Special Issue "Interferon Antiviral Response and Viral Evasion"

Guest Editor
Dr. Luis Martinez-Sobrido
University of Rochester, School of Medicine and Dentistry, 601 Elmwood Avenue, Box 672, KMRB 3-9615 Rochester, 14642 NY, USA
Website: http://www.urmc.rochester.edu/smd/mbi/faculty/martinez.htm
E-Mail:
Interests: microbiology and immunology; evasion of the innate immune response by viruses; type I interferon (IFN); arenaviruses; influenza viruses

Submission Information

Title: Mx GTPases with Antiviral Activity
Authors: Otto Haller and Georg Kochs
Affiliation: Department of Virology, University of Freiburg, D-79008 Freiburg, Germany
Abstract: Mx proteins are found in most vertebrate species, including birds, fish and man. They belong to the class of dynamin-like large guanosin triphosphatases (GTPases) known to be involved in intracellular vesicle trafficking and organelle homeostasis. Mx GTPases share structural and functional properties with dynamin, such as selfassembly and association with intracellular membranes. A unique property of some Mx GTPases is their antiviral activity against a wide range of RNA and some DNA viruses. Interestingly, Mx proteins differ in their subcellular localization which appears to determine their antiviral spectrum. The nuclear murine Mx1 protein specifically blocks the replication of orthomyxoviruses known to replicate in the nucleus, whereas the cytoplasmic human MxA protein is active against a wide range of viruses, including viruses with a cytoplasmic replication phase. MxA is partly associated with a COP-I-positive subcompartment of the endoplasmic reticulum. This membrane association may provide an interaction platform that facilitates viral target recognition. The current model of Mx action proposes that Mx proteins recognize viral ribonucleoprotein complexes and immobilize or missort these target structures, thereby aborting the viral life cycle.

Title: Buying Time – Respiratory Virus Inhibition of Host Immunity
Type of paper: Review
Authors: Tamar Hermesh, Bruno Moltedo, Carolina B. Lopez and Thomas M. Moran
Affiliation: Department of Microbiology, Mount Sinai School of Medicine, New York, NY, USA
Abstract: The manifestations of illness associated with an infection are often delayed for a significant period of time after the invasion by the pathogen. This period is referred to as the incubation period. In most instances the symptoms associated with the infection result not from the infectious agent itself but from the immune response generated against it. The release of inflammatory cytokines believed to be primarily responsible for many of the symptoms including fever, malaise, and weight loss is among the earliest immune events. This mixture of cytokines, chemokines and growth factors functions to recruit cells to the site of infection and initiate the adaptive immune response. The lack of symptoms during the incubation period suggests that inflammatory proteins have yet to be released. Thus, the termination of the incubation period is likely to be concomitant with inflammatory protein release. In the case of virus infection a prolonged incubation period may have two major consequences. Virus infection will proceed without interference from cytokines such as type 1 interferon and activated phagocytes and the appearance of the effector cells of adaptive immunity will be delayed. In this review we will discuss strategies utilized by pathogenic human respiratory viruses that allow them to avoid detection and inhibit activation of innate immunity. Such strategies are likely to define the incubation period and correlate with the time needed for efficient transmission.

Title: Inhibition of the innate immune response by alphaviruses
Type of paper: Review
Authors: Patricia V. Aguilar¹, Reed S. Shabman² and Christopher F. Basler²
Affiliation: ¹U.S. Naval Medical Research Center Detachment Lima, Peru and ²Department of Microbiology, Mount Sinai School of Medicine, New York, NY, USA
Abstract: Alphaviruses are a group of positive strand RNA viruses, members of the family Togaviridae, that are transmitted to human and animals mainly by mosquitoes. Based on their disease manifestation and geographic distribution, viruses within this genus have been divided into New World and Old World alphaviruses. Diseases caused by Old World alphaviruses are characterized by febrile illness with rash and polyarthralgia, whereas New World aphaviruses cause a central nervous system infection. Consistent with the differences in pathogenesis in humans, recent studies have also described interesting differences in the way New World and Old World alphaviruses inhibit the innate immune response. While Old World alphaviruses utilize the nonstructural protein, nsP2, to inhibit gene expression, New World alphaviruses use the capsid protein. The ability of alphaviruses to counteract the interferon response appears to be mediated by an overall inhibition of gene expression. In this review, we will discuss the countermeasures developed by alphaviruses to inhibit host cell responses.

Title: Avian bornaviruses escape recognition by the innate immune system
Type of paper: Article
Authors: Antje Reuter¹, Andreas Ackermann¹, Sonja Kothlow², Monika Rinder3, Bernd Kaspers² and Peter Staeheli¹
Affiliation: ¹Department of Virology, University of Freiburg, Freiburg, Germany; ²Institute for Animal Physiology, University of Munich, Munich, Germany; ³Clinic for Birds, University of Munich, Oberschleissheim, Germany
Abstract: Like other pathogens that readily persist in animal hosts, members of the Bornaviridae family have evolved effective mechanisms to evade the innate immune response. The prototype of this virus family, Borna disease virus employs an unusual replication strategy that removes the triphosphates from the 5’ termini of the viral RNA genome. This strategy allows the virus to avoid activation of RIG-I and other innate immune response receptors in infected cells. Here we determined whether the newly discovered avian bornaviruses (ABV) might use a similar strategy to evade the interferon response. We found that de novo infection of QM7 and CEC32 quail cells with two different ABV strains was efficiently inhibited by exogenous chicken IFN-α. IFN-α also reduced the viral load in QM7 and CEC32 cells persistently infected with both ABV strains, suggesting that ABV is highly sensitive to type I IFN. Although quail cells persistently infected with ABV contained high levels of viral RNA, the supernatants of infected cultures did not contain detectable levels of biologically active type I IFN. These results indicate that bornaviruses of mammals and birds use similar strategies to evade the host immune response.

Title: Inhibition of the type I interferon antiviral response during arenavirus infection
Type of paper: Review
Authors: Persephone Borrow¹, Luis Martinez-Sobrido² and Juan Carlos de la Torre³
Affiliation: ¹The Edward Jenner Institute for Vaccine Research, Compton, Newbury, Berkshire RG20 7NN, UK; ²Department of Microbiology and Immunology, Universtity of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA; ³Department of Immunology and Microbial Science, IMM-6, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Abstract: Arenaviruses merit interest both as tractable model systems to study acute and persistent viral infections and as clinically-important human pathogens. Several arenaviruses cause hemorrhagic fevers (HF) in humans. In addition, the globally-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a human pathogen of clinical significance in congenital infections and poses also a great danger to immunosuppressed individuals. Evidence indicates that arenavirus persistence and pathogenesis are facilitated by the ability of these viruses to overcome the host innate immune response. Mammalian hosts have developed both membrane toll-like receptors (TLR) and cytoplasmic pattern recognition receptors (PRRs) that recognize specific pathogen associated molecular patterns (PAMPs), which results in activation of the transcription factors IRF3 or IRF7, or both. Together these factors with NF-kB and ATF-2/c-JUN induce production of type I interferon (IFN-I), subsequently leading to up-regulation of IFN-I stimulated genes (ISGs). IFN-I plays a key role in the host innate immune response, mediating direct antiviral effects, activating innate subsets including dendritic cells (DCs) plus natural killer (NK) cells, and promoting the induction of adaptive responses. Accordingly, viruses have developed a plethora of strategies to disrupt the IFN-I mediated antiviral defense of the host and to interfere with the activity of DCs, thus also affecting the downstream host adaptive immune response. Importantly, the viral gene products responsible for these disruptions are often major virulence determinants. Many viruses have evolved strategies to prevent IRF3- and IRF7-dependent induction of innate immune responses. The LCMV nucleoprotein (NP) was shown to inhibit the IFN-I response in infected and transfected cells by interfering with the activation of IRF3, a feature shared by the NP of many other arenaviruses. In addition, DC responsiveness to TLR ligation has been shown to be impaired in mice chronically infected with LCMV, via unknown mechanisms. In this review we will discuss current knowledge about the cellular and molecular mechanisms by which arenaviruses can subvert the host innate immune response and their implications for understanding HF arenaviral disease, as well as the persistence of arenaviruses in their natural hosts.