A molecular arms race between host innate antiviral response and emerging human coronaviruses

Coronaviruses have been closely related with mankind for thousands of years. Communityacquired human coronaviruses have long been recognized to cause common cold. However, zoonotic coronaviruses are now becoming more a global concern with the discovery of highly pathogenic severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses causing severe respiratory diseases. Infections by these emerging human coronaviruses are characterized by less robust interferon production. Treatment of patients with recombinant interferon regimen promises beneficial outcomes, suggesting that compromised interferon expression might contribute at least partially to the severity of disease. The mechanisms by which coronaviruses evade host innate antiviral response are under intense investigations. This review focuses on the fierce arms race between host innate antiviral immunity and emerging human coronaviruses. Particularly, the host pathogen recognition receptors and the signal transduction pathways to mount an effective antiviral response against SARS and MERS coronavirus infection are discussed. On the other hand, the counter-measures evolved by SARS and MERS coronaviruses to circumvent host defense are also dissected. With a better understanding of the dynamic interaction between host and coronaviruses, it is hoped that insights on the pathogenesis of newly-identified highly pathogenic human coronaviruses and new strategies in antiviral development can be derived.postprin

Middle East respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3

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SARS-CoV-2-specific immunoglobulin Y antibodies are protective in infected mice

Safe, passive immunization methods are required against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its variants. Immunization of chickens with antigen is known to induce specific IgY antibodies concentrated in the egg yolk and has a good safety profile, high yield of IgY per egg, can be topically applied, not requiring parenteral delivery. Our data provide the first evidence of the prophylactic efficacy of Immunoglobulin Y antibodies against SARS-CoV-2 in mice. Lohmann hens were injected with recombinant SARS-CoV-2 RBD protein; IgY-Abs were extracted from the eggs and characterized using SDS-PAGE. Antiviral activity was evaluated using plaque reduction neutralization tests. In additional experiments, IgY-RBD efficacy was examined in mice sensitized to SARS-CoV-2 infection by transduction with Ad5-hACE2 (mild disease) or by using mouse-adapted virus (severe disease). In both cases, prophylactic intranasal administration of IgY-Abs reduced SARS-CoV-2 replication, and reduced morbidity, inflammatory cell infiltration, hemorrhage, and edema in the lungs and increased survival compared to control groups that received non-specific IgY-Abs. These results indicate that further evaluation of IgY-RBD antibodies in humans is warranted

Middle-East respiratory syndrome coronavirus M protein is a type I IFN antagonist that impedes TRAF3-TBK1 complex formation

Workshop 38. Virus-Host Interactions, Positive Strand RNA Viruses II: Innate Immunity: no. W38-5Middle-East respiratory syndrome coronavirus (MERS-CoV) is a novel human coronavirus first identified in 2012. Individuals infected by MERSCoV present symptoms of acute respiratory distress syndrome with a high mortality rate. MERS-CoV is the second coronavirus identified to cause severe respiratory disorders after the outbreak of severe acute respiratory syndrome (SARS) in 2003. Exactly why MERS-CoV and SARS-CoV are particularly virulent in human remains to be elucidated. The ability to perturb host innate antiviral response might be a major determinant of viral pathogenicity and disease severity. In this study we reported on the inhibition of poly (I:C)- and Sendai virus-induced production of type I interferons (IFNs) by MERS-CoV membrane (M) protein. Coimmunoprecipitation experiments showed that M protein inhibits host type I IFN production by binding specifically to TRAF3 and therefore impeding the formation of TRAF3-TBK1 complex, leading eventually to diminution of IRF3 phosphorylation and dimerization. Furthermore, chimeric and truncation M protein mutants indicated that the N-terminal transmembrane domains of M protein alone are sufficient for IFN antagonism. Comparative analysis revealed that M proteins from the highly pathogenic SARS-CoV and MERS-CoV are capable of suppressing type I IFN production, whereas the counterpart in human coronavirus HKU1, which causes common cold only, has no influence on IFN expression, implicating a role for IFN antagonism of M protein in viral pathogenesis. Taken together, our findings suggest that the M protein of MERSCoV is an IFN antagonist that suppresses innate antiviral response by impeding the formation of TRAF3-TBK1 complex. Supported by HMRF (13121032, 14130822 and HKM-15-M01) and RGC (HKU1/CRF/11G, N-HKU712/12, HKU171091/14M, C7011-15R and T11-707/15-R)

PACT facilitates RNA-induced activation of MDA5 by promoting MDA5 oligomerization.

MDA5 is a RIG-I-like cytoplasmic sensor of dsRNA and certain RNA viruses, such as encephalomyocarditis virus, for the initiation of the IFN signaling cascade in the innate antiviral response. The affinity of MDA5 toward dsRNA is low, and its activity becomes optimal in the presence of unknown cellular coactivators. In this article, we report an essential coactivator function of dsRNA-binding protein PACT in mediating the MDA5-dependent type I IFN response. Virus-induced and polyinosinic-polycytidylic acid-induced activation of MDA5 were severely impaired in PACT-knockout cells and attenuated in PACT-knockdown cells, but they were potentiated when PACT was overexpressed. PACT augmented IRF3-dependent type I IFN production subsequent to dsRNA-induced activation of MDA5. In contrast, PACT had no influence on MDA5-mediated activation of NF-κB. PACT required dsRNA interaction for its action on MDA5 and promoted dsRNA-induced oligomerization of MDA5. PACT had little stimulatory effect on MDA5 mutants deficient for oligomerization and filament assembly. PACT colocalized with MDA5 in the cytoplasm and potentiated MDA5 recruitment to the dsRNA ligand. Taken together, these findings suggest that PACT functions as an essential cellular coactivator of RIG-I, as well as MDA5, and it facilitates RNA-induced formation of MDA5 oligomers

Stem exclusion and mortality in unmanaged subalpine forests of the Swiss Alps

Understanding the causes and consequences of spatiotemporal structural development in forest ecosystems is an important goal of basic and applied ecological research. Most existing knowledge about the sequence and timing of distinct structural stages following stand origin in unmanaged (not actively managed in \u3e50 years) forests has been derived from forests in North America, which are characterized by particular topographic, climatic, biotic and other environmental factors. Thus, the effects on structural development remain poorly understood for many other forest systems, such as the dense, unmanaged, subalpine Norway spruce forests of the Swiss Alps. Over the past century, land abandonment and reductions in active forest management have led to a substantial increase in the density of these forests types. Consequently, many stands are entering the stem exclusion stage and are currently characterized by associated self-thinning mortality. However, the environmental influences on the rate of this structural development as well as this structural stage itself have not yet been examined. We studied stem exclusion processes based on forest inventory data (National Swiss Forest Inventory; NFI) over three survey periods (1983-1985, 1993-1995 and 2004-2006) using repeated measures statistics. To complement these analyses, we also collected and analysed 3,700 increment cores from 20 field plots within dense subalpine Norway spruce forests dispersed across the Swiss Alps. Over the past decades, basal area (BA) has generally increased, particularly on N-facing and steeper slopes, and within 300 m of potential treeline. The number of dead trees was higher on N-facing compared with S-facing slopes, but the BA of dead wood was higher on S-facing slopes. Tree ring analysis confirmed important differences in growth patterns between N- and S-facing slopes and verified the results of the NFI analysis. This study provides a detailed example of how environmental heterogeneity and management history can influence the spatiotemporal structural development of forest ecosystems. © 2012 Springer-Verlag