A broadly protective antibody targeting glycoprotein Gn inhibits severe fever with thrombocytopenia syndrome virus infection.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging bunyavirus that causes severe viral hemorrhagic fever and thrombocytopenia syndrome with a fatality rate of up to 30%. No licensed vaccines or therapeutics are currently available for humans. Here, we develop seven monoclonal antibodies (mAbs) against SFTSV surface glycoprotein Gn.

Pathogenesis and virulence of Heartland virus.

Heartland virus (HRTV), an emerging tick-borne pathogenic bunyavirus, has been a concern since 2012, with an increasing incidence, expanding geographical distribution, and high pathogenicity in the United States. Infection from HRTV results in fever, thrombocytopenia, and leucopenia in humans, and in some cases, symptoms can progress to severe outcomes, including haemorrhagic disease, multi-organ failure, and even death. Currently, no vaccines or antiviral drugs are available for treatment of the HRTV disease.

Host factor MxA restricts Dabie bandavirus infection by targeting the viral NP protein to inhibit NP-RdRp interaction and ribonucleoprotein activity.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high case mortality rates, which is caused by Dabie bandavirus (DBV), a novel pathogen also termed as SFTS virus (SFTSV). Currently, no specific therapeutic drugs or vaccines are available for SFTS. Myxovirus resistance protein A (MxA) has been shown to inhibit multiple viral pathogens; however, the role of MxA in DBV infection is unknown.

Interactome profiling of Crimean-Congo hemorrhagic fever virus glycoproteins.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a biosafety level-4 pathogen requiring urgent research and development efforts. The glycoproteins of CCHFV, Gn and Gc, are considered to play multiple roles in the viral life cycle by interactions with host cells; however, these interactions remain largely unclear to date. Here, we analyzed the cellular interactomes of CCHFV glycoproteins and identified 45 host proteins as high-confidence Gn/Gc interactors.

SARS-CoV-2 NSP13 interacts with host IRF3, blocking antiviral immune responses.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an unprecedented threat to human health since late 2019. Notably, the progression of the disease is associated with impaired antiviral interferon (IFN) responses. Although multiple viral proteins were identified as potential IFN antagonists, the underlying molecular mechanisms remain to be fully elucidated.

A New Cellular Interactome of SARS-CoV-2 Nucleocapsid Protein and Its Biological Implications.

There is still much to uncover regarding the molecular details of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. As the most abundant protein, coronavirus nucleocapsid (N) protein encapsidates viral RNAs, serving as the structural component of ribonucleoprotein and virion, and participates in transcription, replication, and host regulations. Virus-host interaction might give clues to better understand how the virus affects or is affected by its host during infection and identify promising therapeutic candidates.

SFTS bunyavirus NSs protein sequestrates mTOR into inclusion bodies and deregulates mTOR-ULK1 signaling, provoking pro-viral autophagy.

Autophagy is emerging as a critical player in host defense against diverse infections, in addition to its conserved function to maintain cellular homeostasis. Strikingly, some pathogens have evolved strategies to evade, subvert or exploit different steps of the autophagy pathway for their lifecycles. Here, we present a new viral mechanism of manipulating autophagy for its own benefit with severe fever with thrombocytopenia syndrome bunyavirus (SFTSV, an emerging high-pathogenic virus) as a model.

Transcriptome profiling highlights regulated biological processes and type III interferon antiviral responses upon Crimean-Congo hemorrhagic fever virus infection.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a biosafety level-4 (BSL-4) pathogen that causes Crimean-Congo hemorrhagic fever (CCHF) characterized by hemorrhagic manifestation, multiple organ failure and high mortality rate, posing great threat to public health. Despite the recently increasing research efforts on CCHFV, host cell responses associated with CCHFV infection remain to be further characterized. Here, to better understand the cellular response to CCHFV infection, we performed a transcriptomic analysis in human kidney HEK293 ​cells by high-throughput RNA sequencing (RNA-seq) technology.

Antitumor efficacy of CRISPR/Cas9-engineered ICP6 mutant herpes simplex viruses in a mouse xenograft model for lung adenocarcinoma.

Oncolytic viruses (OVs), including oncolytic herpes simplex viruses (oHSVs), are promising therapeutics against cancer. Here, we report two ICP6-mutated HSVs (type I) generated by CRISPR/Cas9, rHSV1/∆RR (with ICP6 ribonucleotide reductase [RR] domain deleted) and rHSV1/∆ICP6 (with a complete deletion of ICP6), exhibiting potent antitumor efficacy against lung adenocarcinoma. Both the mutants showed strong cytotoxicity in vitro, comparable with the control viruses expressing intact ICP6, but in relatively lower titers.

Animal Model of Severe Fever With Thrombocytopenia Syndrome Virus Infection.

Severe fever with thrombocytopenia syndrome (SFTS), an emerging life-threatening infectious disease caused by SFTS bunyavirus (SFTSV; genus , family , order ), has been a significant medical problem. Currently, there are no licensed vaccines or specific therapeutic agents available and the viral pathogenesis remains largely unclear. Developing appropriate animal models capable of recapitulating SFTSV infection in humans is crucial for both the study of the viral pathogenic processes and the development of treatment and prevention strategies.

Recent Advances in Bunyavirus Reverse Genetics Research: Systems Development, Applications, and Future Perspectives.

Bunyaviruses are members of the order, which is the largest group of RNA viruses, comprising 12 families, including a large group of emerging and re-emerging viruses. These viruses can infect a wide variety of species worldwide, such as arthropods, protozoans, plants, animals, and humans, and pose substantial threats to the public. In view of the fact that a better understanding of the life cycle of a highly pathogenic virus is often a precondition for developing vaccines and antivirals, it is urgent to develop powerful tools to unravel the molecular basis of the pathogenesis.

Non-structural Proteins of Severe Fever With Thrombocytopenia Syndrome Virus Suppress RNA Synthesis in a Transcriptionally Active cDNA-Derived Viral RNA Synthesis System.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the tick-borne SFTS bunyavirus (SFTSV) resulting in a high fatality rate up to 30%. SFTSV is a negative-strand RNA virus containing three single-stranded RNA genome segments designated as L, M, and S, which respectively, encode the RNA-dependent RNA polymerase (RdRp), glycoproteins Gn and Gc, and nucleoprotein (N) and non-structural proteins (NSs). NSs can form inclusion bodies (IBs) in infected and transfected cells.

Immune evasion of SARS-CoV-2 from interferon antiviral system.

The on-going pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to unprecedented medical and socioeconomic crises. Although the viral pathogenesis remains elusive, deficiency of effective antiviral interferon (IFN) responses upon SARS-CoV-2 infection has been recognized as a hallmark of COVID-19 contributing to the disease pathology and progress. Recently, multiple proteins encoded by SARS-CoV-2 have been shown to act as potential IFN antagonists with diverse possible mechanisms.

Host restriction of emerging high-pathogenic bunyaviruses via MOV10 by targeting viral nucleoprotein and blocking ribonucleoprotein assembly.

Bunyavirus ribonucleoprotein (RNP) that is assembled by polymerized nucleoproteins (N) coating a viral RNA and associating with a viral polymerase can be both the RNA synthesis machinery and the structural core of virions. Bunyaviral N and RNP thus could be assailable targets for host antiviral defense; however, it remains unclear which and how host factors target N/RNP to restrict bunyaviral infection. By mass spectrometry and protein-interaction analyses, we here show that host protein MOV10 targets the N proteins encoded by a group of emerging high-pathogenic representatives of bunyaviruses including severe fever with thrombocytopenia syndrome virus (SFTSV), one of the most dangerous pathogens listed by World Health Organization, in RNA-independent manner.

SARS-CoV-2 nsp1: Bioinformatics, Potential Structural and Functional Features, and Implications for Drug/Vaccine Designs.

The emerging coronavirus disease (COVID-19) caused by SARS-CoV-2 has led to social and economic disruption globally. It is urgently needed to understand the structure and function of the viral proteins for understanding of the viral infection and pathogenesis and development of prophylaxis and treatment strategies. Coronavirus non-structural protein 1 (nsp1) is a notable virulence factor with versatile roles in virus-host interactions and exhibits unique characteristics on sequence, structure, and function mode.

A RIG-I-like receptor directs antiviral responses to a bunyavirus and is antagonized by virus-induced blockade of TRIM25-mediated ubiquitination.

The RIG-I-like receptors (RLRs) retinoic acid-inducible gene I protein (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) are cytosolic pattern recognition receptors that recognize specific viral RNA products and initiate antiviral innate immunity. Severe fever with thrombocytopenia syndrome virus (SFTSV) is a highly pathogenic member of the RIG-I, but not MDA5, has been suggested to sense some bunyavirus infections; however, the roles of RLRs in anti-SFTSV immune responses remain unclear. Here, we show that SFTSV infection induces an antiviral response accompanied by significant induction of antiviral and inflammatory cytokines and that RIG-I plays a main role in this induction by recognizing viral 5'-triphosphorylated RNAs and by signaling via the adaptor mitochondrial antiviral signaling protein.

Combinatorial Minigenome Systems for Emerging Banyangviruses Reveal Viral Reassortment Potential and Importance of a Protruding Nucleotide in Genome "Panhandle" for Promoter Activity and Reassortment.

is a new genus ( family, order) that comprises a group of emerging tick-borne viruses with severe fever with thrombocytopenia syndrome virus (SFTSV) and Heartland virus (HRTV) as virulent representatives. As segmented RNA viruses, bunyaviruses may have genome reassortment potential, increasing the concern about new life-threatening bunyavirus emergence. Using a series of combinatory minigenome reporter assays based on transfection and superinfection, we showed that replication machinery proteins of designated banyangviruses can recognize genomic untranslated regions (UTRs) of other banyangviruses and assemble heterogenous minigenomes into functional ribonucleoproteins (RNPs).

The Nonstructural Protein of Guertu Virus Disrupts Host Defenses by Blocking Antiviral Interferon Induction and Action.

Guertu virus (GTV) is a potentially highly pathogenic bunyavirus newly isolated in China, which is genetically related to the severe fever with thrombocytopenia syndrome virus (SFTSV) and Heartland virus (HRTV), two other emerging life-threatening bunyaviruses. Previous studies suggested that SFTSV and HRTV antagonize the interferon (IFN) system by targeting antiviral signaling proteins in different ways. However, whether and how GTV counteracts the host innate immunity are unclear.

Interferon-γ-Directed Inhibition of a Novel High-Pathogenic Phlebovirus and Viral Antagonism of the Antiviral Signaling by Targeting STAT1.

Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening infectious disease caused by a novel phlebovirus, SFTS virus (SFTSV). Currently, there is no vaccine or antiviral available and the viral pathogenesis remains largely unknown. In this study, we demonstrated that SFTSV infection results in substantial production of serum interferon-γ (IFN-γ) in patients and then that IFN-γ in turn exhibits a robust anti-SFTSV activity in cultured cells, indicating the potential role of IFN-γ in anti-SFTSV immune responses.

The Major Hurdle for Effective Baculovirus Transduction into Mammalian Cells Is Passing Early Endosomes.

Baculoviruses, although they infect insects in nature, can transduce a wide variety of mammalian cells and are therefore promising gene therapy vectors. However, baculovirus transduction into many mammalian cells is very inefficient, and the limiting stages and factors remain unknown. An important finding is that a short-duration trigger with low pH can significantly enhance virus transduction efficiency, but the mechanism is poorly understood.

Heartland virus antagonizes type I and III interferon antiviral signaling by inhibiting phosphorylation and nuclear translocation of STAT2 and STAT1.

Heartland virus (HRTV) is a pathogenic phlebovirus recently identified in the United States and related to severe fever with thrombocytopenia syndrome virus (SFTSV) emerging in Asia. We previously reported that SFTSV disrupts host antiviral responses directed by interferons (IFNs) and their downstream regulators, signal transducer and activator of transcription (STAT) proteins. However, whether HRTV infection antagonizes the IFN-STAT signaling axis remains unclear.

Heartland virus NSs protein disrupts host defenses by blocking the TBK1 kinase-IRF3 transcription factor interaction and signaling required for interferon induction.

Heartland virus (HRTV) is a pathogenic phlebovirus related to the severe fever with thrombocytopenia syndrome virus (SFTSV), another phlebovirus causing life-threatening disease in humans. Previous findings have suggested that SFTSV can antagonize the host interferon (IFN) system via viral nonstructural protein (NSs)-mediated sequestration of antiviral signaling proteins into NSs-induced inclusion bodies. However, whether and how HRTV counteracts the host innate immunity is unknown.