to guide the functional dissection of host-virus interactions [9] .
T95 15721-15865 Sentence denotes These studies have led to the identification of novel aspects of the innate immune system and have revealed corresponding viral escape pathways.
T96 15866-16112 Sentence denotes In order to enhance the power of this approach, it will be important to curate panels of cell lines from species that constitute viral reservoirs in nature, as well as from species that may serve as new or intermediate hosts for emerging disease.
T97 16113-16372 Sentence denotes By extending the model organisms paradigm with a cross-species view of virology, which incorporates the vast genetic diversity driving the dynamics of host-virus interactions, we may be poised to gain the upper-hand in these continuing struggles for survival.
T98 16373-16551 Sentence denotes • Dynamic aspects of virology often aren't well suited to traditional model system approaches • Many viruses are well adapted to their natural hosts, masking pathways of immunity
T99 16552-16620 Sentence denotes • Cross-species infections yield unique insight into innate immunity
T100 16621-16698 Sentence denotes • Viral adaptation can be effectively studied in novel host cells and species
T101 16699-16754 Sentence denotes Different types of virus-host dynamics are illustrated.
T102 16755-16907 Sentence denotes The hypothetical phylogenetic trees depict class-specific genetic divergence of viruses (left) and species-specific genetic divergence of hosts (right).
T103 16908-16998 Sentence denotes Not shown are additional genetic differences that exist within host and viral populations.
T104 16999-17225 Sentence denotes All of these genetic differences have the potential to contribute to viral host range, which may be broad or narrow (colored triangles), and may make some viruses more likely to evolve to expand their host range (dotted line).
T105 17226-17403 Sentence denotes This dynamic interplay between hosts and viruses is difficult to recapitulate in laboratory-based studies that employ a single viral clone infecting an isogenic host population.
T106 17404-17642 Sentence denotes In cases where resistance is conveyed by a dominant genetic factor, as would be the case with a cellular restriction factor or other immunity protein, the genetic basis for resistance can be uncovered by performing the illustrated screen.
T107 17643-17741 Sentence denotes A cDNA library prepared from the resistant cell line is introduced into the susceptible cell line.
T108 17742-17816 Sentence denotes The resulting cells are screened for a cDNA clone that conveys resistance.
T109 17817-17890 Sentence denotes This scheme was used to identify the HIV restriction factor, TRIM5α [5] .
T110 17891-18051 Sentence denotes B) Once cellular immunity proteins have been identified, heterologous gene studies can also be used to finely map the genetic determinants of viral recognition.
T111 18052-18164 Sentence denotes In this case, multiple orthologs of the gene of interest (here, "gene X") from related species will be required.
T112 18165-18325 Sentence denotes These orthologous genes are introduced into a common cell background, and these cells are then tested for susceptibility or resistance to the virus of interest.
T113 18326-18528 Sentence denotes Phenotypic differences can be compared to the genotypes of each ortholog as shown on the top right, where black tick marks indicate mutational differences compared to the top blue ortholog of species 1.
T114 18529-18707 Sentence denotes By comparing unique mutations in the resistant (red) versus susceptible (blue and green) orthologs, the genetic determinants of viral detection can be identified (orange arrows).
T115 18708-18950 Sentence denotes Of these, the best candidate protein regions or residues (dark orange arrows) will be those with signatures of positive selection over the evolution of these species (bottom right, positions under positive selection indicated with asterisks).
T116 18951-19043 Sentence denotes This scheme was used to identify the region of TRIM5α that conveys HIV/SIV recognition [6] .
T117 19044-19194 Sentence denotes Experimental cross-species infections are commonly used in the laboratory for viral attenuation and evolution studies, and sometimes out of necessity.
T118 19195-19357 Sentence denotes For instance, most research on the human hepatitis C virus was historically performed in chimpanzees, because this virus was not easily studied in tissue culture.
T119 19358-19462 Sentence denotes B) Sometimes cell lines from heterologous species are used in tissue culture-based virology experiments.
T120 19463-19687 Sentence denotes In cases where incompatibility is observed between a virus and a cell line of a heterologous species, this presents an opportunity to identify cellular barriers to infection in a genetically tractable system (see Figure 2 ).
T121 19688-19803 Sentence denotes C) It is becoming more common to express single genes from one species in cell lines derived from a second species.
T122 19804-19925 Sentence denotes This allows one to study the significance of genetic divergence at a single host locus with regards to viral replication.
T123 19926-20034 Sentence denotes Also, in such systems viral evolution experiments elucidate how a virus can escape specific cellular blocks.
T124 20035-20096 Sentence denotes New diseases arise when existing viruses acquire novel hosts.
T125 20097-20209 Sentence denotes This diagram illustrates the steps by which a virus is transmitted from its original host to a new host species.
T126 20210-20403 Sentence denotes While all organisms are continuously exposed to the viruses of other species, infection resulting in virus replication and potentially illness (step 1) is thought to be a relatively rare event.
T127 20404-20527 Sentence denotes Rarer still will be infections that are successful enough to transmit between individuals in the new host species (step 2).
T128 20528-20644 Sentence denotes Of these, only some will progress to the point of epidemic or pandemic spread through the new host species (step 3).
T129 20645-20917 Sentence denotes In theory, each of these steps may or may not require the acquisition of novel mutations in the viral genome, although existing evidence suggests that additional mutations usually do accumulate in viral genomes as viruses become more and more adapted to a particular host.
T130 20918-21026 Sentence denotes Virus mutations can be acquired through point mutation, insertion, deletion, recombination, or reassortment.
T131 21027-21132 Sentence denotes The acquisition of combinations of mutations may be required for viruses to advance through this process.
T132 21133-21167 Sentence denotes Figure adapted in part from [55] .