Snail-borne parasitic diseases:an update on global epidemiological distribution,transmission interruption and control methods

Background:Snail-borne parasitic diseases,such as angiostrongyliasis,clonorchiasis,fascioliasis,fasciolopsiasis,opisthorchiasis,paragonimiasis and schistosomiasis,pose risks to human health and cause major socioeconomic problems in many tropical and sub-tropical countries.In this review we summarize the core roles of snails in the life cycles of the parasites they host,their clinical manifestations and disease distributions,as well as snail control methods.Main body:Snails have four roles in the life cycles of the parasites they host:as an intermediate host infected by the first-stage larvae,as the only intermediate host infected by miracidia,as the first intermediate host that ingests the parasite eggs are ingested,and as the first intermediate host penetrated by miracidia with or without the second intermediate host being an aquatic animal.Snail-borne parasitic diseases target many organs,such as the lungs,liver,biliary tract,intestines,brain and kidneys,leading to overactive immune responses,cancers,organ failure,infertility and even death.Developing countries in Africa,Asia and Latin America have the highest incidences of these diseases,while some endemic parasites have developed into worldwide epidemics through the global spread of snails.Physical,chemical and biological methods have been introduced to control the host snail populations to prevent disease.Conclusions:In this review,we summarize the roles of snails in the life cycles of the parasites they host,the worldwide distribution of parasite-transmitting snails,the epidemiology and pathogenesis of snail-transmitted parasitic diseases,and the existing snail control measures,which will contribute to further understanding the snail-parasite relationship and new strategies for controlling snail-borne parasitic diseases.

Biological characteristics, biosafety prevention and control strategies for the 2022 multi-country outbreak of monkeypox

Monkeypox is a zoonotic disease caused by the monkeypox virus(MPXV),which is a potential biological warfare agent of bioterrorism and poses the greatest threat to the world’s public biosafety and health after variola virus(VARV).While the coronavirus disease 2019(COVID-19)pandemic has not ended yet,monkeypox is spreading menacingly.The first case of monkeypox in a nonendemic country was confirmed on May 6^(th),2022,while the first imported case from Asia was found on June 21^(st).There were more than 16 thousand reported cases as of July 23^(rd),the day the World Health Organization(WHO)declared the global monkeypox outbreak a public health emergency of international concern(PHEIC)at the same level as smallpox and COVID-19;while there were more than 53 thousand cases as of September 1^(st).Therefore,we will propose relevant biosafety prevention and control strategies after analyzing the etiology of the 2022 multi-country monkeypox outbreak from the biological feature,transmissibility,epidemic,and variability of MPXV.

Toll-like receptors in innate immunity and infectious diseases

The protective ability of host defense system is largely dependent on germ-line encoded pattern-recogni-tion receptors(PRRs).These PRRs respond to a variety of exogenous pathogens or endogenous danger signals,by recognizing some highly conserved structures such as pathogen-associated molecular patterns(PAMPs)and danger/damage associated molecular patterns(DAMPs).The most studied PRRs are Toll-like receptors(TLRs).Activation of TLRs triggers production of inflammatory cytokines and type I interferons(IFNs)via myeloid differentiation primary response gene 88(MyD88)-depen-dent or-independent signaling respectively,thereby modulating innate and adaptive immunity,as well as inflammatory responses.This review introduces the classification,structure,and specific ligands of TLRs,and focuses on their signal pathways and biological activities,as well as clinical relevance.These studies of TLRs in the innate immune system have implications for the prevention and treatment of a variety of infectious diseases,including tuberculosis(TB),microbial keratitis,and hepatitis B and C.

Dopamine Inhibits the Expression of Hepatitis B Virus Surface and e Antigens by Activating the JAK/STAT Pathway and Upregulating Interferon-stimulated Gene 15 Expression

Background and Aims:Hepatitis B virus(HBV)infection is a major risk factor for cirrhosis and liver cancer,and its treatment continues to be difficult.We previously demonstrated that a dopamine analog inhibited the packaging of pregenomic RNA into capsids.The present study aimed to determine the effect of dopamine on the expressions of hepatitis B virus surface and e antigens(HBsAg and HBeAg,respectively)and to elucidate the underlying mechanism.Methods:We used dopamine-treated HBVinfected HepG2.2.15 and NTCP-G2 cells to monitor HBsAg and HBeAg expression levels.We analyzed interferon-stimulated gene 15(ISG15)expression in dopamine-treated cells.We knocked down ISG15 and then monitored HBsAg and HBeAg expression levels.We analyzed the expression of Janus kinase(JAK)/signal transducer and activator of transcription(STAT)pathway factors in dopamine-treated cells.We used dopamine hydrochloride-treated adeno-associated virus/HBV-infected mouse model to evaluate HBV DNA,HBsAg,and HBeAg expression.HBV virus was collected from HepAD38.7 cell culture medium.Results:Dopamine inhibited HBsAg and HBeAg expression and upregulated ISG15 expression in HepG2.2.15 and HepG2-NTCP cell lines.ISG15 knockdown increased HBsAg and HBeAg expression in HepG2.2.15 cells.Dopamine-treated cells activated the JAK/STAT pathway,which upregulated ISG15 expression.In the adeno-associated virus-HBV murine infection model,dopamine downregulated HBsAg and HBeAg expression and activated the JAK-STAT/ISG15 axis.Conclusions:Dopamine inhibits the expression of HBsAg and HBeAg by activating the JAK/STAT pathway and upregulating ISG15 expression.

Fight or flee,a vital choice for Clostridioides difficile

Clostridioides difficile is a leading cause of healthcare-associated infections,causing billions of economic losses every year.Its symptoms range from mild diarrhea to life-threatening damage to the colon.Transmission and recurrence of c.difficile infection(CDl)are mediated by the metabolically dormant spores,while the virulence of C.difficile is mainly due to the two large clostridial toxins,TcdA and TcdB.Producing toxins or forming spores are two different strategies for C.difficile to cope with harsh environmental conditions.It is of great significance to understand the molecular mechanisms for C.difficile to skew to either of the cellular processes.Here,we summarize the current understanding of the regulation and connections between toxin production and sporulation in C.difficile and further discuss the potential solutions for yet-to-be-answered questions.

Metagenomics analysis identifies oral Streptococcus as potential biomarkers for nasopharyngeal carcinoma

Nasopharyngeal carcinoma(NPC)is a malignancy originating from the nasopharyngeal epithelial cells.Although some studies have identified potential biomarkers for early diagnosis of NPC based on metabolomics data(Chen et al.,2023;Zhou et al.,2023)and Epstein-Barr virus subtypes(Xu et al.,2019),their effectiveness and applicability need further investigation,particularly when consideringthe roles of oral microbiota.

Acceptance and Factors Associated With Participation in Functional Cure–Related Trials Among People Living With HIV: A Cross-sectional Study in Southern China

HIV remains a global health challenge,and research efforts directed towards a functional cure require people living with HIV(PLHIV)in-volvement in clinical trials.Our study assessed willingness to participate in HIV functional cure–related clinical trials and associated factors among PLHIV in Guangzhou,China,using a questionnaire survey approach.We analyzed responses from 718 questionnaires,finding that 71.2%were willing to participate in Phase Ⅲtrials,while 51.7%were willing to participate in Phase I trials and 42.9%expressed acceptability for analytic treatment interruption.Multivariate logistic regression demonstrated that male PLHIV,those with awareness of functional cure,and PLHIV,who had been on antiretroviral therapy(ART)for less than 1 year,were more willing to partic-ipate in Phase Ⅲtrials.Those with a body mass index greater than 24,and those without resistance to ART drug were more willing to participate in Phase I trials.The major motivations for participation in Phase Ⅲtrials were access to cutting-edge treatments(62.6%)and supporting research(55.3%).Safety was the main concern contributing to hesitancy.Our study revealed a high willingness to participate in HIV functional cure–related trials among PLHIV in Guangzhou,China,and willingness varied across different trial phases and was influenced by multiple factors.This study provides valuable references for future clinical trial recruitment strategies and public health policy formulation.

Reduction in Intrahepatic cccDNA and Integration of HBV in Chronic Hepatitis B Patients with a Functional Cure

Background and Aims:Functional cure(FC)is characterized by the clearance of the hepatitis B surface antigen from the serum of patients with chronic hepatitis B(CHB).However,the level of intrahepatic covalently closed circular DNA(cccDNA)and hepatitis B virus(HBV)integration remains unclear.We conducted this study to determine them and reveal their value in the treatment of CHB.Methods:There were two sessions to elucidate the changes in intrahepatic cccDNA and HBV integration after antiviral therapy.In the first session,116 patients were enrolled and divided into FC,non-functional cure(NFC),and CHB groups,including 48 patients with functionally cured CHB,27 with CHB without functional cure after antiviral treatment,and 41 with treatment-naïve CHB.Patients were tested for both intrahepatic cccDNA and other viral markers.All patients in the FC group were followed up for at least 24 weeks to observe relapse.In the second session,another ten patients were included for in-depth whole-genome sequencing to analyze HBV integration.Results:Thirteen patients in the FC group were negative for intrahepatic cccDNA.Intrahepatic cccDNA was much higher in the CHB group compared with the FC group.Seven patients had HBsAg seroreversion,including two with virological relapse.Integration of HBV was detected in one(33.3%)functionally cured patients and in seven(100%)with CHB.28.0%of the HBV breakpoints were assigned in the 1,500 nt to 1,900 nt range of the HBV genome.Conclusions:After achieving an FC,the rate of intrahepatic cccDNA and HBV integration was significantly reduced in patients with CHB.For those patients who cleared intrahepatic cccDNA,the chances of developing virological relapse were even lower.

Double Plasma Molecular Adsorption System with Sequential Low-dose Plasma Exchange in Patients with Hepatitis B Virus-related Acute-on-chronic Liver Failure:A Prospective Study

Background and Aims:To investigate the safety and efficacy of double plasma molecular adsorption system(DPMAS)with sequential low-dose plasma exchange(LPE)in treating early hepatitis B virus-related acute-on-chronic liver failure(HBV-ACLF).Methods:Clinical data of patients with HBVACLF were prospectively collected,including patients in a DPMAS with sequential LPE(DPMAS+LPE)group and those in a standard medical treatment(SMT)group.The primary endpoint was death or liver transplantation(LT)at 12 weeks of follow-up.Propensity-score matching was performed to control the effects of confounding factors on prognosis between the two groups.Results:After 2 weeks,total bilirubin,alanine aminotransferase,blood urea nitrogen levels,and Chinese Group on the Study of Severe Hepatitis B score,were significantly lower in the DPMAS+LPE group than those in the SMT group(p<0.05).After 4 weeks,laboratory parameters of the two groups were similar.The cumulative survival rate of the DPMAS+LPE group was significantly higher than that of the SMT group at 4 weeks(97.9%vs.85.4%,p=0.027),but not at 12 weeks(85.4%vs.83.3%,p=0.687).Cytokine levels were significantly lower in 12-week survival group than in the death-or-LT group(p<0.05).Functional enrichment analysis showed that downregulated cytokines were mainly involved in positive regulation of proliferation and activation of lymphocytes and monocytes,regulation of immune effect response,regulation of endotoxin response,and glial cell proliferation.Conclusion:DPMAS+LPE significantly improved the 4-week cumulative survival rate,and ameliorated the inflammatory response in patients.DPMAS+LPE may be a promising modality for patients with early HBV-ACLF.

Predictive value of Th17 and Treg cells at baseline for HBsAg loss in chronic hepatitis B patients with low HBsAg quantification treated with pegylated interferon and nucleos(t)ide analogue

Background and aims:The primary goal of chronic hepatitis B(CHB)treatment is to reduce hepatitis B surface antigen(HBsAg).T helper 17(Th17)and regulatory T(Treg)cells are essential for the development of CHB.However,how Th17 and Treg cells contribute to HBsAg loss is still unknown.Therefore,this study aimed to search for the predictive value of Th17 and Treg cells for HBsAg loss in CHB patients with low HBsAg quantification.Methods:The study included 99 hepatitis B e antigen(HBeAg)-negative CHB patients who had completed a year of nucleos(t)ide analogue(NA)monotherapy and had received both NA and pegylated interferon(PEG-IFN)treatment for less than 96 weeks(96 wk).In the cured group,48 patients lost HBsAg within 48 wk,while 51 patients did not(uncured group).Blood samples and clinical data were collected for research.Results:During PEG-IFN and NA combination therapy,the proportion of Th17 cells in the cured group increased significantly,while the proportion of Treg cells in the uncured group increased.From 0 to 24 wk,the proportion of Th17 cells in the cured group was significantly higher than in the uncured group,while the opposite was true for Treg cells.Patients with alanine aminotransferase(ALT)2.5 upper limit of normal(ULN)at 12 wk had a higher proportion of Th17 cells and a lower proportion of Treg cells than those with ALT<2.5 ULN at 12 wk.Additionally,the proportion of Th17 cells is inversely associated with the level of HBsAg,whereas the level of Treg cells is positively related to HBsAg quantification.The clinical cure index,including age,HBsAg quantification,and the proportions of Th17 and Treg cells,had a higher area under the curve(0.957)for predicting HBsAg loss when compared to the proportions of Th17 and Treg cells and HBsAg quantification alone.Conclusions:Combined with quantification of HBsAg,the proportions of Th17 cells and Treg cells at baseline can be used as good predictors of HBsAg loss in patients with low HBsAg quantification treated with NA and PEG-IFN.

Safety and Immunogenicity of SARS-CoV-2 Vaccines in People Living With HIV:A Systematic Review and Meta-analysis of Real-World Studies

The safety and immunogenicity of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)vaccines in people living with HIV(PLWH)in real-world studies remain controversial.Thus,we conducted a comprehensive systematic review and meta-analysis to address this issue.Data search were conducted from PubMed,Web of Science and EMBASE.Adverse events following vaccination,the risk ratio(RR)of SARS-CoV-2–specific IgG seroconversion and the level of anti–SARS-CoV-2 neutralizing antibodies were compared between the PLWH group and a healthy control group.A total of 10,582 PLWH from 22 studies were included.In our analysis,the incidence of local or systemic adverse events after the first SARS-CoV-2 vaccine dose was not statistically different between PLWH and healthy controls.However,there was a statistical difference after the second dose(RR,0.83;95%CI,0.71–0.98).The seroconversion rate of SARS-CoV-2 IgGantibodies in PLWH was significantly lower than that in the healthy control group(RR,0.94;95%CI,0.89–0.98;I2=80%,P<0.01).The anti–SARS-CoV-2 neutralizing antibody titers in PLWH after full immunization were also significantly lower than those in the healthy control group(RR,0.91;95%CI,0.85–0.98;I2=81%,P<0.01).The safety and tolerance of COVID-19 vaccines in PLWHare acceptable.However,their immunogenicitymay be impaired to a certain extent,characterized by a lower IgGseroconversion rate and neutralizing antibody titers compared with healthy individuals.These findings should provide guidance for optimizing future COVID-19 vaccination strategies among PLWH.

Pure Red Cell Aplasia Caused by Parvovirus B19 in Patients with Human Immunodeficiency Virus Infection: A Series of Four Cases

Parvovirus B19(B19V)infection can cause pure red cell aplasia(PRCA)in patients with human immunodeficiency virus(HIV)infection.Intravenous immunoglobulin(IVIG)is a preferred treatment option.From July 2019 to March 2022,four patients with HIV infection were admitted to Guangzhou Eighth People’s Hospital with dizziness and fatigue and were diagnosed with PRCA.Blood investigations revealed severe anemia and the B19V genome.Therefore,the four patients were diagnosed with B19V-induced PRCA.All four patients received red blood cell transfusion in the setting of antiretroviral therapy,and two of the four patients received intravenous immunoglobulin(IVIG).After 3-7 months of treatment,all four patients recovered,although two did not receive IVIG.This suggests that IVIG is not always necessary for the treatment of PRCA in patients with HIV infection and that effective antiretroviral therapy and immunological reconstitution play an important role in the eradication of parvovirus.

B cell engineering in vivo:Accelerating induction of broadly neutralizing antibodies against HIV-1 infection

In a recent study published in Nature Biotechnology,1 Nahmad and colleagues reported in vivo B-cell engineering to generate broadly neutralizing antibodies(bnAbs)against human immunodeficiency virus type 1(HIV-1)in mice.This proof-of-concept study suggests the possibility of in vivo B-cell engineering as a novel preventive or therapeutic approach against HIV-1 infection.

First clinical study of germline-targeting strategy: One step closer to a successful bnAb-based HIV vaccine

The epidemic of human immunodeficiency virus type 1(HIV-1)remains amajor threat to global public health,with approximately 38 million people living with HIV-1 worldwide.However,a prophylactic vaccine against HIV-1 is not available yet.In a recent study,1 Leggat and colleagues reported the first-in-human test of a germline-targeting HIV-1 vaccine candidate,eOD-GT860-mer adjuvanted with AS01B.Encouragingly,this strategy effectively activated the B cell precursors(germlines)of VRC01-class broadly neutralizing antibodies(bnAbs)in 97%(35 of 36)of vaccine recipients.

Recent advances in the identification of the host factors involved in dengue virus replication

Dengue virus(DENV) belongs to the genus Flavivirus of the family Flaviviridae and it is primarily transmitted via Aedes aegypti and Aedes albopictus mosquitoes. The life cycle of DENV includes attachment, endocytosis, protein translation, RNA synthesis, assembly, egress, and maturation.Recent researches have indicated that a variety of host factors, including cellular proteins and micro RNAs, positively or negatively regulate the DENV replication process. This review summarizes the latest findings(from 2014 to 2016) in the identification of the host factors involved in the DENV life cycle and Dengue infection.

Risk assessment and genomic characterization of Zika virus in China and its surrounding areas

Background:Zika virus (ZIKV) has emerged as a global pathogen causing significant public health concerns.China has reported several imported cases where ZIKV were carried by travelers who frequently travel between China and ZIKV-endemic regions.To fully characterize the ZIKV strains isolated from the cases reported in China and assess the risk of ZIKV transmission in China,comprehensive phylogenetic and genetic analyses were performed both on all ZIKV sequences of China and on a group of scientifically selected ZIKV sequences reported in some of the top interested destinations for Chinese travelers.Methods:ZIKV genomic sequences were retrieved from the National Center for Biotechnology Information database through stratified sampling.Recombination event detection,maximum likelihood (ML) phylogenetic analysis,molecular clock analysis,selection pressure analysis,and amino acid substitution analysis were used to reconstruct the epidemiology and molecular transmission of ZIKV.Results:The present study investigated 18 ZIKV sequences from China and 70 sequences from 16 selected countries.Recombination events rarely happens in all ZIKV Asian lineage.ZIKV genomes were generally undergone episodic positive selection (17 sites),and only one site was under pervasive positive selection.All ZIKV imported into China were Asian lineage and were assigned into two clusters:Venezuela-origin (cluster A) and Samoa-origin cluster (cluster B) with common ancestor from French Polynesia.The time of most recent common ancestors of Cluster A dated to approximately 2013/11 (95% highest posterior density [HPD] 2013/06,2014/ 03) and cluster B dated to 2014/08 (95% HPD 2014/02,2015/01).Cluster B is more variable than Cluster A in comparison with other clusters,but no varied site of biological significance was revealed.ZIKV strains in Southeast Asia countries are independent from strains in America epidemics.Conclusions:The genetic evolution of ZIKV is conservative.There are two independent introductions of ZIKV into China and China is in danger of autochthonous transmission of ZIKV because of high-risk surrounding areas.Southeast Asia areas have high risk of originating the next large-scale epidemic ZIKV strains.

Compare the epidemiological and clinical features of imported and local COVID-19 cases in Hainan, China

Background:Effective management of imported cases is an important part of epidemic prevention and control.Hainan Province,China reported 168 coronavirus disease 2019(COVID-19),including 112 imported cases on February 19,2020,but successfully contained the epidemic within 1 month.We described the epidemiological and clinical characteristics of COVID-19 in Hainan and compared these features between imported and local cases to provide information for other international epidemic areas.Methods:We included 91 patients(56 imported and 35 local cases)from two designated hospitals for COVID-19 in Haikou,China,from January 20 to February 19,2020.Data on the demographic,epidemiological,clinical and laboratory characteristics were extracted from medical records.Patients were followed until April 21,2020,and the levels of antibodies at the follow-ups were also analysed by the Wilcoxon matched-pairs signed ranks test.Results:Of the 91 patients,78(85.7%)patients were diagnosed within the first three weeks after the first case was identified(Day 1:Jan 22,2020),while the number of local cases started to increase during the third week No new cases occurred after Day 29.Fever and cough were two main clinical manifestations.In total,15(16.5%)patients were severe,14(15.4%)had complicated infections,nine(9.9%)were admitted to the intensive care unit,and three died.The median duration of viral shedding in feces was longer than that in nasopharyngeal swabs(19 days vs 16 days,P=0.007).Compared with local cases,imported cases were older and had a higher incidence of fever and concurrent infections.There was no difference in outcomes between the two groups.IgG was positive in 92.8%patients(77/83)in the follow-up at week 2 after discharge,while 88.4%patients(38/43)had a reduction in IgG levels in the follow-up at week 4 after discharge,and the median level was lower than that in the follow-up at week 2(10.95 S/Cut Off(S/CO)vs 15.02 S/CO,P<0.001).Conclusion:Imported cases were more severe than local cases but had similar prognoses.The level of IgG antibodies declined from week 6 to week 8 after onset.The short epidemic period in Hainan suggests that the epidemic could be quickly brought under control if proper timely measures were taken.

Rapid isolation and immune profiling of SARS-CoV-2 specific memory B cell in convalescent COVID-19 patients via LIBRA-seq

B cell response plays a critical role against SARS-CoV-2 infection.However,little is known about the diversity and frequency of the paired SARS-CoV-2 antigen-specific BCR repertoire after SARS-CoV-2 infection.Here,we performed single-cell RNA sequencing and VDJ sequencing using the memory and plasma B cells isolated from five convalescent COVID-19 patients,and analyzed the spectrum and transcriptional heterogeneity of antibody immune responses.Via linking BCR to antigen specificity through sequencing(LIBRA-seq),we identified a distinct activated memory B cell subgroup(CD11c^(high) CD95^(high))had a higher proportion of SARS-CoV-2 antigen-labeled cells compared with memory B cells.Our results revealed the diversity of paired BCR repertoire and the non-stochastic pairing of SARS-CoV-2 antigen-specific immunoglobulin heavy and light chains after SARS-CoV-2 infection.The public antibody clonotypes were shared by distinct convalescent individuals.Moreover,several antibodies isolated by LIBRA-seq showed high binding affinity against SARS-CoV-2 receptor-binding domain(RBD)or nucleoprotein(NP)via ELISA assay.Two RBD-reactive antibodies C14646P3S and C2767P3S isolated by LIBRA-seq exhibited high neutralizing activities against both pseudotyped and authentic SARS-CoV-2 viruses in vitro.Our study provides fundamental insights into B cell response following SARS-CoV-2 infection at the single-cell level.

Midline2 is overexpressed and a prognostic indicator in human breast cancer and promotes breast cancer cell proliferation in vitro and in vivo

Midline2 （MID2） is an ubiquitin-conjugating E2 enzyme linked to tumor progression and a novel interacting partner of breast cancer 1, early-onset 0BRCA1）. However, the role of MID2 in breast cancer remains unknown. This study investigated the expression, prognostic value, and role of MID2 in breast cancer. The expression of MID2 mRNA and protein was significantly upregulated in breast cancer tissue and established cell lines compared with that in normal breast epithelial cells and paired adjacent non-tumor tissue （P 〈 0.001）. Immunohistochemical analysis demonstrated that MID2 was overexpressed in 272 of 284 （95.8%） paraffin- embedded, archived breast cancer tissue. Moreover, MID2 expression increased with advanced clinical stage （P 〈 0.001）. High MID2 expression was significantly associated with advanced clinical stages and T, N, and M staging （all P 〈 0.05）. Univariate and multivariate analyses indicated that high MID2 expression was an independent prognostic factor for poor overall survival in the entire cohort （93.73 vs. 172.1 months; P 〈 0.001, log- rank test） and in subgroups with stages Tis ＋ Ⅰ ＋ Ⅱ and Ⅲ ＋ Ⅳ. Furthermore, 3-（4,5-dimethyl-2-thiazolyl）-2,5- diphenyl-2H-tetrazolium bromide colony formation, and anchorage-independent growth ability assays were conducted. Results showed that siRNA silencing of MID2 expression significantly reduced MCF-7 and MDA-MB- 231 cell proliferation in vitro and blocked the growth of MDA-MB-231 cell xenograft tumors in vivo （P 〈 0.05）. This study indicated that MID2 may be a novel prognostic marker and interventional target in breast cancer.

Rottlerin plays an antiviral role at early and late steps of Zika virus infection

Infection of Zika virus(ZIKV)may cause microcephaly and other neurological disorders,while no vaccines and drugs are available.Our study revealed that rottlerin confers a broad antiviral activity against several enveloped viruses,including ZIKV,vesicular stomatitis virus,and herpes simplex virus,but not against two naked viruses(enterovirus 71 and encephalomyocarditis virus).Rottlerin does not have a direct virucidal effect on the virions,and its antiviral effect is independent of its regulation on PKCδor ATP.Both pretreatment and post-treatment of rottlerin effectively reduce the viral replication of ZIKV.The pretreatment of rottlerin disturbs the endocytosis of enveloped viruses,while the post-treatment of rottlerin acts at a late stage through disturbing the maturation of ZIKV.Importantly,administration of rottlerin in neonatal mice significantly decreased the ZIKV replication in vivo,and alleviated the neurological symptoms caused by ZIKV.Our work suggests that rottlerin exerts an antiviral activity at two distinct steps of viral infection,and can be potentially developed as a prophylactic and therapeutic agent.