Immune response to poxvirus infections in various animals

The study of infections of vertebrate animals by poxviruses has remained a dynamic area of research for the last century. The host range of poxviruses vary from extremely narrow to exceedingly broad, and they have been shown to enter their host by either the respiratory route or through the skin. The severity of infection varies dramatically from one species to another, causing anywhere from a local, self-limiting infection, to a devastating systemic disease, such as smallpox. Although the immune response to poxvirus infections are very similar to that seen in other viral infections, the poxviruses, unlike most other viruses (with the exception of Herpes viruses), are able to defend themselves. They have been shown to carry a repertoire of proteins involved in immune evasion and immune modulation. Poxviruses encode proteins involved in blocking many of the strategies employed by the host to combat viral infections; they encode for proteins that block activity of many chemokines, cytokines, serine proteases, and even complement. Traditionally, different animal models have been used to study the pathogenesis of poxvirus infections, and the characterization of virulence genes using mutant poxviruses. Additionally, new animal models are being developed to study the possible therapeutic uses many of these poxvirus immune modulating proteins might have. This review discusses the host immune response against poxvirus infections in various animals, the viral counter response to the host, and the animal models used to study poxvirus infection and immune modulating proteins.     

Immune Response to Poxvirus Infections in Various Animals

The study of infections of vertebrate animals by poxviruses has remained a dynamic area of research for the last century. The host range of poxviruses vary from extremely narrow to exceedingly broad, and they have been shown to enter their host by either the respiratory route or through the skin. The severity of infection varies dramatically from one species to another, causing anywhere from a local, self-limiting infection, to a devastating systemic disease, such as smallpox. Although the immune response to poxvirus infections are very similar to that seen in other viral infections, the poxviruses, unlike most other viruses (with the exception of Herpes viruses), are able to defend themselves. They have been shown to carry a repertoire of proteins involved in immune evasion and immune modulation. Poxviruses encode proteins involved in blocking many of the strategies employed by the host to combat viral infections; they encode for proteins that block activity of many chemokines, cytokines, serine proteases, and even complement. Traditionally, different animal models have been used to study the pathogenesis of poxvirus infections, and the characterization of virulence genes using mutant poxviruses. Additionally, new animal models are being developed to study the possible therapeutic uses many of these poxvirus immune modulating proteins might have. This review discusses the host immune response against poxvirus infections in various animals, the viral counter response to the host, and the animal models used to study poxvirus infection and immune modulating proteins.     

Viral immune evasion strategies and the underlying cell biology

Evasion of the immune system by viruses is a well-studied field. It remains a challenge to understand how these viral tactics affect pathogenesis and the viral lifecycle. At the same time, the study of viral proteins involved in immune evasion has helped us to better understand a number of cellular processes at the molecular level. Here we review recent data on different viral tactics for immune evasion and highlight what these viral interventions might teach us about cell biology.     

Immune evasion mechanisms of hepatitis C virus. Review

Hepatitis Virus C (HCV) is a major worldwide health care problem. HCV infection usually tends to become chronic and can generate long-term hepatic cirrhosis and hepatocellular carcinoma. These affections frequently require a liver transplant to prolong the patients life. Maintenance of the chronic infection implies evasion of the host immune responses. Viral mechanisms involved in this evasion are being profusely studied in order to develop new and effective therapies and vaccines against HCV. An important HCV characteristic, its high genetic variability, has been proposed to contribute to immune evasion by means of antigenic change and variation. On the other hand, some studies suggest that genetic variability is not necessary to establish a chronic infection. Other studies related to immune responses in patients with spontaneous virus clearance and patients with chronic infection show a possible immunosuppression caused by some viral proteins, that may be essential to persist in the host. Specifically, it is believed that viral proteins NS5A, E2 and Core modulate some innate and specific immune mechanisms. The analysis of all data related to this topic suggests the existence of synergistic cooperation between viral variation and immunosuppression to overcome the immune defenses of the host.     

Immunoglobulin superfamily members encoded by viruses and their multiple roles in immune evasion

Pathogens have developed a plethora of strategies to undermine host immune defenses in order to guarantee their survival. For large DNA viruses, these immune evasion mechanisms frequently rely on the expression of genes acquired from host genomes. Horizontally transferred genes include members of the immunoglobulin superfamily, whose products constitute the most diverse group of proteins of vertebrate genomes. Their promiscuous immunoglobulin domains, which comprise the building blocks of these molecules, are involved in a large variety of functions mediated by ligand‐binding interactions. The flexible structural nature of the immunoglobulin domains makes them appealing targets for viral capture due to their capacity to generate high functional diversity. Here, we present an up‐to‐date review of immunoglobulin superfamily gene homologs encoded by herpesviruses, poxviruses, and adenoviruses, that include CD200, CD47, Fc receptors, interleukin‐1 receptor 2, interleukin‐18 binding protein, CD80, carcinoembryonic antigen‐related cell adhesion molecules, and signaling lymphocyte activation molecules. We discuss their distinct structural attributes, binding properties, and functions, shaped by evolutionary pressures to disarm specific immune pathways. We include several novel genes identified from extensive genome database surveys. An understanding of the properties and modes of action of these viral proteins may guide the development of novel immune‐modulatory therapeutic tools.     

Evasion of cytotoxic T lymphocytes by murine cytomegalovirus

Murine cytomegalovirus causes lifelong infections with little pathology in normal host animals. Control of viral replication and prevention of pathology depend on both innate and adaptive immune mechanisms, and cytolytic T lymphocytes play a key role in this process. The virus encodes a number of genes which alter the normal assembly of class I major histocompatability complex proteins, and thus interfere with the ability of infected cells to present antigen to CD8(+)T cells. This review will examine what is known about these viral genes, and present some unanswered questions regarding the role of CTL evasion in the viral infectious cycle.     

Cellular Source of the Poxviral N1R/p28 Gene Family

Full-length poxvirus N1R/p28 orthologous proteins feature a prominent C-terminal RING zinc-finger motif. The RING moiety is conspicuously mutated in a number of vaccinia virus strains relative to variola virus. This, together with empirical data, suggests that N1R/p28 proteins promote virulence by suppressing apoptosis. Poxvirus N1R/p28 orthologues are strikingly similar to the RING motif of the cellular Makorin family of zinc-finger proteins, suggesting a homologous relationship connecting the viral and cellular genes. Recently identified avipox N1R/p28 orthologues further encode additional Makorin-like zinc-finger motifs, consistent with this suggestion. Phylogenetic analysis supports a model of poxviral capture of a MKRNcDNA and fusion with an existing viral gene. Establishing an evolutionary link between the viral and cellular genes will facilitate the elucidation of their respective cellular functions, and of how they interact in modulating virulence.     

Viral evasion of T cell immunity: ancient mechanisms offering new applications

Upon infecting a host, viruses are confronted by a coordinated and multi-faceted immune response. Indeed, evolutionary combat between virus and host has contributed signally to the host's development of a formidable innate and adaptive immune defense arsenal, and to the virus' acquisition of effective means to evade it. Cytotoxic T lymphocytes play a key role in the elimination of virus-infected cells, which they detect through recognition of virus-derived peptides displayed at the cell surface in the context of MHC class I molecules. This highly sensitive recognition system is a prime target for immune evasion strategies deployed by many viruses, particularly large DNA viruses such as herpesviruses and poxviruses. Elucidation of the mode of action of the immune evasion proteins encoded by these viruses has not only provided new insights into viral pathogenesis, but has also led to the discovery of hitherto unknown cell biological and immunological phenomena. Moreover, viral immune evasion proteins constitute extremely useful tools to block defined stages of the MHC class I presentation pathway, not only for research purposes, but also for clinical applications.     

The 'supervirus'? Lessons from IL-4-expressing poxviruses

Members of the Poxviridae family are particularly adept at avoiding the host immune system, encoding a plethora of immunomodulatory proteins that subvert host defense. With their large genome, poxviruses are also useful for studying the effect of exogenous genes on virus-host interactions and immune responses. The insertion of the Th2 cytokine interleukin-4 (IL-4) into several poxviruses significantly increases the efficiency of the recombinant virus as a pathogen by directly inhibiting the development of Th1 immunity, which is crucial for viral clearance. In an age in which the fear of genetically modified weaponized pathogens exists, the understanding of how to make viruses more pathogenic further blurs the distinction between fundamental academic research and bioweapons development. Here, the extent of immune evasion by IL-4-expressing poxviruses will be explored, as will the consequences of this increased pathogenicity on protective immune responses.     

Antisense approaches for elucidating ranavirus gene function in an infected fish cell line

Viral virulence/immune evasion strategies and host anti-viral responses represent different sides of the continuing struggle between virus and host survival. To identify virus-encoding molecules whose function is to subvert or blunt host immune responses, we have adapted anti-sense approaches to knock down the expression of specific viral gene products. Our intention is to correlate knock down with loss of function and thus infer the role of a given viral gene. As a starting point in this process we have targeted several structural and catalytic genes using antisense morpholino oligonucleotides (asMO) and small, interfering RNAs (siRNA). In proof of concept experiments we show the feasibility of this approach and describe recent work targeting five frog virus 3 genes. Our results indicate that both 46K and 32R, two immediate-early viral proteins, are essential for replication in vitro, and confirm earlier findings that the major capsid protein, the largest subunit of the viral homolog of RNA polymerase II, and the viral DNA methyltransferase are also essential for replication in cell culture.     

Viral noncoding RNAs: more surprises

Eukaryotic cells produce several classes of long and small noncoding RNA (ncRNA). Many DNA and RNA viruses synthesize their own ncRNAs. Like their host counterparts, viral ncRNAs associate with proteins that are essential for their stability, function, or both. Diverse biological roles—including the regulation of viral replication, viral persistence, host immune evasion, and cellular transformation—have been ascribed to viral ncRNAs. In this review, we focus on the multitude of functions played by ncRNAs produced by animal viruses. We also discuss their biogenesis and mechanisms of action.     

Viral manipulation of cellular protein conjugation pathways: The SUMO lesson

Small ubiquitin-like modifier (SUMO)ylation is a key post-translational modification mechanism that controls the function of a plethora of proteins and biological processes. Given its central regulatory role, it is not surprising that it is widely exploited by viruses. A number of viral proteins are known to modify and/or be modified by the SUMOylation system to exert their function, to create a cellular environment more favorable for virus survival and propagation, and to prevent host antiviral responses. Since the SUMO pathway is a multi-step cascade, viral proteins engage with it at many levels, to advance and favor each stage of a typical infection cycle: replication, viral assembly and immune evasion. Here we review the current knowledge on the interplay between the host SUMO system and viral lifecycle.     

Single Nucleotide Polymorphism in Ag85 Genes of Mycobacterium Tuberculosis Complex: Analysis of 178 Clinical Isolates from China and 13 BCG strains

Host immune pressure and associated immune evasion of pathogenic bacteria are key features of host-pathogen co-evolution. Human T-cell epitopes of Mycobacterium tuberculosis (M. tuberculosis) were evolutionarily hyperconserved and thus it was deduced that M. tuberculosis lacks antigenic variation and immune evasion. However, in our previous studies, proteins MPT64, PstS1, Rv0309 and Rv2945c all harbored higher numbers of amino acid substitutions in their T cell epitopes, which suggests their roles in ongoing immune evasion. Here, we used the same set of 180 clinical M. tuberculosis complex (MTBC) isolates from China, amplified the genes encoding Ag85 complex, and compared the sequences. The results showed that Ag85 were hyperconserved in T/B cell epitopes and the genes were more likely to be under purifying selection. The divergence of host immune selection on different proteins may result from different function of the proteins. In addition, A312G of Ag85A and T418C of Ag85B may represent special mutations in BCG strains, which may be used to differentiate M.bovis and BCG strains from MTB strains. Also, C714A in Ag85B seems to be a valuable phylogenetic marker for Beijing strains.     

Products and substrate/template usage of vaccinia virus DNA primase

Poxviruses currently are known to disrupt Jak-STAT signal transduction induced by interferon (IFN) through two distinct mechanisms: (1) secreted poxviral IFN decoy receptors that prevent the initiation of IFN signaling from type I or II receptors at the cell surface; and (2) poxviral phosphatase that dephosphorylates STAT1 intracellularly. Here, we report a novel mechanism by which poxviruses can inhibit Jak-STAT signaling in response to type I IFN. Myxoma virus (MV) is a highly species-restricted member of the poxvirus family that infects only rabbits under the natural setting. Interestingly, primary human fibroblasts support a permissive MV infection that is only partially sensitive to the antiviral state induced by type I IFN. In this study we show that when type I IFN is added to primary human fibroblasts following MV infection, the tyrosine phosphorylation of the Janus kinase Tyk2 is specifically blocked, thereby preventing the subsequent activation of downstream STAT1 and STAT2. In stark contrast, type II IFN-induced activation of Jak1, Jak2 and STAT1 remains largely unaffected in MV-infected human fibroblasts. Unlike the de-activation of STAT1 by the poxvirus phosphatase, which is delivered into the cell by the input virions, the Tyk2 inhibition by MV infection requires new viral gene expression. Thus, our study documents a previously unrecognized immune evasion mechanism exploited by a poxvirus to selectively disrupt the type I IFN-Jak-STAT signaling cascade.     

病毒逃避细胞毒性T细胞免疫研究进展

病毒感染期间,病毒与宿主免疫系统之间发生一系列复杂的互相作用,宿主的目的是清除感染及将病理影响减少至最低限度;而病毒则试图逃避清除,以便长期存在及播散至其他宿主.细胞介导的免疫反应特别是病毒特异性CD8细胞毒T细胞(cytotoxicTlymphocyte,CTL)反应,常常在清除病毒感染中起关键作用,故许多病毒的逃避策略即针对于此.在感染过程中,病毒蛋白上氨基酸改变可影响CTL对其表位的识别,而这种逃避机制在病毒感染过程中可引起发病/病情迁延.     

Poxviral mimicry of complement and chemokine system components: what's the end game?

Numerous viral proteins mimic host immunoregulatory proteins, both structurally and functionally. This phenomenon appears to underlie viral evasion of host defense. These viral immunomodulatory proteins block viral neutralization and destruction of infected cells, and are also able to influence their habitat, preserving habitats that favor their growth and that of their progeny. The end game seems to vary widely among viruses.     

Immunomodulation by viruses: the myxoma virus story

Summary: Myxoma virus is a poxvirus pathogen of rabbits that has evolved to replicate successfully in the presence of an active immune response by an infected host. To accomplish this, the virus has developed a variety of strategies to avoid detection by or obstruct specific aspects of the antiviral response whose consolidated action is antagonistic to virus survival. We describe two distinct viral strategies carried out by viral proteins with which myxoma virus subverts the host immune response. The first strategy is the production of virus-encoded proteins known as viroceptors or virokines that mimic host receptors or cytokines. These seek to actively block extracellular immune signals required for effective virus clearance and produce a local environment in the infected tissue that is "virus friendly". The second strategy, carried out by intracellular viral proteins, seeks to retard the innate antiviral responses such as apoptosis, and hinder attempts by the infected cell to communicate with the cellular arm of the immune system. By studying these viral strategies of immune evasion, the myxoma system can provide insights into virus-host interactions and also provide new insights into the complex immune system.