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The novel human coronavirus disease COVID-19 has become the fifth documented pandemic since the 1918 flu pandemic. COVID-19 was first reported in Wuhan, China, and subsequently spread worldwide. The coronavirus was officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses based on phylogenetic analysis. SARS-CoV-2 is believed to be a spillover of an animal coronavirus and later adapted the ability of human-to-human transmission. Because the virus is highly contagious, it rapidly spreads and continuously evolves in the human population. In this review article, we discuss the basic properties, potential origin, and evolution of the novel human coronavirus. These factors may be critical for studies of pathogenicity, antiviral designs, and vaccine development against the virus.

Taiwan experienced two waves of imported infections with Coronavirus Disease 2019 (COVID-19). This study aimed at investigating the genomic variation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Taiwan and compared their evolutionary trajectories with the global strains. We performed culture and full-genome sequencing of SARS-CoV-2 strains followed by phylogenetic analysis. A 382-nucleotides deletion in open reading frame 8 (ORF8) was found in a Taiwanese strain isolated from a patient on February 4, 2020 who had a travel history to Wuhan. Patients in the first wave also included several sporadic, local transmission cases. Genomes of 5 strains sequenced from clustered infections were classified into a new clade with ORF1ab-V378I mutation, in addition to 3 dominant clades ORF8-L84S, ORF3a-G251V and S-D614G. This highlighted clade also included some strains isolated from patients who had a travel history to Turkey and Iran. The second wave mostly resulted from patients who had a travel history to Europe and Americas. All Taiwanese viruses were classified into various clades. Genomic surveillance of SARS-CoV-2 in Taiwan revealed a new ORF8-deletion mutant and a virus clade that may be associated with infections in the Middle East, which contributed to a better understanding of the global SARS-CoV-2 transmission dynamics.

Induction of type-I interferons (IFNs), IFN-α/β, is crucial to innate immunity against RNA virus infection. Cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptors, including RIG-I and melanoma differentiation-associated gene 5 (MDA5), are critical pathogen sensors for activation of type-I IFN expression in response to RNA virus infection. MDA5 is required for type-I IFN expression in mouse models in response to infection by picornaviruses, such as encephalomyocarditis virus (EMCV) and coxsackievirus B3. Enterovirus 71 (EV71) belongs to picornaviridae and contains positive-stranded RNA genome that is linked with VPg protein at the 5' end. Although a recent study showed that EV71 3C protease could suppress RIG-I-mediated IFN-β response, the cytoplasmic RIG-I-like receptor that is directly involved in the recognition of EV71 RNA remains unclear. Using EV71-derived RNA as an agonist, we demonstrate that MDA5 is involved in EV71 RNA-mediated IRF3 activation and IFN-β transcription. Our data also show that overexpression of the MDA5 protein reverses the suppression of IRF3 activation caused by EV71 infection. These results indicate that MDA5 is an important factor for EV71 RNA-activated type-I IFN expression. Furthermore, we also show that EV71 infection enhances MDA5 degradation and that the degradation could be inhibited by a broad spectrum caspase inhibitor.

The viral ribonucleoprotein (vRNP) of influenza A virus is formed by virion RNA (vRNA), viral polymerase complex, and nucleoprotein (NP). The NP plays an important role in facilitating the replication and stabilization of viral RNA. To explore host factors that may be involved in the regulation of viral replication through interactions with NP, we conducted an immunoprecipitation experiment followed by mass spectrometry to identify NP-associated cellular proteins. Here, we demonstrate that NP can interact and colocalize with heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 in mammalian cells and that the interaction may occur via direct binding to the glycine-rich domain (GRD) of hnRNP A2/B1. In addition, two residues in the tail loop of NP, F412 and R422, are required for the interaction of hnRNP A2/B1. Because the knockdown of hnRNP A2/B1 expression reduces viral RNP activity, hnRNP A2/B1 may act as a positive regulator in viral RNA synthesis of influenza A virus. More importantly, the findings in this research demonstrate that host proteins can regulate the replication of influenza A virus by interacting with NP.

Background Neural stem cells (NSCs) residing in the central nervous system play an important role in neurogenesis. Several viruses can infect these neural progenitors and cause severe neurological diseases. The innate immune responses against the neurotropic viruses in these tissue-specific stem cells remain unclear. Methods Human NSCs were transfected with viral RNA mimics or infected with neurotropic virus for detecting the expression of antiviral interferons (IFNs) and downstream IFN-stimulated antiviral genes. Results NSCs are able to produce interferon-β (IFN-β) (type I) and λ1 (type III) after transfection with poly(I:C) and that downstream IFN-stimulated antiviral genes, such as ISG56 and MxA, and the viral RNA sensors RIG-I, MDA5, and TLR3, can be expressed in NSCs under poly(I:C) or IFN-β stimulation. In addition, our results show that the pattern recognition receptors RIG-I and MDA5, as well as the endosomal pathogen recognition receptor TLR3, but not TLR7 and TLR8, are involved in the activation of IFN-β transcription in NSCs. Furthermore, NSCs infected with the neurotropic viruses, Zika and Japanese encephalitis viruses, are able to induce RIG-I-mediated IFN-β expression. Conclusion Human NSCs have the ability to activate IFN signals against neurotropic viral pathogens.

ISG15 is an IFN-α/β-induced, ubiquitin-like protein that is conjugated to a wide array of cellular proteins through the sequential action of three conjugation enzymes that are also induced by IFN-α/β. Recent studies showed that ISG15 and/or its conjugates play an important role in protecting cells from infection by several viruses, including influenza A virus. However, the mechanism by which ISG15 modification exerts antiviral activity has not been established. Here we extend the repertoire of ISG15 targets to a viral protein by demonstrating that the NS1 protein of influenza A virus (NS1A protein), an essential, multifunctional protein, is ISG15 modified in virus-infected cells. We demonstrate that the major ISG15 acceptor site in the NS1A protein in infected cells is a critical lysine residue (K41) in the N-terminal RNA-binding domain (RBD). ISG15 modification of K41 disrupts the association of the NS1A RBD domain with importin-α, the protein that mediates nuclear import of the NS1A protein, whereas the RBD retains its double-stranded RNA-binding activity. Most significantly, we show that ISG15 modification of K41 inhibits influenza A virus replication and thus contributes to the antiviral action of IFN-β. We also show that the NS1A protein directly and specifically binds to Herc5, the major E3 ligase for ISG15 conjugation in human cells. These results establish a \"loss of function\" mechanism for the antiviral activity of the IFN-induced ISG15 conjugation system, namely, that it inhibits viral replication by conjugating ISG15 to a specific viral protein, thereby inhibiting its function.

A novel mechanistic discovery reveals that the host decay factor XRN1 contributes to influenza A virus replication, which exploits XRN1 activity to inhibit RIG-I-mediated innate immune response. Here, we identified a novel interaction between viral NS1 and host XRN1. Cellular 5′-3′ exoribonuclease 1 (XRN1) is best known for its role as a decay factor, which by degrading 5′ monophosphate RNA after the decapping of DCP2 in P-bodies (PBs) in Drosophila , yeast, and mammals. XRN1 has been shown to degrade host antiviral mRNAs following the influenza A virus (IAV) PA-X-mediated exonucleolytic cleavage processes. However, the mechanistic details of how XRN1 facilitates influenza A virus replication remain unclear. In this study, we discovered that XRN1 and nonstructural protein 1 (NS1) of IAV are directly associated and colocalize in the PBs. Moreover, XRN1 downregulation impaired viral replication while the viral titers were significantly increased in cells overexpressing XRN1, which suggest that XRN1 is a positive regulator in IAV life cycle. We further demonstrated that the IAV growth curve could be suppressed by adenosine 3′,5′-bisphosphate (pAp) treatment, an inhibitor of XRN1. In virus-infected XRN1 knockout cells, the phosphorylated interferon regulatory factor 3 (p-IRF3) protein, interferon beta ( IFN-β ) mRNA, and interferon-stimulated genes (ISGs) were significantly increased, resulting in the enhancement of the host innate immune response and suppression of viral protein production. Our data suggest a novel mechanism by which the IAV hijacks the cellular XRN1 to suppress the host innate immune response and to facilitate viral replication. IMPORTANCE A novel mechanistic discovery reveals that the host decay factor XRN1 contributes to influenza A virus replication, which exploits XRN1 activity to inhibit RIG-I-mediated innate immune response. Here, we identified a novel interaction between viral NS1 and host XRN1. Knockdown and knockout of XRN1 expression in human cell lines significantly decreased virus replication while boosting RIG-I-mediated interferon immune response, suggesting that XRN1 facilitates influenza A virus replication. The pAp effect as XRN1 inhibitor was evaluated; we found that pAp was capable of suppressing viral growth. To our knowledge, this study shows for the first time that a negative-strand and nucleus-replicating RNA virus, as influenza A virus, can hijack cellular XRN1 to suppress the host RIG-I-dependent innate immune response. These findings provide new insights suggesting that host XRN1 plays a positive role in influenza A virus replication and that the inhibitor pAp may be used in novel antiviral drug development.

The influenza A virus (IAV) consists of 8 single-stranded, negative-sense viral RNA (vRNA) segments. After infection, vRNA is transcribed, replicated, and wrapped by viral nucleoprotein (NP) to form viral ribonucleoprotein (vRNP). The transcription, replication, and nuclear export of the viral genome are regulated by the IAV protein, NS2, which is translated from spliced mRNA transcribed from viral NS vRNA. This splicing is inefficient, explaining why NS2 is present in low abundance after IAV infection. The levels of NS2 and its subsequent accumulation are thought to influence viral RNA replication and vRNP nuclear export. Here we show that NS2 is ubiquitinated at the K64 and K88 residues by K48-linked and K63-linked polyubiquitin (polyUb) chains, leading to the degradation of NS2 by the proteasome. Additionally, we show that a host deubiquitinase, OTUB1, can remove polyUb chains conjugated to NS2, thereby stabilizing NS2. Accordingly, knock down of OTUB1 by siRNA reduces the nuclear export of vRNP, and reduces the overall production of IAV. These results collectively demonstrate that the levels of NS2 in IAV-infected cells are regulated by a ubiquitination-deubiquitination system involving OTUB1 that is necessary for optimal IAV replication.

Since the COVID-19 pandemic was declared, vaccines against SARS-CoV-2 have been urgently developed around the world. On the basis of the mRNA vaccine technology developed previously, COVID-19 mRNA vaccines were promptly tested in animals, advanced to clinical trials, and then authorized for emergency use in humans. The administration of COVID-19 mRNA vaccines has successfully reduced the hospitalization and mortality caused by the viral infection, although the virus continuously evolves with its transmission. Therefore, the development of mRNA vaccine technology, including RNA modification and delivery systems, is well recognized for its contribution to moderating the harms caused by the COVID-19 pandemic. The scientists who developed these technologies, Katalin Karikó, Drew Weissman, and Pieter Cullis, were awarded the 2022 Tang Prize in Biopharmaceutical Science. In this review, we summarize the principles, safety and efficacy of as well as the immune response to COVID-19 mRNA vaccines. Since mRNA vaccine approaches could be practical for the prevention of infectious diseases, we also briefly describe mRNA vaccines against other human viral pathogens in clinical trials.

High pathogenicity avian influenza virus (HPAIV) poses major threats to both poultry health and public safety. The viral nonstructural protein 1 (NS1) plays a crucial role in counteracting innate immunity. NS1 typically consists of approximately 230 amino acids with two domains: an RNA-binding domain (RBD) and the effector domain (ED). A novel naturally occurring NS1 variant, termed NS100, was reported herein, isolated during propagation of a recombinant H5N2 virus. NS100 encodes only the 1-95 residues of NS1, lacking the entire ED. Surprisingly, the NS100 virus replicated as efficiently as the wild-type (WT) virus in both cell and animal models. Cells infected with NS100 exhibited reduced interferon and cytokine expression, indicating preserved immune evasion capacity. Biochemical analyses revealed that NS100 retains key NS1 functions mediated by the RBD, including dsRNA binding, PKR interaction, and homodimer formation. In addition, NS100 cooperated with the viral RNA polymerase complex in a mini-genome assay, indicating functional synergy. Interestingly, the NS100 virus showed markedly reduced NS2 protein expression, likely due to impaired splicing caused by a GA transversion at a polypyrimidine tract. Transcriptome analysis further confirmed reduced splicing efficiency of NS transcripts and lower expression of antiviral host genes in NS100-infected cells. In conclusion, our findings demonstrate that NS1 can maintain essential pro-viral functions despite the loss of its ED, and that NS100 provides new insights into the modularity of NS1 and its broader role in regulating host-virus interactions.