Molecular Bases and Role of Viruses in the Human Microbiome

Viruses are dependent biological entities that interact with the genetic material of most cells on the planet, including the trillions within the human microbiome. Their tremendous diversity renders analysis of human viral communities (“viromes”) to be highly complex. Because many of the viruses in humans are bacteriophage, their dynamic interactions with their cellular hosts add greatly to the complexities observed in examining human microbial ecosystems. We are only beginning to be able to study human viral communities on a large scale, mostly as a result of recent and continued advancements in sequencing and bioinformatic technologies. Bacteriophage community diversity in humans not only is inexorably linked to the diversity of their cellular hosts but also is due to their rapid evolution, horizontal gene transfers, and intimate interactions with host nucleic acids. There are vast numbers of observed viral genotypes on many body surfaces studied, including the oral, gastrointestinal, and respiratory tracts, and even in the human bloodstream, which previously was considered a purely sterile environment. The presence of viruses in blood suggests that virome members can traverse mucosal barriers, as indeed these communities are substantially altered when mucosal defenses are weakened. Perhaps the most interesting aspect of human viral communities is the extent to which they can carry gene functions involved in the pathogenesis of their hosts, particularly antibiotic resistance. Persons in close contact with each other have been shown to share a fraction of oral virobiota, which could potentially have important implications for the spread of antibiotic resistance to healthy individuals. Because viruses can have a large impact on ecosystem dynamics through mechanisms such as the transfers of beneficial gene functions or the lysis of certain populations of cellular hosts, they may have both beneficial and detrimental roles that affect human health, including improvements in microbial resilience to disturbances, immune evasion, maintenance of physiologic processes, and altering the microbial community in ways that promote or prevent pathogen colonization.     

病毒与宿主互利共生的研究

在病毒与其宿主的相互作用中,病毒所扮演的角色不仅仅是病原体,它们也是宿主保持健康的重要共生体。病毒与微生物、植物、昆虫和哺乳动物之间存在互利共生作用,有的甚至涉及共生功能体的多个生物体。随着新病毒的不断发现,越来越多的互利共生关系被发掘,也还有许多有待发掘。本文旨在突出一些近年来关于有益病毒的典型例子,阐明为何需要重新认识病毒——病毒不仅是病原体,同时也是共生功能体中的一个完整个体。     

Proteome analysis of plant-virus interactome: comprehensive data for virus multiplication inside their hosts

Known host-parasite molecular interactions are widespread among parasite families, but these interactions have to be particularly large considering that viruses generally encode few proteins. Although some particular virus-host interactions are well described, no global study has yet shown multiple and simultaneous interactions in a host-parasite biological system. To prove that these multiple interactions occur in biological conditions, the complexes formed by a plant virus (rice yellow mottle virus) and the proteins of its natural host (rice) were extracted and purified from infected tissue sample. Remarkably mass spectrometry permitted the identification of a large number of proteins from the complexes that are involved in different functions not encoded by the virus but probably essential for its biological life cycle. This recruiting of proteins was strongly confirmed by the repetition of experiments using different pairs of virus-host and the use of high salt concentration to extract the complexes. We mainly identified proteins involved in plant defense, metabolism, translation, and protein synthesis and some proteins involved in transport. This study demonstrates that viruses are able to recruit many proteins from their hosts to ensure their development. Among different pairs of virus-host, similar protein functions were identified suggesting a particular importance of these proteins for viruses. The identification of particular paralog proteins among multigenic families suggests the high specificity of the recruiting for some protein functions.     

Biology and Evolution of Beneficial and Detrimental Viruses of Animals, Plants, and Fungi

Virtually every type of organism may serve as a host for viruses. In some hosts, virus presence may be considered beneficial to humans; in other hosts, viruses are considered detrimental. Examples of viruses that are considered beneficial to humans include those that are used for biological control of organisms that themselves are considered detrimental to humans, such as plant pathogenic fungi. Viruses are extremely variable in terms of morphology, structure, and genome organization. However, viruses that attack hosts from different kingdoms may be related, deriving from the same phylogeny. This paper summarizes some of the properties of three related families of viruses that attack hosts in different kingdoms: the animal-infecting Picornaviridae, the plant-infecting Potyviridae, and the fungus-infecting Hypoviridae. Properties of these viruses that set them apart from each other and factors that may affect their evolution are discussed.     

Move Over,Bacteria! Viruses Make Their Mark as Mutualistic Microbial Symbionts

Viruses are being redefined as more than just pathogens. They are also critical symbiotic partners in the health of their hosts. In some cases, viruses have fused with their hosts in symbiogenetic relationships. Mutualistic interactions are found in plant, insect, and mammalian viruses, as well as with eukaryotic and prokaryotic microbes, and some interactions involve multiple players of the holobiont. With increased virus discovery, more mutualistic interactions are being described and more will undoubtedly be discovered.     

The alphaviruses: gene expression, replication, and evolution.

The alphaviruses are a genus of 26 enveloped viruses that cause disease in humans and domestic animals. Mosquitoes or other hematophagous arthropods serve as vectors for these viruses. The complete sequences of the +/- 11.7-kb plus-strand RNA genomes of eight alphaviruses have been determined, and partial sequences are known for several others; this has made possible evolutionary comparisons between different alphaviruses as well as comparisons of this group of viruses with other animal and plant viruses. Full-length cDNA clones from which infectious RNA can be recovered have been constructed for four alphaviruses; these clones have facilitated many molecular genetic studies as well as the development of these viruses as expression vectors. From these and studies involving biochemical approaches, many details of the replication cycle of the alphaviruses are known. The interactions of the viruses with host cells and host organisms have been exclusively studied, and the molecular basis of virulence and recovery from viral infection have been addressed in a large number of recent papers. The structure of the viruses has been determined to about 2.5 nm, making them the best-characterized enveloped virus to date. Because of the wealth of data that has appeared, these viruses represent a well-characterized system that tell us much about the evolution of RNA viruses, their replication, and their interactions with their hosts. This review summarizes our current knowledge of this group of viruses.     

Measures and countermeasures in the modulation of initiation factor activities by viruses

Animal viruses have co-evolved with their hosts for millions of years. During this time, the viruses have developed intricate mechanisms to utilize efficiently their host's metabolic pathways, especially those involving macromolecular synthesis, for virus propagation. In particular, many different viruses modulate and usurp their host's translational machinery for use in the synthesis of their own proteins. However, the infected hosts have developed or adapted cellular mechanisms to interdict virus infection. One of these mechanisms is the interferon response, which entails in part a translational regulatory activity that inhibits virus growth. Viruses, in turn, have devised strategies that act as countermeasures to some aspects of the interferon response. These complex virus-host interactions occur at the level of initiation of translation. Two initiation factors, eIF-2 and eIF-4F, play a significant role in a number of virus-host interactions. The recent advances in our understanding of the mode of action of these translation initiation factors have facilitated research on virus-cell interactions at the level of translation. This review is not intended to summarize the general knowledge in this field, but rather to limit the analysis to several examples of virus-host interactions and to speculate on the interplay between the molecular mechanisms involved in these phenomena.     

Genetic Diversity in RNA Virus Quasispecies Is Controlled by Host-Virus Interactions

Many RNA viruses have genetically diverse populations known as quasispecies. Important biological characteristics may be related to the levels of diversity in the quasispecies (quasispecies cloud size), including adaptability and host range. Previous work using Tobacco mosaic virus and Cucumber mosaic virus indicated that evolutionarily related viruses have very different levels of diversity in a common host. The quasispecies cloud size for these viruses remained constant throughout serial passages. Inoculation of these viruses on a number of hosts demonstrated that quasispecies cloud size is not constant for these viruses but appears to be dependent on the host. The quasispecies cloud size remained constant as long as the viruses were maintained on a given host. Shifting the virus between hosts resulted in a change in cloud size to levels associated with the new host. Quasispecies cloud size for these viruses is related to host-virus interactions, and understanding these interactions may facilitate the prediction and prevention of emerging viral diseases.     

Coral-virus interactions: A double-edged sword?

Marine viruses were little studied until 1989, when they were discovered to be extremely abundant in the sea. Virology is now a growing field of science in coral reef research, largely related to an increase in the frequency of coral bleaching events and other coral diseases. Because viruses are obligate symbionts, they are generally perceived as parasitic and harmful to their hosts. However, evidence that viruses confer benefits to their hosts is growing and their role as mutualists is emerging. Here we review both the detrimental and beneficial aspects of viral infections and argue that as the field of coral virology expands, in addition to their pathogenicity, the idea that viruses represent functionally beneficial components of the coral holobiont be considered.     

How vaccinia virus has evolved to subvert the host immune response

Viruses are obligate intracellular parasites and are some of the most rapidly evolving and diverse pathogens encountered by the host immune system. Large complicated viruses, such as poxviruses, have evolved a plethora of proteins to disrupt host immune signalling in their battle against immune surveillance. Recent X-ray crystallographic analysis of these viral immunomodulators has helped form an emerging picture of the molecular details of virus-host interactions. In this review we consider some of these immune evasion strategies as they apply to poxviruses, from a structural perspective, with specific examples from the European SPINE2-Complexes initiative. Structures of poxvirus immunomodulators reveal the capacity of viruses to mimic and compete against the host immune system, using a diverse range of structural folds that are unique or acquired from their hosts with both enhanced and unexpectedly divergent functions.     

双分子荧光互补技术在动物病毒中的研究进展

病毒侵染宿主的过程存在着一系列相互作用,了解病毒与宿主之间的蛋白质相互作用对于深入研究病毒具有重要意义。在众多研究蛋白质相互作用的方法中,双分子荧光互补技术（bimolecular fluorescence complementation,BiFC）因其能在活细胞中可视化相互作用而被广泛应用。介绍了双分子荧光技术的原理、发展和优势,总结了双分子荧光技术在动物病毒以及抗病毒药物研究中的应用,并进一步阐述了新型双分子荧光系统的原理,以期为研究动物病毒致病机制和抗病毒药物研发提供新的思路。     

Resetting our expectations for parasites and their effects on species interactions: a meta-analysis

Despite the ubiquitous nature of parasitism, how parasitism alters the outcome of host–species interactions such as competition, mutualism and predation remains unknown. Using a phylogenetically informed meta-analysis of 154 studies, we examined how the mean and variance in the outcomes of species interactions differed between parasitized and non-parasitized hosts. Overall, parasitism did not significantly affect the mean or variance of host–species interaction outcomes, nor did the shared evolutionary histories of hosts and parasites have an effect. Instead, there was considerable variation in outcomes, ranging from strongly detrimental to strongly beneficial for infected hosts. Trophically-transmitted parasites increased the negative effects of predation, parasites increased and decreased the negative effects of interspecific competition for parasitized and non-parasitized heterospecifics, respectively, and parasites had particularly strong negative effects on host species interactions in freshwater and marine habitats, yet were beneficial in terrestrial environments. Our results illuminate the diverse ways in which parasites modify critical linkages in ecological networks, implying that whether the cumulative effects of parasitism are considered detrimental depends not only on the interactions between hosts and their parasites but also on the many other interactions that hosts experience.     

Genome-virome interactions: examining the role of common viral infections in complex disease

New technologies have widened our view of 'complex diseases': those with both genetic and environmental risk factors. In this Review, we explore recent genetic and virological evidence implicating host-virus interactions in three diseases: type 1 diabetes, inflammatory bowel disease and asthma. The viruses implicated in these diseases cause mucosal infections that affect most of the population but are asymptomatic or mild in many hosts. These findings place a new emphasis on common viral infections as important environmental factors in the pathogenesis of complex diseases, and they compel the field to pursue a better understanding of host interactions with the human virome.     

Latency of Baculoviruses

Due to their widespread natural occurrence, baculoviruses and their insect hosts are a convenient model to study the pathogen-host interactions. However, the absence of reliable techniques for the detection of latent viral infection, which is common in insect populations, is among the constraints of such studies. The recent progress in molecular biology techniques made it possible to obtain the fundamental data on the detection of latent viruses in different insect species as well as on the mechanism of latent infection induction, which are reviewed below. The obtained data in many respects expand our knowledge about the role of latency in the system of interactions between baculoviruses and their insect hosts at different ecological levels.     

Two-stepping through time: mammals and viruses

Recent studies have identified ancient virus genomes preserved as fossils within diverse animal genomes. These fossils have led to the revelation that a broad range of mammalian virus families are older and more ubiquitous than previously appreciated. Long-term interactions between viruses and their hosts often develop into genetic arms races where both parties continually jockey for evolutionary dominance. It is difficult to imagine how mammalian hosts have kept pace in the evolutionary race against rapidly evolving viruses over large expanses of time, given their much slower evolutionary rates. However, recent data has begun to reveal the evolutionary strategy of slowly-evolving hosts. We review these data and suggest a modified arms race model where the evolutionary possibilities of viruses are relatively constrained. Such a model could allow more accurate forecasting of virus evolution.     

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

Summary: Host range is a viral property reflecting natural hosts that are infected either as part of a principal transmission cycle or, less commonly, as “spillover” infections into alternative hosts. Rarely, viruses gain the ability to spread efficiently within a new host that was not previously exposed or susceptible. These transfers involve either increased exposure or the acquisition of variations that allow them to overcome barriers to infection of the new hosts. In these cases, devastating outbreaks can result. Steps involved in transfers of viruses to new hosts include contact between the virus and the host, infection of an initial individual leading to amplification and an outbreak, and the generation within the original or new host of viral variants that have the ability to spread efficiently between individuals in populations of the new host. Here we review what is known about host switching leading to viral emergence from known examples, considering the evolutionary mechanisms, virus-host interactions, host range barriers to infection, and processes that allow efficient host-to-host transmission in the new host population.     

Phylogeny, integration and expression of sigma virus-like genes in Drosophila

The recent and surprising discovery of widespread NIRVs (non-retroviral integrated RNA viruses) has highlighted the importance of genomic interactions between non-retroviral RNA viruses and their eukaryotic hosts. Among the viruses with integrated representatives are the rhabdoviruses, a family of negative sense single-stranded RNA viruses. We identify sigma virus-like NIRVs of Drosophila spp. that represent unique cases where NIRVs are closely related to exogenous RNA viruses in a model host organism. We have used a combination of bioinformatics and laboratory methods to explore the evolution and expression of sigma virus-like NIRVs in Drosophila. Recent integrations in Drosophila provide a promising experimental system to study functionality of NIRVs. Moreover, the genomic architecture of recent NIRVs provides an unusual evolutionary window on the integration mechanism. For example, we found that a sigma virus-like polymerase associated protein (P) gene appears to have been integrated by template switching of the blastopia-like LTR retrotransposon. The sigma virus P-like NIRV is present in multiple retroelement fused open reading frames on the X and 3R chromosomes of Drosophila yakuba - the X-linked copy is transcribed to produce an RNA product in adult flies. We present the first account of sigma virus-like NIRVs and the first example of NIRV expression in a model animal system, and therefore provide a platform for further study of the possible functions of NIRVs in animal hosts.     

Mixed infection,risk projection,and misdirection: Interactions among pathogens alter links between host resources and disease

A growing body of literature links resources of hosts to their risk of infectious disease. Yet most hosts encounter multiple pathogens, and projections of disease risk based on resource availability could be fundamentally wrong if they do not account for interactions among pathogens within hosts. Here, we measured infection risk of grass hosts (Avena sativa) exposed to three naturally co‐occurring viruses either singly or jointly (barley and cereal yellow dwarf viruses [B/CYDVs]: CYDV‐RPV, BYDV‐PAV, and BYDV‐SGV) along experimental gradients of nitrogen and phosphorus supply. We asked whether disease risk (i.e., infection prevalence) differed in single versus co‐inoculations, and whether these differences varied with rates and ratios of nitrogen and phosphorus supply. In single inoculations, the viruses did not respond strongly to nitrogen or phosphorus. However, in co‐inoculations, we detected illustrative cases of 1) resource‐dependent antagonism (lower prevalence of RPV with increasing N; possibly due to competition), 2) resource‐dependent facilitation (higher prevalence of SGV with decreasing N:P; possibly due to immunosuppression), and 3) weak or no interactions within hosts (for PAV). Together, these within‐host interactions created emergent patterns for co‐inoculated hosts, with both infection prevalence and viral richness increasing with the combination of low nitrogen and high phosphorus supply. We demonstrate that knowledge of multiple pathogens is essential for predicting disease risk from host resources and that projections of risk that fail to acknowledge resource‐dependent interactions within hosts could be qualitatively wrong. Expansions of theory from community ecology theory may help anticipate such relationships by linking host resources to diverse pathogen communities.     

病毒编码的miRNA:基因表达新的调控因子

微小RNA(microRNA,miRNA)是一类长约22个核苷酸的RNA,在数量、序列、结构、表达和功能上具有多样性。目前,通过生物信息学手段和分子克隆方法,已发现了3518种miRNA,在控制细胞的生长发育、分化、凋亡等过程中发挥着十分重要的作用。最近研究发现疱疹病毒、多瘤病毒、逆转录病毒的某些病毒基因组也能够编码miRNA,这些miRNA在调控病毒基因自身表达以及病毒与宿主相互作用方面可能起重要的作用。某些病毒甚至能够利用宿主体内的miRNA调控其自身表达。找出病毒可能编码的miRNA,探索其对病毒感染、复制、表达的作用,有助于病毒分子生物学的研究,也会为研发防治病毒的新方法和新途径提供新的思路。