A Report on the Death of Mixed Infection of HEV and HBV

Mixed infection with hepatitis E virus (HEV) in patients with chronic hepatitis B virus (HBV) infection is frequent. HEV mixed infection often leads to activation of hepatic pathological changes and worsens the inflammatory activity. However, it is not known clearly how these two types of virus influence each other in human body. Intensive investigation has revealed that HEV mixed infection inhibits HBV replication. We have just encountered a relative rare case. The patient who was a HBV carrier and was infected by HEV. Before he was infected by the HEV, the measurement of his HBV DNA fixed quantity examination on fluorescence was 3 copies/ml;his routine biochemistry was normal;and his anti HEV-IgM and anti-HEV-IgG appeared to be negative reaction. After he was infected by HEV, his routine biochemistry increased, and the measurement of his HBV DNA fixed quantity examination on fluorescence was 8.51 × 105 copies/ml. It indicated that the replication of HBV was activated after the patient infected HEV. Finally, he was dead. This case revealed that HEV mixed infection may activate the replication of HBV, not inhibit HBV replication, and demonstrated the needs for further studies about the mechanism of the interaction of the two viruses.

Newcastle disease virus suppresses antigen presentation via inhibiting IL-12 expression in dendritic cells

As a potential vectored vaccine,Newcastle disease virus(NDV)has been subject to various studies for vaccine development,while relatively little research has outlined the immunomodulatory effect of the virus in antigen presentation.To elucidate the key inhibitory factor in regulating the interaction of infected dendritic cells(DCs)and T cells,DCs were pretreated with the NDV vaccine strain LaSota as an inhibitor and stimulated with lipopolysaccharide(LPS)for further detection by enzyme-linked immunosorbent assay(ELISA),flow cytometry,immunoblotting,and quantitative real-time polymerase chain reaction(qRT-PCR).The results revealed that NDV infection resulted in the inhibition of interleukin(IL)-12p40 in DCs through a p38 mitogen-activated protein kinase(MAPK)-dependent manner,thus inhibiting the synthesis of IL-12p70,leading to the reduction in T cell proliferation and the secretion of interferon-(IFN-),tumor necrosis factor-α(TNF-α),and IL-6 induced by DCs.Consequently,downregulated cytokines accelerated the infection and viral transmission from DCs to T cells.Furthermore,several other strains of NDV also exhibited inhibitory activity.The current study reveals that NDV can modulate the intensity of the innate-adaptive immune cell crosstalk critically toward viral invasion improvement,highlighting a novel mechanism of virus-induced immunosuppression and providing new perspectives on the improvement of NDV-vectored vaccine.

Tauroursodeoxycholic acid(TUDCA) inhibits influenza A viral infection by disrupting viral proton channel M2

Influenza is a persistent threat to human health and there is a continuing requirement for updating antiinfluenza strategies. Initiated by observations of different endoplasmic reticulum(ER) responses of host to seasonal H1N1 and highly pathogenic avian influenza(HPAI) A H5N1 infections, we identified an alternative antiviral role of tauroursodeoxycholic acid(TUDCA), a clinically available ER stress inhibitor, both in vitro and in vivo. Rather than modulating ER stress in host cells, TUDCA abolished the proton conductivity of viral M2 by disrupting its oligomeric states, which induces inefficient viral infection. We also showed that M2 penetrated cells, whose intracellular uptake depended on its proton channel activity,an effect observed in both TUDCA and M2 inhibitor amantadine. The identification and application of TUDCA as an inhibitor of M2 proton channel will expand our understanding of IAV biology and complement current anti-IAV arsenals.

Molecular and serological surveillance of Getah virus in the Xinjiang Uygur Autonomous Region,China,2017–2020

The Getah virus(GETV),a mosquito-borne RNA virus,is widely distributed in Oceania and Asia.GETV is not the only pathogenic to horses,pigs,cattle,foxes and boars,but it can also cause fever in humans.Since its first reported case in Chinese mainland in 2017,the number of GETV-affected provinces has increased to seventeen till now.Therefore,we performed an epidemiologic investigation of GETV in the Xinjiang region,located in northwestern China,during the period of 2017-2020.ELISA was used to analyze 3299 serum samples collected from thoroughbred horse,local horse,sheep,goat,cattle,and pigs,with thoroughbred horse(74.8%),local horse(67.3%),goat(11.7%),sheep(10.0%),cattle(25.1%)and pigs(51.1%)being positive for anti-GETV antibodies.Interestingly,the neutralizing antibody titer in horses was much higher than in other species.Four samples from horses and pigs were positive for GETV according to RT-PCR.Furthermore,from the serum of a local horse,we isolated GETV which was designated as strain XJ-2019-07,and determined its complete genome sequence.From the phylogenetic relationships,it belongs to the Group III lineage.This is the first evidence of GETV associated to domestic animals in Xinjiang.Overall,GETV is prevalent in Xinjiang and probably has been for several years.Since no vaccine against GETV is available in China,detection and monitoring strategies should be improved in horses and pigs,especially imported and farmed,in order to prevent economic losses.

Chimeric Newcastle Disease Virus-like Particles Containing DC-Binding Peptide-Fused Haemagglutinin Protect Chickens from Virulent Newcastle Disease Virus and H9N2 Avian Influenza Virus Challenge

Newcastle disease virus(NDV)and H9N2 subtype Avian influenza virus(AIV)are two notorious avian respiratory pathogens that cause great losses in the poultry industry.Current inactivated commercial vaccines against NDV and AIV have the disadvantages of inadequate mucosal responses,while an attenuated live vaccine bears the risk of mutation.Dendritic cell(DC)targeting strategies are attractive for their potent mucosal and adaptive immune-stimulating ability against respiratory pathogens.In this study,DC-binding peptide(DCpep)-decorated chimeric virus-like particles(cVLPs),containing NDV haemagglutinin–neuraminidase(HN)and AIV haemagglutinin(HA),were developed as a DC-targeting mucosal vaccine candidate.DCpep-decorated cVLPs activated DCs in vitro,and induced potent immune stimulation in chickens,with enhanced secretory immunoglobulin A(sIgA)secretion and splenic T cell differentiation.40μg cVLPs can provide full protection against the challenge with homologous,heterologous NDV strains,and AIV H9N2.In addition,DCpep-decorated cVLPs could induce a better immune response when administered intranasally than intramuscularly,as indicated by robust s IgA secretion and a reduced virus shedding period.Taken together,this chimericVLPs are a promising vaccine candidate to control NDV and AIV H9N2 and a useful platform bearing multivalent antigens.

Orally administered BZL-s RNA-20 oligonucleotide targeting TLR4 effectively ameliorates acute lung injury in mice

The global COVID-19 pandemic emerged at the end of December 2019.Acute respiratory distress syndrome(ARDS)and acute lung injury(ALI)are common lethal outcomes of bacterial lipopolysaccharide(LPS),avian influenza virus,and SARS-Co V-2.Toll-like receptor 4(TLR4)is a key target in the pathological pathway of ARDS and ALI.Previous studies have reported that herbal small RNAs(s RNAs)are a functional medical component.BZL-s RNA-20(Accession number:B59471456;Family ID:F2201.Q001979.B11)is a potent inhibitor of Toll-like receptor 4(TLR4)and pro-inflammatory cytokines.Furthermore,BZLs RNA-20 reduces intracellular levels of cytokines induced by lipoteichoic acid(LTA)and polyinosinic-polycytidylic acid(poly(I:C)).We found that BZL-s RNA-20 rescued the viability of cells infected with avian influenza H5N1,SARS-Co V-2,and several of its variants of concern(VOCs).Acute lung injury induced by LPS and SARS-Co V-2 in mice was significantly ameliorated by the oral medical decoctosome mimic(bencaosome;sphinganine(d22:0)+BZL-s RNA-20).Our findings suggest that BZLs RNA-20 could be a pan-anti-ARDS/ALI drug.

The associated killing of hepatoma cells using multilayer drug-loaded mats combined with fast neutron therapy

Chemotherapeutic and radiation therapy have emerged as two most important treatment strategies to treat cancer in clinical practice;however,to improve anticancer efficacy,combination chemotherapy still remains challenge.Dichloroacetate(DCA)could produce significant cytotoxic effects in certain tumor cells through its distinct mechanism.Radiation therapy with fast neutrons(FNT)has high relative biolgical effectiveness compared to other radiotherapeutics.Herein,we reported the combination chemotherapy with FNT for effective tumor growth inhibition with the assistance of a multilayered nanofiber loading DCA and DCA derivatives.We first synthesized a biodegradable polylysine to condense DCA with negative charge,or to conjugate DCA by condensing synthesis,to obtain Ion-DCA and Co-DCA,respectively.DCA,Ion-DCA or Co-DCA was then loaded into fibers to form multilayer drug-loaded mats.Upon adhesion on the surface of subcutaneous and orthotopic liver tumors,the multilayer drug-loaded mats realized a controllable release of DCA,which reversed the Warburg effect and inhibited cancer cell proliferation.Meantime,irradiation of fast neutrons could seriously damage DNA structure.Combination of the controllable release of DCA and FNT resulted in synergistic cell apoptosis in vitro,and the tumor inhibition in vivo.This study thus provides a new approach to integrate chemotherapy and FNT with the assistance of biocompatible nanofiber for synergistic tumor therapy.

Rapidly developable therapeutic-grade equine immunoglobulin against the SARS-CoV-2 infection in rhesus macaques

Dear Editor,The unprecedented COVID-19 pandemic caused by SARS-CoV-2 remains ongoing,but there is a lack of fully effective treatments.Convalescent plasma-derived hyperimmune globulins have been a safe and effective treatment but restricted by the difficulties in obtaining sufficient plasma with high antibody titers from a large number of recovered patients.Heterologous antibodies,particularly equine antibodies,have been widely used for decades as the therapeutics against some viral infections or as antivenoms.1 Equine antibodies could be rapidly developed and manufactured into therapeutic antibodies in large quantities under WHO standardized guidelines.Here we explored the development of equine antibody-derived F(ab′)2 as an option to treat COVID-19 by targeting the receptor-binding domain(RBD)of the viral spike protein that is essential for the viral entry into the host cells.2 We observed excellent neutralization titers of the F(ab′)2 in vitro and high potency against SARS-CoV-2 infection in the nonhuman primate rhesus macaques.

A micro-sized vaccine based on recombinant Lactiplantibacillus plantarum fights against SARS-CoV-2 infection via intranasal immunization

COVID-19 has globally spread to burden the medical system.Even with a massive vaccination,a mucosal vaccine offering more comprehensive and convenient protection is imminent.Here,a micro-sized vaccine based on recombinant Lactiplantibacillus plantarum(rLP)displaying spike or receptor-binding domain(RBD)was characterized as microparticles,and its safety and protective effects against SARS-CoV-2 were evaluated.We found a 66.7%mortality reduction and 100%protection with rLP against SARS-CoV-2 in a mouse model.The histological analysis showed decreased hemorrhage symptoms and increased leukocyte infiltration in the lung.Especially,rLP:RBD significantly decreased pulmonary viral loads.For the first time,our study provides a L.plantarum-vectored vaccine to prevent COVID-19 progress and transmission via intranasal vaccination.

The E3 ligase RNF5 restricts SARS-CoV-2 replication by targeting its envelope protein for degradation

The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has caused a severe global health crisis;its structural protein envelope(E)is critical for viral entry,budding,production,and induction of pathology which makes it a potential target for therapeutics against COVID-19.Here,we find that the E3 ligase RNF5 interacts with and catalyzes ubiquitination of E on the 63rd lysine,leading to its degradation by the ubiquitin-proteasome system(UPS).Importantly,RNF5-induced degradation of E inhibits SARS-CoV-2 replication and the RNF5 pharmacological activator Analog-1 alleviates disease development in a mouse infection model.We also found that RNF5 is distinctively expressed in different age groups and in patients displaying different disease severity,which may be exploited as a prognostic marker for COVID-19.Furthermore,RNF5 recognized the E protein from various SARS-CoV-2 strains and SARS-CoV,suggesting that targeting RNF5 is a broad-spectrum antiviral strategy.Our findings provide novel insights into the role of UPS in antagonizing SARS-CoV-2 replication,which opens new avenues for therapeutic intervention to combat the COVID-19 pandemic.

Taurolidine improved protection against highly pathogenetic avian influenza H5N1 virus lethal-infection in mouse model by regulating the NF-κB signaling pathway

Taurolidine(TRD),a derivative of taurine,has anti-bacterial and anti-tumor effects by chemically reacting with cell-walls,endotoxins and exotoxins to inhibit the adhesion of microorganisms.However,its application in antiviral therapy is seldom reported.Here,we reported that TRD significantly inhibited the replication of influenza virus H5N1 in MDCK cells with the half-maximal inhibitory concentration(EC_(50))of 34.45μg/mL.Furthermore,the drug inhibited the amplification of the cytokine storm effect and improved the survival rate of mice lethal challenged with H5N1(protection rate was 86%).Moreover,TRD attenuated virus-induced lung damage and reduced virus titers in mice lungs.Administration of TRD reduced the number of neutrophils and increased the number of lymphocytes in the blood of H5N1 virus-infected mice.Importantly,the drug regulated the NF-κB signaling pathway by inhibiting the separation of NF-κB and IκBa,thereby reducing the expression of inflammatory factors.In conclusion,our findings suggested that TRD could act as a potential anti-influenza drug candidate in further clinical studies.

Transmembrane domain of IFITM3 is responsible for its interaction with influenza virus HA_(2) subunit

Interferon-inducible transmembrane protein 3(IFITM3)inhibits influenza virus infection by blocking viral membrane fusion,but the exact mechanism remains elusive.Here,we investigated the function and key region of IFITM3 in blocking influenza virus entry mediated by hemagglutinin(HA).The restriction of IFITM3 on HAmediated viral entry was confirmed by pseudovirus harboring HA protein from H5 and H7 influenza viruses.Subcellular co-localization and immunocoprecipitation analyses revealed that IFITM3 partially co-located with the full-length HA protein and could directly interact with HA_(2) subunit but not HA_(1) subunit of H5 and H7 virus.Truncated analyses showed that the transmembrane domain of the IFITM3 and HA_(2) subunit might play an important role in their interaction.Finally,this interaction of IFITM3 was also verified with HA_(2) subunits from other subtypes of influenza A virus and influenza B virus.Overall,our data demonstrate for the first time a direct interaction between IFITM3 and influenza HA protein via the transmembrane domain,providing a new perspective for further exploring the biological significance of IFITM3 restriction on influenza virus infection or HA-mediated antagonism or escape.

Avian influenza viruses suppress innate immunity by inducingtrans-transcriptional readthrough via SSU72

Innate immunity plays critical antiviral roles. The highly virulent avian influenza viruses (AIVs) H5N1, H7N9, and H5N6 can betterescape host innate immune responses than the less virulent seasonal H1N1 virus. Here, we report a mechanism by whichtranscriptional readthrough (TRT)-mediated suppression of innate immunity occurs post AIV infection. By using cell lines, mouselungs, and patient PBMCs, we showed that genes on the complementary strand (“trans” genes) influenced by TRT were involved inthe disruption of host antiviral responses during AIV infection. The trans-TRT enhanced viral lethality, and TRT abolishmentincreased cell viability and STAT1/2 expression. The viral NS1 protein directly bound to SSU72, and degradation of SSU72 inducedTRT. SSU72 overexpression reduced TRT and alleviated mouse lung injury. Our results suggest that AIVs infection induce TRT byreducing SSU72 expression, thereby impairing host immune responses, a molecular mechanism acting through the NS1-SSU72-trans-TRT-STAT1/2 axis. Thus, restoration of SSU72 expression might be a potential strategy for preventing AIV pandemics.

Correction To:The E3 ligase RNF5 restricts SARS-CoV-2 replication by targeting its envelope protein for degradation

Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-023-01335-5,published online 03 February 2023 In the process of collating the raw data,the authors noticed 7 inadvertent mistakes occurred in Figs.3a,3b,3e,5d,6b,6d and 6e that need to be corrected after online publication of the article.1 The correct data are provided as follows.The key findings of the article are not affected by these corrections.The original article has been corrected.

Corrigendum to"Tauroursodeoxycholic acid(TUDCA)inhibits influenza A viral infection by disrupting viral proton channel M2"[Sci.Bull.,64(3)(2019)180-188]

Following the published article[1].the authors noticed an error duplication of image of DAPI in Fig.2c"AF"and"No pretreated and without TUDCA".The correct DAPI image was in the merged image of"No pretreated and without TUDCA"of the published article.Therefore,the corrected Fig.2c should be as follows:The online version of the original artice can be found at https://doi.org/10.101/j.scib.2018.08.0131.