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1.
Viruses ; 11(11)2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31683550

RESUMO

Ebola virus (EBOV) is a highly lethal pathogen that has caused several outbreaks of severe hemorrhagic fever in humans since its emergence in 1976. The EBOV glycoprotein (GP1,2) is the sole viral envelope protein and a major component of immunogenicity; it is encoded by the GP gene along with two truncated versions: soluble GP (sGP) and small soluble GP (ssGP). sGP is, in fact, the primary product of the GP gene, and it is secreted in abundance during EBOV infection. Since sGP shares large portions of its sequence with GP1,2, it has been hypothesized that sGP may subvert the host immune response by inducing antibodies against sGP rather than GP1,2. Several reports have shown that sGP plays multiple roles that contribute to the complex pathogenesis of EBOV. In this review, we focus on sGP and discuss its possible roles with regards to the pathogenesis of EBOV and the development of specific antiviral drugs.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31610042

RESUMO

BACKGROUND: A missense variant (rs6967330) of the gene encoding cadherin-related family member 3 (CDHR3) was associated with recurrent severe exacerbations in pre-schoolers. However, there were limited data on its relationship with pre-school lung function and school-age asthma. This study replicated the association between polymorphic markers at the region of CDHR3 around rs6967330 and wheezing phenotypes in two independent cohorts of Chinese children. METHODS: Ten tagging SNPs located 10 kb around rs6967330 were selected by HaploView 5.0 based on 1000 Genomes database for Southern Han Chinese. Their associations with wheezing and lung function were examined in 1341 Chinese pre-school children, while those for asthma phenotypes were examined in an independent group of 2079 school-age children. Genotypic and haplotypic associations were analyzed by multivariate regression, and generalized multifactor dimensionality reduction was used to examine epistatic interactions for wheezing traits. RESULTS: The mean (SD) age of pre-school cohort was 4.7 (1.0) years. Rs6967330 was associated with current wheeze (odds ratio [OR] 1.63, 95% confidence interval [CI] 1.09-2.43) and its severity (OR 1.64, 95% CI 1.10-2.44) among pre-school children. This SNP was also associated with school-age asthma (OR 1.32, 95% CI 1.04-1.69). The minor allele of rs408223 was associated with lower FEV0.5 (ß = -2.411, P = .004) and FEV0.5 /FVC (ß = -1.292, P = .015). Lower spirometric indices were also associated with minor allele of rs140154310. GAC haplotype from rs4730125, rs6967330, and rs408223 was associated with pre-school current wheeze and school-age asthma. Epistatic interaction was found between unrelated CDHR3 SNPs for FEV0.5 among pre-schoolers. CONCLUSION: CDHR3 is a candidate gene for early-life wheezing, school-age asthma, and lung function in Chinese children.

5.
Biochem J ; 476(20): 2953-2963, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31657439

RESUMO

The formin FHOD1 acts as a nucleating, capping and bundling protein of actin filaments. In cells, release from the C-terminal diaphanous autoregulatory domain (DAD) of FHOD1 stimulates the protein into the active form. However, the cellular physiological relevance of active form FHOD1 and the phenotypic regulation by FHOD1 depletion are not completely understood. Here, we show that in contrast with the cytosolic diffused expression of auto-inhibited FHOD1, active FHOD1 by C-terminal truncation was recruited into all three types of actin stress fibers in human osteosarcoma cells. Notably, the recruited active FHOD1 was more incorporated with myosin II than α-actinin, and associated with both naïve and mature focal adhesions. Active FHOD1 displayed faster turnover than actin molecules on ventral stress fibers. Moreover, we witnessed the emergence of active FHOD1 from the cell periphery, which subsequently moved centripetally together with transverse arcs. Furthermore, FHOD1 knockdown resulted in defective maturation of actomyosin bundles and subsequently longer non-contractile dorsal stress fibers, whereas the turnover of both actin and myosin II were maintained normally. Importantly, the loss of FHOD1 led to slower actin centripetal flow, resulting in abnormal cell spreading and migration defects. Taken together, these results reveal a critical role of FHOD1 in temporal- and spatial- control of the morphology and dynamics of functional actin stress fibers during variable cell behavior.

6.
Viruses ; 11(10)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597372

RESUMO

Rift Valley fever virus (RVFV), which causes Rift Valley fever (RVF), is a mosquito-borne zoonotic pathogen that causes serious morbidity and mortality in livestock and humans. RVF is a World Health Organization (WHO) priority disease and, together with rabies, is a major health burden in Africa. Here, we present the development and characterization of an inactivated recombinant RVFV and rabies virus (RABV) vaccine candidate (rSRV9-eGn). Immunization with rSRV9-eGn stimulated the production of RVFV-specific IgG antibodies and induced humoral and cellular immunity in mice but did not induce the production of neutralizing antibodies. IgG1 and IgG2a were the main isotypes observed by IgG subtype detection, and IgG3 antibodies were not detected. The ratios of IgG1/IgG2a > 1 indicated a Type 2 humoral immune response. An effective vaccine is intended to establish a long-lived population of memory T cells, and mice generated memory cells among the proliferating T cell population after immunization with rSRV9-eGn, with effector memory T cells (TEM) as the major population. Due to the lack of prophylactic treatment experiments, it is impossible to predict whether this vaccine can protect animals from RVFV infection with only high titres of anti-RVFV IgG antibodies and no neutralizing antibodies induced, and thus, protection confirmation needs further verification. However, this RVFV vaccine designed with RABV as the vector provides ideas for the development of vaccines that prevent RVFV and RABV infections.

7.
BMC Vet Res ; 15(1): 316, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477101

RESUMO

BACKGROUND: Canine distemper (CD) is an acute infectious disease with high morbidity rates caused by a highly contagious pathogen (Canine Morbillivirus, also known as canine distemper virus, CDV). CDV can infect a broad range of carnivores resulting in complex clinical signs. Currently, there is no effective method to treat for CDV infections. Favipiravir (T-705), a pyrazine derivative, was shown to be an effective antiviral drug against RNA viruses, acting on RNA-dependent RNA polymerase (RdRp). However, whether the T-705 has antiviral effects following CDV infection is unclear. Here, we investigated the antiviral effect of T-705 against CDV-3 and CDV-11 strains in Vero and DH82 cell lines. RESULTS: Our data demonstrated that T-705 significantly inhibited the replication of CDV-3 and CDV-11 in both Vero and DH82 cells at different concentrations, ranging from 2.441 µg/ml to 1250 µg/ml. Additionally, T-705 exhibited efficacious antiviral effects when administered at different time points after virus infection. Cytotoxicity tests showed a slight decline in viability in Vero cells after T-705 treatment, and no apparent cytotoxicity was detected in T-705 treated DH82 cells. Comparison of anti-CDV polyclonal serum only inhibition of CDV in supernatant, T-705 directly inhibited viral replication in cells, and indirectly reduced the amount of virions in supernatant. The combination application of T-705 and anti-CDV polyclonal serum exhibited a rapid and robust inhibition against virions in supernatant and virus replication in cells. CONCLUSIONS: Our data strongly indicated that T-705 effectively inhibited viral replication following CDV infection in vitro, and could be a potential candidate for treatment for CD.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31381928

RESUMO

BACKGROUND: Childhood asthma prevalence is significantly greater in urban areas compared with rural/farm environments. Murine studies have shown that TNF-α-induced protein 3 (TNFAIP3; A20), an anti-inflammatory regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, mediates environmentally induced asthma protection. OBJECTIVE: We aimed to determine the role of TNFAIP3 for asthma development in childhood and the immunomodulatory effects of environmental factors. METHODS: In a representative selection of 250 of 2168 children from 2 prospective birth cohorts and 2 cross-sectional studies, we analyzed blood cells of healthy and asthmatic children from urban and rural/farm environments from Europe and China. PBMCs were stimulated ex vivo with dust from "asthma-protective" farms or LPS. NF-κB signaling-related gene and protein expression was assessed in PBMCs and multiplex gene expression assays (NanoString Technologies) in isolated dendritic cells of schoolchildren and in cord blood mononuclear cells from newborns. RESULTS: Anti-inflammatory TNFAIP3 gene and protein expression was consistently decreased, whereas proinflammatory Toll-like receptor 4 expression was increased in urban asthmatic patients (P < .05), reflecting their increased inflammatory status. Ex vivo farm dust or LPS stimulation restored TNFAIP3 expression to healthy levels in asthmatic patients and shifted NF-κB signaling-associated gene expression toward an anti-inflammatory state (P < .001). Farm/rural children had lower expression, indicating tolerance induction by continuous environmental exposure. Newborns with asthma at school age had reduced TNFAIP3 expression at birth, suggesting TNFAIP3 as a possible biomarker predicting subsequent asthma. CONCLUSION: Our data indicate TNFAIP3 as a key regulator during childhood asthma development and its environmentally mediated protection. Because environmental dust exposure conferred the anti-inflammatory effects, it might represent a promising future agent for asthma prevention and treatment.

10.
MBio ; 10(4)2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311887

RESUMO

Research progress over the past 20 years has yielded several experimental Ebola virus (EBOV) vaccine candidates, which were shown to be effective in nonhuman primates when given 28 days before a lethal challenge. Of these, the vesicular stomatitis virus (VSV)-vectored vaccine against EBOV (VSV-EBOV) is unique at being able to induce rapid protection, with 100% survival achieved as soon as 7 days after EBOV challenge. In a recent mBio article, Menicucci et al. carried out a transcriptome analysis of host responses in monkeys immunized with VSV-EBOV from 28 to 3 days before challenge (A. R. Menicucci, A. Jankeel, H. Feldmann, A. Marzi, and I. Messaoudi, mBio 10:e00597-19, 2019, https://doi.org/10.1128/mBio.00597-19). It was found that surviving animals had a controlled innate immune response coupled with rapid adaptive immunity, but this was not detected in nonsurviving animals. These studies highlight the important role innate immunity plays in creating an antiviral state to restrict EBOV replication and ensuring enough time for the vaccine to induce an effective adaptive immune response.

11.
Pediatr Allergy Immunol ; 30(7): 681-688, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31220363

RESUMO

The rapidly increasing prevalence of allergic disorders over the past 2 decades highlights the need to understand the epidemiology of anaphylaxis. In Europe, the United States, and Australia, the incidence of anaphylaxis is estimated to be between 60 and 950 cases per 100 000 population, with a lifetime prevalence of anaphylaxis of 0.05%-2%. The incidence appears to be increasing over time. Although the existing Asian literature is heterogeneous and limited by under-reporting, it also suggests a similar increasing trend in anaphylaxis incidence in Asia. Anaphylaxis triggers in Asia, such as the predominance of shellfish and wheat in older children and adolescents, differ from those seen in Western populations. Triggers unique to Asia such as traditional Chinese medications, galacto-oligosaccharides, and food delicacies have also been reported. Low usage of adrenaline as first-line treatment of anaphylaxis is evident across all countries and is particularly concerning. There is a need to establish prospective, standardized protocols for anaphylaxis data collection and reporting, to enhance the collective understanding of anaphylaxis and its burden, gaps in management and to identify areas for future research and intervention in each region. Understanding of the underlying reasons explaining the difference between East and West will facilitate future primary preventive strategies.

12.
N Engl J Med ; 380(21): 2064-2066, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31112381
13.
Nat Microbiol ; 4(7): 1231-1241, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30936489

RESUMO

Rift Valley fever virus (RVFV) is a mosquito-borne pathogen that causes substantial morbidity and mortality in livestock and humans. To date, there are no licensed human vaccines or therapeutics available. Here, we report the isolation of monoclonal antibodies from a convalescent patient, targeting the RVFV envelope proteins Gn and Gc. The Gn-specific monoclonal antibodies exhibited much higher neutralizing activities in vitro and protection efficacies in mice against RVFV infection, compared to the Gc-specific monoclonal antibodies. The Gn monoclonal antibodies were found to interfere with soluble Gn binding to cells and prevent infection by blocking the attachment of virions to host cells. Structural analysis of Gn complexed with four Gn-specific monoclonal antibodies resulted in the definition of three antigenic patches (A, B and C) on Gn domain I. Both patches A and B are major neutralizing epitopes. Our results highlight the potential of antibody-based therapeutics and provide a structure-based rationale for designing vaccines against RVFV.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Febre do Vale de Rift/prevenção & controle , Vírus da Febre do Vale do Rift/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Antivirais/administração & dosagem , Cercopithecus aethiops , Cristalografia por Raios X , Epitopos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Testes de Neutralização , Domínios Proteicos , Febre do Vale de Rift/imunologia , Células Vero , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/metabolismo , Ligação Viral
14.
Emerg Microbes Infect ; 8(1): 94-102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30866763

RESUMO

There was a substantial increase with infections of H7N9 avian influenza virus (AIV) in humans during Wave 5 (2016-2017). To investigate whether H7N9 had become more infectious/transmissible and pathogenic overall, we characterized the receptor binding and experimentally infected ferrets with highly pathogenic (HP)- and low pathogenic (LP)-H7N9 isolates selected from Wave 5, and compared their pathogenicity and transmissibility with a Wave 1 isolate from 2013. Studies show that A/Anhui/1/2013 (LP) and A/Chicken/Heyuan/16876/2016 (HP) were highly virulent in ferrets, A/Guangdong/Th008/2017 (HP) and A/Chicken/Huizhou/HZ-3/2017 (HP) had moderate virulence and A/Shenzhen/Th001/2016 (LP) was of low virulence in ferrets. Transmission was observed only in ferrets infected with A/Anhui/1/2013 and A/Chicken/Heyuan/16876/2016, consistent with the idea that sicker ferrets had a higher probability to transmit virus to naive animals. Given the Varied virulence and transmissibility observed in circulating H7N9 viruses from Wave 5, we conclude that the current public health risk of H7N9 has not substantially increased compared to 2013 and the circulating viruses are quite diverse.


Assuntos
Furões/virologia , Subtipo H7N9 do Vírus da Influenza A/patogenicidade , Infecções por Orthomyxoviridae/transmissão , Receptores de Superfície Celular/metabolismo , Proteínas Virais/metabolismo , Animais , Genótipo , Humanos , Subtipo H7N9 do Vírus da Influenza A/genética , Subtipo H7N9 do Vírus da Influenza A/isolamento & purificação , Subtipo H7N9 do Vírus da Influenza A/metabolismo , Influenza Humana/virologia , Nariz/virologia , Infecções por Orthomyxoviridae/virologia , Faringe/virologia , Virulência
16.
Arch Virol ; 164(5): 1335-1341, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30848390

RESUMO

In infants, hepatitis B virus (HBV) infections are mainly acquired by mother-to-child transmission (MTCT). Current tests for the presence of HBV markers at birth can neither confirm nor exclude MTCT. The aim of this study was to find an early diagnostic marker of HBV MTCT. From 2011 to 2016, we studied a total of 5999 pregnant women who gave birth at our hospital in Shenzhen City, China. HBsAg-positive mothers and their offspring (n=386 pairs) were tested at birth for HBV markers, and 207 infants were followed up at 7-12 months after birth. The HBsAg-seropositive rate of the pregnant women was 12.5%. Additionally, 28.0%, 36.0%, 98.5% and 6.6% of umbilical cord (UC) blood samples of neonates were found to be positive for HBsAg, HBeAg, anti-HBc and HBV-DNA, respectively, whereas for neonatal femoral venous (FV) blood, the percentages were 16.2%, 38.0%, 98.8% and 2.6%, respectively. Mothers with high HBV DNA loads and those who were HBeAg positive were the most likely to have HBV-positive offspring. Immunoprophylaxis failed in five infants: the difference in median HBV DNA titer between UC blood from infants with and without HBV MTCT was statistically significant, and there was no significant difference in HBV DNA titer between UC blood and in peripheral blood of infants with HBV MTCT. In conclusion, we found that HBeAg positivity and high HBV loads are strong risk factors for MTCT of HBV and that the HBV DNA titer in the UC is a good predictor for HBV MTCT.


Assuntos
Anticorpos Antivirais/sangue , Anticorpos Anti-Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/isolamento & purificação , Hepatite B/diagnóstico , Biomarcadores , DNA Viral/sangue , Diagnóstico Precoce , Feminino , Hepatite B/epidemiologia , Hepatite B/transmissão , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Humanos , Lactente , Recém-Nascido , Transmissão Vertical de Doença Infecciosa , Gravidez , Complicações Infecciosas na Gravidez , Carga Viral
18.
Mikrochim Acta ; 186(4): 223, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30847625

RESUMO

The authors describe a field effect transistor (FET) based immunoassay for the detection of inactivated ebola virus (EBOV). An equine antibody against the EBOV glycoprotein was immobilized on the surface of the FET that was previously modified with reduced graphene oxide (RGO). The antibody against EBOV was immobilized on the modified FET, and the response to EBOV was measured as a function of the shift of Dirac voltage. The method can detect the EBOV over the concentration range from 2.4 × 10-12 g·mL-1 to 1.2 × 10-7 g·mL-1 and with a limit of detection as low as 2.4 pg·mL-1. The assay has satisfactory specificity and was applied to the quantitation of inactivated EBOV in spiked serum. Graphical abstract Schematic presentation of the field effect transistor (FET) modified with reduced graphene oxide (RGO) for Ebola Virus (EBOV) detection. Specific binding between EBOV and the anti-EBOV antibody (Ab) on the FET device leads to obvious current change.


Assuntos
Ebolavirus/química , Campos Eletromagnéticos , Grafite/química , Transistores Eletrônicos/virologia , Anticorpos Antivirais/metabolismo , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Imunoensaio/métodos , Limite de Detecção , Oxirredução , Sensibilidade e Especificidade
19.
J Infect ; 78(3): 241-248, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30664912

RESUMO

OBJECTIVE: The newly emerged highly pathogenic (HP) H7N9 avian influenza virus during Wave Five has caused 28 human infections, while differences in disease severity between low pathogenic (LP)- and HP-H7N9 human infections remain unclear. METHODS: Clinical data, concentrations of serum cytokines, dynamics of virus shedding and PaO2/FiO2 from patients infected with LP-H7N9 (n = 7, LP group) and HP-H7N9 (n = 5, HP group) viruses during Wave Five were compared. In addition, critical mutations associated with H7N9 virulence in mammal/human were analyzed. RESULTS: Lymphopenia, elevated aspartate aminotransferase, alanine aminotransferase, C-reactive protein and lactate dehydrogenase were common features, with higher incidences of leukopenia and thrombocytopenia in the LP group. The acute phase of both groups was accompanied with elevated cytokines associated with disease severity, including MIF, MCP-1 and IP-10. Diffuse exudation of the lungs and consolidation were observed from all patients. The dynamics of virus shedding and PaO2/FiO2 were similar between both groups. Notably, a higher prevalence of neuraminidase inhibitors (NAIs) resistance in the HP-H7N9 virus was found. CONCLUSIONS: Our results indicate that this newly emerged HP-H7N9 virus caused similar disease severity in humans compared with LP-H7N9 virus, while higher case fatality rate and prevalence of NAI-resistance in human HP-H7N9 infections were of great concern.

20.
Nat Commun ; 10(1): 105, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30631063

RESUMO

The 2013-2016 Ebola virus (EBOV) disease epidemic demonstrated the grave consequences of filovirus epidemics in the absence of effective therapeutics. Besides EBOV, two additional ebolaviruses, Sudan (SUDV) and Bundibugyo (BDBV) viruses, as well as multiple variants of Marburg virus (MARV), have also caused high fatality epidemics. Current experimental EBOV monoclonal antibodies (mAbs) are ineffective against SUDV, BDBV, or MARV. Here, we report that a cocktail of two broadly neutralizing ebolavirus mAbs, FVM04 and CA45, protects nonhuman primates (NHPs) against EBOV and SUDV infection when delivered four days post infection. This cocktail when supplemented by the anti-MARV mAb MR191 exhibited 100% efficacy in MARV-infected NHPs. These findings provide a solid foundation for clinical development of broadly protective immunotherapeutics for use in future filovirus epidemics.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Ebolavirus/imunologia , Infecções por Filoviridae/imunologia , Marburgvirus/imunologia , Doenças dos Primatas/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Ebolavirus/classificação , Ebolavirus/efeitos dos fármacos , Ebolavirus/fisiologia , Infecções por Filoviridae/terapia , Infecções por Filoviridae/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Imunoterapia/métodos , Marburgvirus/efeitos dos fármacos , Marburgvirus/fisiologia , Doenças dos Primatas/terapia , Doenças dos Primatas/virologia , Primatas , Resultado do Tratamento
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