Viral mechanisms of immune evasion

During the millions of years they have coexisted with their hosts, viruses have learned how to manipulate host immune control mechanisms. Viral gene functions provide an overview of many relevant principles in cell biology and immunology. Our knowledge of viral gene functions must be integrated into virus-host interaction networks to understand viral pathogenesis, and could lead to new anti-viral strategies and the ability to exploit viral functions as tools in medicine.     

Viral mechanisms of immune evasion

During the millions of years they have coexisted with their hosts, viruses have learned how to manipulate host immune control mechanisms. Viral gene functions provide an overview of many relevant principles in cell biology and immunology. Our knowledge of viral gene functions must be integrated into virus-host interaction networks to understand viral pathogenesis, and could lead to new anti-viral strategies and the ability to exploit viral functions as tools in medicine.     

Viral evasion of autophagy

Autophagy is an evolutionarily ancient pathway for survival during different forms of cellular stress, including infection with viruses and other intracellular pathogens. Autophagy may protect against viral infection through degradation of viral components (xenophagy), by promoting the survival or death of infected cells, through delivery of Toll-like receptor (TLR) ligands to endosomes to activate innate immunity, or by feeding antigens to MHC class II compartments to activate adaptive immunity. Given this integral role of autophagy in innate and adaptive antiviral immunity, selective pressure likely promoted the emergence of escape mechanisms by pathogenic viruses. This review will briefly summarize the current understanding of autophagy as an antiviral pathway, and then discuss strategies that viruses may utilize to evade this host defense mechanism.     

Viral evasion of autophagy

Restriction of both bacterial and viral pathogen growth by autophagy has been documented in vitro. In this issue of Cell Host & Microbe, Orvedahl et al. demonstrate for the first time that inhibition of autophagy by a viral gene product is essential for neurovirulence of herpesviruses.     

Viral evasion of autophagy

Autophagy is an evolutionarily ancient pathway for survival during different forms of cellular stress, including infection with viruses and other intracellular pathogens. Autophagy may protect against viral infection through degradation of viral components (xenophagy), by promoting the survival or death of infected cells, through delivery of Toll-like receptor (TLR) ligands to endosomes to activate innate immunity, or by feeding antigens to MHC class II compartments to activate adaptive immunity. Given this integral role of autophagy in innate and adaptive antiviral immunity, selective pressure likely promoted the emergence of escape mechanisms by pathogenic viruses. This review will briefly summarize the current understanding of autophagy as an antiviral pathway, and then discuss strategies that viruses may utilize to evade this host defense mechanism.     

Viral tegument proteins restrict cGAS-DNA phase separation to mediate immune evasion

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Viral miRNAs exploiting the endosomal-exosomal pathway for intercellular cross-talk and immune evasion

The class of persistent gamma-herpesviruses has developed a variety of strategies that exploit host-cell regulatory pathways to ensure a long-lasting, well-balanced infection of their host. However when these pathways are deregulated, an otherwise harmless infection can lead to disease including cancer. We recently demonstrated that the human herpes virus 4 (HHV4) also known as Epstein-Barr virus (EBV), encodes for small regulatory non-coding microRNAs (miRNAs) that can be transferred from an infected cell to uninfected neighboring cells. Upon arrival these miRNAs are functional in the recipient cell, in that they are able to down regulate specific target genes. These secreted miRNAs are transported to recipient cells via small nano-sized vesicles (known as exosomes) that are of endosomal origin, formed as intraluminal vesicles (ILV) inside multivesicular bodies (MVB). One question that needs to be addressed is how viral miRNAs are sorted into these exosomes. Mature miRNAs, including those of viral origin, are loaded into RNA-induced silencing complexes (RISC) for gene silencing via blocking mRNA translation and/or initiating mRNA decay. Recent insights indicate that cytoplasmic RNA granules rich in RISC complexes are closely associated with endosomes. In fact, selective components of RISC, including GW182 and Argonaut proteins, miRNAs and mRNAs are present in exosomes. Thus miRNA function, mRNA stability and exosome-mediated intercellular communication converge at the level of endosomes. Since endosomes can be considered as key intracellular cross-roads that regulate communication of cells with their exterior, including neighboring cells, it is perhaps not surprising that viruses have found means to exploit this pathway to their benefit. Little is known however, how and if (micro) RNA species are specifically sorted into ILVs and what (micro)RNA-binding proteins are involved. Here we discuss recent developments relating to intracellular trafficking and function of miRNA-containing protein complexes that EBV may exploit for promoting or restricting miRNAs sorting into exosomes for intercellular regulatory functions. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation.     

Parasite immune evasion: a momentous molecular war

Current research in immunology shows that parasite evasion of host immunity is ubiquitous and involves a wide range of molecular mechanisms. Furthermore, immune evasion appears to generate a large spectrum of pathogenic effects, such as cytokine storms and inflammation. Understanding the relationships between the beneficial effects of immune evasion and its pathogenic consequences therefore provides a new framework to reassess many of the core questions of the evolutionary ecology of host-parasite interactions, such as the evolution of virulence, immune defence strategies, infective dose and host specificity, and to address questions that thus far could not be satisfactorily analysed.     

Pneumocystis: immune recognition and evasion

Pulmonary infection caused by the opportunistic fungal organism Pneumocystis continues to be a leading AIDS defining illness. The initiation of highly active antiretroviral therapy (HAART) in the HIV-infected population has led to a significant reduction in the incidence of Pneumocystis pneumonia (PCP), although recent trends suggest the incidence has plateaued rather than decreased. Host defense against Pneumocystis involves a delicate, concerted balance between the inflammatory response and immune-mediated clearance. Innate cellular immunity is a cornerstone in this response as it provides the initial recognition event that precipitates an immune response, ultimately leading to clearance of the organism from the host. This review will focus on carbohydrate moieties found in the Pneumocystis cell wall and the immune events that occur following their recognition.     

Malaria: immune evasion by parasites

Malaria is one of the most life-threatening infectious diseases worldwide. Specific immunity to natural infection is acquired slowly despite a high degree of repeated exposure and rarely continues for a long time even in endemic areas. Malaria parasites have evolved to acquire diverse immune evasion mechanisms that evoke poor immune responses and allow infection of individuals previously exposed. The shrewd schema of malaria parasites also hampers the development of effective vaccines. Furthermore, some of those mechanisms are essential for malaria pathogenesis. In this article, an outline of protective immunity to malaria is given, then strategies used by malaria parasites to evade host immunity, including antigen diversity/polymorphism, antigen variation and total immune suppression, are reviewed. Finally, trials to control malaria based on accumulating insights into the host-parasite relationship are discussed.     

Staphylococcal innate immune evasion

Upon entering the human body, bacteria are confronted with the sophisticated innate defense mechanisms of the human host. From work in recent years it has become obvious that a new and growing family of small and excreted proteins can counteract the antibacterial effects of innate immunity. These highly selective proteins pick out crucial elements of our immune system and inhibit their function. In Staphylococcus aureus these proteins act on specific cellular receptors, on antimicrobial peptides and especially on the complement system. The combined action of this growing group of essential virulence factors ascertains efficient innate immune evasion.     

Vaccine-driven evolution of parasite virulence and immune evasion in age-structured population: the case of pertussis

Despite enormous success of mass immunization programs in reducing incidence of infectious diseases, vaccine-escape strains have emerged perhaps as a consequence of strong selection pressures exerted on parasites by vaccines. Pertussis presents a well-documented example. As a childhood infection, it exhibits age-specific transmission biased to children. Assuming different transmission rates between children and adults, I study, by means of an age-structured epidemic model, evolutionary dynamics of parasite virulence in a vaccinated population. I find that the age-structure does not affect the evolutionary dynamics of parasite virulence. Also, based on empirical data reporting antigenic divergence with vaccine strains and mutations in virulence-associated genes in pertussis populations, I allow for parallel occurrence of mutations in parasite virulence and associated immune evasion. I conclude that this simultaneous adaptation of both traits may substantially alter the evolutionary course of the parasite. In particular, higher values of virulence are favoured once the parasite is able to evade the transmission-blocking vaccine-induced immunity. On the other hand, lower values of virulence are selected for once the parasite evolves the ability to evade the virulence-blocking vaccine-induced immunity. I emphasize the importance of multi-trait evolution to assess the direction of parasite adaptation more accurately.     

羊口疮病毒分子特征与免疫逃逸策略

羊传染性脓疱皮炎(Contagious ecthyma)俗称羊口疮(Orf)是由羊口疮病毒(Orf virus,ORFV)引起的一种人畜共患传染病。ORFV是痘病毒科副痘病毒属的代表性成员之一,具有鲜明而独特的种属特征。在进化过程中,病毒捕获一系列免疫调节/致病性相关基因,通过各种表达产物协同性地限制宿主的免疫清除效应,以庇护种群的增殖和病毒粒子成熟。本文综述了ORFV的分子特征,着重分析了病毒主动干预宿主免疫应答、设计免疫逃逸的分子机制。明确病毒的免疫调节/致病性元件及其效应途径,有利于加深对ORFV生物学特性的理解,同时有利于针对Orf建立有效的防制。     

Phase-dependent immune evasion of herpesviruses

Viruses employ various modes to evade immune detection. Two possible evasion modes are a reduction of the number of epitopes presented and the mimicry of host epitopes. The immune evasion efforts are not uniform among viral proteins. The number of epitopes in a given viral protein and the similarity of the epitopes to host peptides can be used as a measure of the viral attempts to hide this protein. Using bioinformatics tools, we here present a genomic analysis of the attempts of four human herpesviruses (herpes simplex virus type 1-human herpesvirus 1, Epstein-Barr virus-human herpesvirus 4, human cytomegalovirus-human herpesvirus 5, and Kaposi's sarcoma-associated herpesvirus-human herpesvirus 8) and one murine herpesvirus (murine herpesvirus 68) to escape from immune detection. We determined the full repertoire of CD8 T-lymphocyte epitopes presented by each viral protein and show that herpesvirus proteins present many fewer epitopes than expected. Furthermore, the epitopes that are presented are more similar to host epitopes than are random viral epitopes, minimizing the immune response. We defined a score for the size of the immune repertoire (the SIR score) based on the number of epitopes in a protein. The numbers of epitopes in proteins expressed in the latent and early phases of infection were significantly smaller than those in proteins expressed in the lytic phase in all tested viruses. The latent and immediate-early epitopes were also more similar to host epitopes than were lytic epitopes. A clear trend emerged from the analysis. In general, herpesviruses demonstrated an effort to evade immune detection. However, within a given herpesvirus, proteins expressed in phases critical to the fate of infection (e.g., early lytic and latent) evaded immune detection more than all others. The application of the SIR score to specific proteins allows us to quantify the importance of immune evasion and to detect optimal targets for immunotherapy and vaccine development.     

Variola virus immune evasion proteins

Variola virus, the causative agent of smallpox, encodes approximately 200 proteins. Over 80 of these proteins are located in the terminal regions of the genome, where proteins associated with host immune evasion are encoded. To date, only two variola proteins have been characterized. Both are located in the terminal regions and demonstrate immunoregulatory functions. One protein, the smallpox inhibitor of complement enzymes (SPICE), is homologous to a vaccinia virus virulence factor, the vaccinia virus complement-control protein (VCP), which has been found experimentally to be expressed early in the course of vaccinia infection. Both SPICE and VCP are similar in structure and function to the family of mammalian complement regulatory proteins, which function to prevent inadvertent injury to adjacent cells and tissues during complement activation. The second variola protein is the variola virus high-affinity secreted chemokine-binding protein type II (CKBP-II, CBP-II, vCCI), which binds CC-chemokine receptors. The vaccinia homologue of CKBP-II is secreted both early and late in infection. CKBP-II proteins are highly conserved among orthopoxviruses, sharing approximately 85% homology, but are absent in eukaryotes. This characteristic sets it apart from other known virulence factors in orthopoxviruses, which share sequence homology with known mammalian immune regulatory gene products. Future studies of additional variola proteins may help illuminate factors associated with its virulence, pathogenesis and strict human tropism. In addition, these studies may also assist in the development of targeted therapies for the treatment of both smallpox and human immune-related diseases.