MicrobiologyBytes

A myriad of factors favor the emergence and re-emergence of arthropod-borne viruses (arboviruses), including migration, climate change, intensified livestock production, an increasing volume of international trade and transportation, and changes to ecosystems (e.g., deforestation and loss of biodiversity). Consequently, arboviruses are distributed worldwide and represent over 30% of all emerging infectious diseases identified in the past decade. Although some arboviral infections go undetected or are associated with mild, flu-like symptoms, many are important human and veterinary pathogens causing serious illnesses such as arthritis, gastroenteritis, encephalitis and hemorrhagic fever and devastating economic loss as a consequence of lost productivity and high mortality rates among livestock. One of the most consistent molecular features of emerging arboviruses, in addition to their near exclusive use of RNA genomes, is the inclusion of viral, non-structural proteins that act as interferon antagonists. In this review, we describe these interferon antagonists and common strategies that arboviruses use to counter the host innate immune response. In addition, we discuss the complex interplay between host factors and viral determinants that are associated with virus emergence and re-emergence, and identify potential targets for vaccine and anti-viral therapies.

The Role of Interferon Antagonist, Non-Structural Proteins in the Pathogenesis and Emergence of Arboviruses. (2011) Viruses 3(6): 629-658; doi:10.3390/v3060629

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Given the critical role of interferons (IFNs) as a first line of defense against infection, it is not surprising that many viruses have evolved strategies to block an IFN response as a means to increase their replication efficiency. Virus-mediated inhibition of IFNs can be generalized into three categories, including disruption of IFN induction, disruption of IFN-inducible signaling and disruption of IFN-mediated effector functions.

The non-structural protein 1 (NS1) of influenza A viruses exerts its inhibitory effects on IFN predominately by interfering with IFN productionType I interferons (IFNs) function as the first line of defense against viral infections by modulating cell growth, establishing an antiviral state and influencing the activation of various immune cells. Viruses such as influenza have developed mechanisms to evade this defense mechanism and during infection with influenza A viruses, the non-structural protein 1 (NS1) encoded by the virus genome suppresses induction of IFNs-α/β.

Expression of avian H5N1 NS1 in HeLa cells leads to a block in IFN signaling. H5N1 NS1 reduces IFN-inducible tyrosine phosphorylation of STAT1, STAT2 and STAT3 and inhibits the nuclear translocation of phospho-STAT2 and the formation of IFN-inducible STAT1:1-, STAT1:3- and STAT3:3- DNA complexes. Inhibition of IFN-inducible STAT signaling by NS1 in HeLa cells is, in part, a consequence of NS1-mediated inhibition of expression of the IFN receptor subunit, IFNAR1. However, treatment of ex vivo human lung tissues with IFN-α results in the up-regulation of a number of IFN-stimulated genes and inhibits both H5N1 and H1N1 virus replication. The data suggest that NS1 can directly interfere with IFN signaling to enhance viral replication, but that treatment with IFN can nevertheless override these inhibitory effects to block H5N1 and H1N1 virus infections.

Influenza Virus Non-Structural Protein 1 (NS1) Disrupts Interferon Signaling. (2010) PLoS ONE 5(11): e13927. doi:10.1371/journal.pone.0013927

Related:

• Virus tricks to grid-lock the type I interferon system
• Interferons and Viruses
• The Interferon Antiviral Response

The innate immune system forms the first line of defence against invading micro-organisms such as viruses. It dampens initial virus replication and ensures survival of the host until specialized adaptive responses are developed. Type I interferons (IFNs) are secreted key cytokines on the innate immune axis that protect uninfected cells and stimulate leukocytes residing at the interface of innate and adaptive immunity, such as macrophages and dendritic cells. These cells prod the adaptive immune system to mount a full, specialized response against the invading microbe.

The ability to outrun innate immunity before adaptive immune responses are mounted is crucial for the survival of virtually all the mammalian viruses, regardless of their genome type and complexity. Relatively simple viruses such as RNA viruses from the Picornavirus family, as well as DNA viruses with large genomes, such as members from the Poxvirus family, have been shown to inhibit the IFN system. This review covers the latest insights into how virus-encoded antagonists sidetrack the IFN machinery and how this knowledge is currently used to generate second generation live vaccines and antiviral compounds.

Viral tricks to grid-lock the type I interferon system. Curr Opin Microbiol. Jun 9 2010
Type I interferons (IFNs) play a crucial role in the innate immune avant-garde against viral infections. Virtually all viruses have developed means to counteract the induction, signaling, or antiviral actions of the IFN circuit. Over 170 different virus-encoded IFN antagonists from 93 distinct viruses have been described up to now, indicating that most viruses interfere with multiple stages of the IFN response. Although every viral IFN antagonist is unique in its own right, four main mechanisms are employed to circumvent innate immune responses: (i) general inhibition of cellular gene expression, (ii) sequestration of molecules in the IFN circuit, (iii) proteolytic cleavage, and (iv) proteasomal degradation of key components of the IFN system. The increasing understanding of how different viral IFN antagonists function has been translated to the generation of viruses with mutant IFN antagonists as potential live vaccine candidates. Moreover, IFN antagonists are attractive targets for inhibition by small-molecule compounds.

Related:

• MicrobiologyBytes: Interferon
• Interferons and Viruses
• The Interferon Antiviral Response
• Interferon – 50 years on

In response to invasion with bacterial or viral pathogens, cells are able to mount an immediate immune response through their ability to use specialized cellular molecules, referred to as pattern recognition receptors or PRRs, to detect unusual DNA, ssRNA or dsRNA structures. This leads to induction of the interferons and pro-inflammatory cytokines that are involved in the innate immune response.

Hepatitis C virus (HCV) is one of the RNA helicase RIG-I-activating viruses, because of its 5′ppp-structured RNA, 3′-structured genomic RNA and replicative RNA duplexes. In contrast to other RIG-I activating viruses such as Sendai virus, influenza, or vesicular stomatitis virus, HCV is a poor inducer of IFN and pro-inflammatory cytokines in cell culture systems. One reason for this is that the HCV NS3/4A protease cleaves cellular proteins (MAVS), resulting in a rapid disruption of the IFN induction pathway.

A recent paper shows that HCV infection can stimulate the IFN induction pathway up to 12 hrs post-infection, whereas detection of MAVS cleavage begins at 18 hrs post-infection and is maximal at 24 hrs. The data reveal that 12 hrs post-infection, HCV promotes a rapid inhibition of IFN induction at the level of translation, indicating a new mechanism of regulation. This regulation was linked to activation of the dsRNA-activated eIF2α kinase PKR. Altogether, the results show that HCV uses PKR to control the translation of newly transcribed IFN mRNAs before sufficient NS3/4A protein can be synthesized to efficiently restrain transcription of IFN.

Although PKR is also recognized in several virus infections for its antiviral proprieties, it may be more suitable to control its action in the case of HCV infection. Therefore, a carefully-controlled use of PKR inhibitors, in conjunction with IFN/ribavirin, might be beneficial for the treatment of chronically HCV-infected patients, since it would lead to a boost in the induction of innate immunity and a sustained inhibition of the virus propagation.

Hepatitis C Virus Controls Interferon Production through PKR Activation. 2010 PLoS ONE 5(5): e10575. doi:10.1371/journal.pone.0010575

Related:

• Hepatitis C Virus: a mountain to climb
• The Interferon Antiviral Response
• Update on HBV and HCV Therapy

The flavivirus genus includes viruses with a remarkable ability to produce disease on a large scale. The expansion and increased endemicity of dengue and West Nile viruses in the Americas exemplifies their medical and epidemiological importance. The rapid detection of virus infection and induction of the innate antiviral response are crucial to determining the outcome of infection. The intracellular pathogen receptors RIG-I and MDA5 play a central role in detecting flavivirus infections and initiating a robust antiviral response. Yet, these viruses are still capable of producing acute illness in humans. It is now clear that flaviviruses utilize a variety of mechanisms to modulate the interferon response. The non-structural proteins of the various flaviviruses reduce expression of interferon dependent genes by blocking phosphorylation, enhancing degradation or down-regulating expression of major components of the JAK/STAT pathway. Recent studies indicate that interferon modulation is an important factor in the development of severe flaviviral illness. This suggests that an increased understanding of viral-host interactions will facilitate the development of novel therapeutics to treat these viral infections and improved biological models to study flavivirus pathogenesis.

How Flaviviruses Activate and Suppress the Interferon Response. Viruses 2010, 2(2), 676-691; doi:10.3390/v2020676

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• MicrobiologyBytes: Flaviviruses
• MicrobiologyBytes: Interferon

The family Bunyaviridae contains more than 350 viruses that are distributed throughout the world. Most members of the family are transmitted by arthopods, and several cause disease in man, domesticated animals and crop plants. Despite being recognized as an emerging threat, details of the virulence mechanisms employed by bunyaviruses are scant. This article summarises the information currently available on how these viruses are able to establish infections when confronted with a powerful antiviral interferon system.

Viruses 2009, 1(3), 1003-102; doi: 10.3390/v1031003

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• Bunyaviruses
• The Interferon Antiviral Response
• Interferon – 50 years on

Lipid droplets consist of a core of neutral lipids surrounded by an outer phospholipid monolayer and associated proteins. These organelles are thought to be generated when neutral lipids accumulate in the endoplasmic reticulum (ER) bilayer. Recently, lipid droplets have been shown to play a role in several cellular processes, including lipid storage, lipid trafficking, and protein storage and degradation. The importance of this organelle is underscored by the fact that lipid droplets have been linked to several metabolic diseases, most notably diabetes and obesity. Lipid droplets have also been shown to play a critical role in the replication of several pathogens. One of the most well characterized examples is hepatitis C virus (HCV).

Viperin is an interferon (IFN)-induced antiviral protein that is induced upon HCV infection and inhibits HCV replication. Like the HCV NS proteins, viperin has been shown to localize to the cytosolic face of the ER through an N-terminal amphipathic
alpha-helix. This N-terminal amphipathic
alpha-helix is essential for viperin to inhibit HCV and influenza, as mutants lacking this domain have greatly reduced antiviral activity. Although the precise mechanism by which viperin inhibits HCV is still unknown, viperin was previously shown to inhibit influenza virus budding by disrupting plasma membrane lipid raft microdomains, which are sites of influenza virion assembly and budding. Independent of viral infection, the N-terminal amphipathic
alpha-helix of viperin inhibits protein secretion and appears to induce ER membrane curvature.

Numerous questions remain about how lipid droplets are generated and used by viruses. This paper shows that the IFN-induced antiviral protein viperin, which localizes to the cytosolic face of the ER and inhibits HCV, localizes to lipid droplets. This paper shows that the N-terminal amphipathic alpha-helix of viperin that is responsible for ER localization is also necessary and sufficient to localize both viperin and the fluorescent protein dsRed to lipid droplets. Point mutations in the alpha-helix that prevent ER association also disrupt lipid droplet association, and sequential deletion mutants indicate that the same number of helical turns are necessary for ER and lipid droplet association. The N-terminal amphipathic alpha-helix of the hepatitis C viral protein NS5A can localize dsRed and viperin to lipid droplets. These findings indicate that the amphipathic alpha-helices of viperin and NS5A are lipid droplet-targeting domains and suggest that viperin inhibits HCV by localizing to lipid droplets using a domain and mechanism similar to that used by HCV itself.

The antiviral protein, viperin, localizes to lipid droplets via its N-terminal amphipathic αalpha-helix. PNAS USA November 17 2009. doi: 10.1073/pnas.0911679106

Related:

• Viperin (cig5), an IFN-inducible antiviral protein directly induced by human cytomegalovirus. 2001 PNAS USA 98(26): 15125-15130
• Viroporins
• Hepatitis C Virus: a mountain to climb
• The Interferon Antiviral Response