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Discrimination of False Negative Results in RT-PCR Detection of SARS-CoV-2 RNAs in Clinical Specimens by Using an Internal Reference
Yafei Zhang, Changtai Wang, Mingfeng Han, Jun Ye, Yong Gao, Zhongping Liu, Tengfei He, Tuantuan Li, Mengyuan Xu, Luping Zhou, Guizhou Zou, Mengji Lu, Zhenhua Zhang
当前状态: , doi: 10.1007/s12250-020-00273-8
收稿日期: 2020-05-25 录用日期: 2020-07-15 出版日期: 2020-07-23
[摘要] [PDF] Springerlink
Reverse transcription-polymerase chain reaction (RT-PCR) is an essential method for specific diagnosis of SARS-CoV-2 infection. Unfortunately, false negative test results are often reported. In this study, we attempted to determine the principal causes leading to false negative results of RT-PCR detection of SARSCoV-2 RNAs in respiratory tract specimens. Multiple sputum and throat swab specimens from 161 confirmed COVID-19 patients were tested with a commercial fluorescent RT-PCR kit targeting the ORF1ab and N regions of SARS-CoV-2 genome. The RNA level of a cellular housekeeping gene ribonuclease P/MRP subunit p30 (RPP30) in these specimens was also assessed by RT-PCR. Data for a total of 1052 samples were retrospectively re-analyzed and a strong association between positive results in SARS-CoV-2 RNA tests and high level of RPP30 RNA in respiratory tract specimens was revealed. By using the ROC-AUC analysis, we identified Ct cutoff values for RPP30 RT-PCR which predicted false negative results for SARS-CoV-2 RTPCR with high sensitivity (95.03%-95.26%) and specificity (83.72%-98.55%) for respective combination of specimen type and amplification reaction. Using these Ct cutoff values, false negative results could be reliably identified. Therefore, the presence of cellular materials, likely infected host cells, are essential for correct SARS-CoV-2 RNA detection by RT-PCR in patient specimens. RPP30 could serve as an indicator for cellular content, or a surrogate indicator for specimen quality. In addition, our results demonstrated that false negativity accounted for a vast majority of contradicting results in SARS-CoV-2 RNA test by RT-PCR.
Mild Cytokine Elevation, Moderate CD4+ T Cell Response and Abundant Antibody Production in Children with COVID-19
Ran Jia, Xiangshi Wang, Pengcheng Liu, Xiaozhen Liang, Yanling Ge, He Tian, Hailing Chang, Hao Zhou, Mei Zeng, Jin Xu
当前状态: , doi: 10.1007/s12250-020-00265-8
收稿日期: 2020-07-02 录用日期: 2020-07-06 出版日期: 2020-07-22
[摘要] [PDF] Springerlink
Children with Coronavirus Disease 2019 (COVID-19) were reported to show milder symptoms and better prognosis than their adult counterparts, but the difference of immune response against SARS-CoV-2 between children and adults hasn’t been reported. Therefore we initiated this study to figure out the features of immune response in children with COVID-19. Sera and whole blood cells from 19 children with COVID-19 during different phases after disease onset were collected. The cytokine concentrations, SARS-CoV-2 S-RBD or N-specific antibodies and T cell immune responses were detected respectively. In children with COVID-19, only 3 of 12 cytokines were increased in acute sera, including interferon (IFN)-γ-induced protein 10 (IP10), interleukin (IL)-10 and IL-16. We observed an increase in T helper (Th)-2 cells and a suppression in regulatory T cells (Treg) in patients during acute phase, but no significant response was found in the IFN-γ-producing or tumor necrosis factor (TNF)-α-producing CD8+ T cells in patients. S-RBD and N IgM showed an early induction, while S-RBD and N IgG were prominently induced later in convalescent phase. Potent S-RBD IgA response was observed but N IgA seemed to be inconspicuous. Children with COVID-19 displayed an immunophenotype that is less inflammatory than adults, including unremarkable cytokine elevation, moderate CD4+ T cell response and inactive CD8+ T cell response, but their humoral immunity against SARS-CoV-2 were as strong as adults. Our finding presented immunological characteristics of children with COVID-19 and might give some clues as to why children develop less severe disease than adults.
A Small-Scale Medication of Leflunomide as a Treatment of COVID-19 in an Open-Label Blank-Controlled Clinical Trial
Ke Hu, Mengmei Wang, Yang Zhao, Yunting Zhang, Tao Wang, Zhishui Zheng, Xiaochen Li, Shaolin Zeng, Dong Zhao, Honglin Li, Ke Xu, Ke Lan
当前状态: , doi: 10.1007/s12250-020-00258-7
收稿日期: 2020-06-03 录用日期: 2020-06-16 出版日期: 2020-07-21
[摘要] [PDF] Springerlink
We recently reported that inhibitors against human dihydroorotate dehydrogenase (DHODH) have broad-spectrum antiviral activities including their inhibitory efficacies on SARS-CoV-2 replication in infected cells. However, there are limited data from clinical studies to prove the application of DHODH inhibitors in Coronavirus Disease 2019 (COVID-19) patients. In present study, we evaluated Leflunomide, an approved DHODH inhibitor widely used as a modest immune regulator to treat autoimmune diseases, in treating COVID-19 disease with a small-scale of patients. Cases of 10 laboratory-confirmed COVID-19 patients of moderate type with obvious opacity in the lung were included. Five of the patients were treated with Leflunomide, and another five were treated as blank controls without a placebo. All the patients accepted standard supportive treatment for COVID-19. The patients given Leflunomide had a shorter viral shedding time (median of 5 days) than the controls (median of 11 days, P=0.046). The patients given Leflunomide also showed a significant reduction in C-reactive protein levels, indicating that immunopathological inflammation was well controlled. No obvious adverse effects were observed in Leflunomide-treated patients, and they all discharged from the hospital faster than controls. This preliminary study on a small-scale compassionate use of Leflunomide provides clues for further understanding of Leflunomide as a potential antiviral drug against COVID-19.
On the Calculation of TCID50 for Quantitation of Virus Infectivity
Chengfeng Lei, Jian Yang, Jia Hu, Xiulian Sun
当前状态: , doi: 10.1007/s12250-020-00230-5
收稿日期: 2020-03-10 录用日期: 2020-04-15 出版日期: 2020-05-26
[摘要] [PDF] Springerlink
The most important property of a virus is its infectivity. To measure infectivity, one can assay viral replication in cells to obtain a titer for a given virus stock. A titer is defined as a given number of infectious viral units per unit volume, and an infectious unit is the smallest amount of virus that produces recognizable effects [e.g., cytopathic effect (CPE), dot blot immunoreactivity]. The median tissue culture infectious dose (TCID50) is defined as the dilution of a virus required to infect 50% of a given cell culture.
First Fatal Infection and Phylodynamic Analysis of Severe Fever with Thrombocytopenia Syndrome Virus in Jilin Province, Northeastern China
Xu Zhang, Nina Wang, Zedong Wang, Lihe Che, Chen Chen, Wen-Zhong Zhao, Quan Liu
当前状态: , doi: 10.1007/s12250-020-00228-z
收稿日期: 2019-10-30 录用日期: 2020-03-16 出版日期: 2020-05-26
[摘要] [PDF] Springerlink
Severe fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV) in the genus Banyangvirus of the family Phenuiviridae, is an emerging tick-borne viral zoonosis (Liu et al. 2014). Typical clinical symptoms of SFTS include fever, headache, thrombocytopenia, and leukocytopenia (Yu et al. 2011). Since SFTSV was identified in 2009, it has been found in more than 20 provinces in China and is closely related to strains from Japan and South Korea (Kim et al. 2013; Takahashi et al. 2014). In Northeastern China, the disease was discovered in Liaoning Province in 2010 (Wang et al. 2016), and the virus was detected in Haemaphysalis longicornis in Jilin Province in 2013 (Liu et al. 2016). Here we describe the first fatal case of SFTS in Jilin Province and conduct phylodynamic analysis of SFTSV.
Construction and Characterization of a Novel Recombinant Attenuated and Replication-Deficient Candidate Human Adenovirus Type 3 Vaccine: “Adenovirus Vaccine Within an Adenovirus Vector”
Yuqian Yan, Shuping Jing, Liqiang Feng, Jing Zhang, Zhiwei Zeng, Min Li, Shan Zhao, Junxian Ou, Wendong Lan, Wenyi Guan, Xiaowei Wu, Jianguo Wu, Donald Seto, Qiwei Zhang
当前状态: , doi: 10.1007/s12250-020-00234-1
收稿日期: 2020-02-22 录用日期: 2020-04-13 出版日期: 2020-05-26
[摘要] [PDF] Springerlink
Human adenoviruses (HAdVs) are highly contagious and result in large number of acute respiratory disease (ARD) cases with severe morbidity and mortality. Human adenovirus type 3 (HAdV-3) is the most common type that causes ARD outbreaks in Asia, Europe, andtheAmericas.However, there is currently no vaccine approvedfor its general use.The hexon protein contains themain neutralizing epitopes, provoking strong and lasting immunogenicity. In this study, a novel recombinant and attenuated adenovirus vaccine candidate against HAdV-3 was constructed based on a commercially-available replication-defective HAdV-5 gene therapy and vaccine vector. The entire HAdV-3 hexon gene was integrated into the E1 region of the vector by homologous recombination using a bacterial system. Theresultantrecombinants expressing the HAdV-3 hexon protein were rescued in AD293 cells, identified and characterized by RT-PCR, Western blots, indirect immunofluorescence, and electron microscopy. This potential vaccine candidate had a similar replicative efficacy as the wild-type HAdV-3 strain. However, and importantly, the vaccine strain had been rendered replication-defective and was incapable of replication in A549 cells after more than twenty-generation passages in AD293 cells. This represents a significant safety feature. The mice immunized both intranasally and intramuscularly by this vaccine candidate raised significant neutralizing antibodies against HAdV-3. Therefore, this recombinant, attenuated, and safe adenovirus vaccine is a promising HAdV-3 vaccine candidate. The strategy of using a clinically approved and replication-defective HAdV-5 vector provides a novel approach to develop universal adenovirus vaccine candidates against all the other types of adenoviruses causing ARDs and perhaps other adenovirus-associated diseases.
Establishment of Murine Infection Models with Biological Clones of Dengue Viruses Derived from a Single Clinical Viral Isolate
Zhihang Zheng, Min Li, Zhihua Liu, Xia Jin, Jin Sun
当前状态: , doi: 10.1007/s12250-020-00229-y
收稿日期: 2019-11-09 录用日期: 2020-03-11 出版日期: 2020-05-25
[摘要] [PDF] Springerlink
Dengue virus (DENV) is a single-stranded RNA virus transmitted by mosquitoes in tropical and subtropical regions. It causes dengue fever, dengue hemorrhagic fever and dengue shock syndrome in patients. Each year, 390 million people are estimated to be infected by four serotypes of dengue virus, creating a great burden on global public health and local economy. So far, no antiviral drug is available for dengue disease, and the newly licensed vaccine is far from satisfactory. One large obstacle for dengue vaccine and drug development is the lack of suitable small animal models. Although some DENV infection models have been developed, only a small number of viral strains can infect immunodeficient mice. In this study, with biologically cloned viruses from a single clinical isolate, we have established two mouse models of DENV infection, one is severe lethal infection in immunocompromised mice, and the other resembles self-limited disease manifestations in Balb/c mice with transient blockage of type I IFN responses. This study not only offers new small animal models of dengue viral infection, but also provides new viral variants for further investigations on dengue viral pathogenesis.
Recombination of T4-like Phages and Its Activity against Pathogenic Escherichia coli in Planktonic and Biofilm Forms
Min Li, Donglin Shi, Yanxiu Li, Yuyi Xiao, Mianmian Chen, Liang Chen, Hong Du, Wei Zhang
当前状态: , doi: 10.1007/s12250-020-00233-2
收稿日期: 2019-10-09 录用日期: 2020-03-10 出版日期: 2020-05-25
[摘要] [PDF] Springerlink
The increasing emergence of multi-drug resistant Escherichia coli (E. coli) has become a global concern, primarily due to the limitation of antimicrobial treatment options. Phage therapy has been considered as a promising alternative for treating infections caused by multi-drug resistant E. coli. However, the application of phages as a promising antimicrobial agent is limited by their narrow host range and specificity. In this research, a recombinant T4-like phage, named WGqlae, has been obtained by changing the receptor specificity determinant region of gene 37, using a homologous recombination platform of T4-like phages established by our laboratory previously. The engineered phage WGqlae can lyse four additional hosts, comparing to its parental phages WG01 and QL01. WGqlae showed similar characteristics, including thermo and pH stability, optimal multiplicity of infection and one-step growth curve, to the donor phage QL01. In addition, sequencing results showed that gene 37 of recombinant phage WGqlae had genetically stable even after 20 generations. In planktonic test, phage WGqlae had significant antimicrobial effects on E. coli DE192 and DE205B. The optical density at 600 nm (OD600) of E. coli in phage WGqlae treating group was significantly lower than that of the control group (P < 0.01). Besides, phage WGqlae demonstrated an obvious inhibitory effect on the biofilm formation and the clearance of mature biofilms. Our study suggested that engineered phages may be promising candidates for future phage therapy applications against pathogenic E. coli in planktonic and biofilm forms.
Depletion but Activation of CD56dimCD16+ NK Cells in Acute Infection with Severe Fever with Thrombocytopenia Syndrome Virus
Mengmeng Li, Yan Xiong, Mingyue Li, Wenjing Zhang, Jia Liu, Yanfang Zhang, Shue Xiong, Congcong Zou, Boyun Liang, Mengji Lu, Dongliang Yang, Cheng Peng, Xin Zheng
当前状态: , doi: 10.1007/s12250-020-00224-3
收稿日期: 2019-08-11 录用日期: 2020-02-28 出版日期: 2020-05-19
[摘要] [PDF] Springerlink
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality (12%–30%). The mechanism by which the SFTS bunyavirus (SFTSV) causes severe illness remains unclear. To evaluate the phenotypic and functional characteristics of the NK cell subsets in SFTS patients, twenty-nine SFTS patients were sequentially sampled from admission until recovery. Phenotypic and functional characteristics of NK cell subsets in circulating blood were analysed via flow cytometry. Then, correlations between NK cell subset frequencies and the SFTS index (SFTSI) were evaluated in all SFTS patients (15 mild, 14 severe) upon admission. The frequencies of CD56dimCD16+ NK cells were greatly decreased in early SFTSV infection and were negatively correlated with disease severity. Additionally, higher Ki-67 and granzyme B expression and relatively lower NKG2A expression in CD56dimCD16+ NK cells were observed in acute infection. Moreover, the effector function of CD56dim NK cells was increased in the acute phase compared with the recovery phase in nine severe SFTS patients. Additionally, interleukin (IL)-15, interferon (IFN)-α, IL-18 and IFN-γ secretion was markedly increased during early infection. Collectively, despite depletion of CD56dimCD16+ NK cells, activation and functional enhancement of CD56dimCD16+ NK cells were still observed, suggesting their involvement in defence against early SFTSV infection.
Myristoylation of EV71 VP4 is Essential for Infectivity and Interaction with Membrane Structure
Jiaming Cao, Meng Qu, Hongtao Liu, Xuan Wan, Fang Li, Ali Hou, Yan Zhou, Bo Sun, Linjun Cai, Weiheng Su, Chunlai Jiang
当前状态: , doi: 10.1007/s12250-020-00226-1
收稿日期: 2019-12-12 录用日期: 2020-03-03 出版日期: 2020-05-12
[摘要] [PDF] Springerlink
The Enterovirus 71 (EV71) VP4 is co-translationally linked to myristic acid at its amino-terminal glycine residue. However, the role of this myristoylation in the EV71 life cycle remains largely unknown. To investigate this issue, we developed a myristoylation-deficient virus and reporter (luciferase) pseudovirus with a Gly-to-Ala mutation (G2A) on EV71 VP4. When transfecting the EV71-G2A genome encoding plasmid in cells, the loss of myristoylation on VP4 did not affect the expression of viral proteins and the virus morphology, however, it did significantly influence viral infectivity. Further, in myristoylation-deficient reporter pseudovirus-infected cells, the luciferase activity and viral genome RNA decreased significantly as compared to that of wild type virus; however, cytopathic effect and viral capsid proteins were not detected in myristoylation-deficient virus-infected cells. Also, although myristoylation-deficient viral RNA and proteins were detected in the second blind passage of infection, they were much fewer in number compared to that of the wild type virus. The replication of genomic RNA and negative-strand viral RNA were both blocked in myristoylation-deficient viruses, suggesting that myristoylation affects viral genome RNA release from capsid to cytoplasm. Besides, loss of myristoylation on VP4 altered the distribution of VP4-green fluorescent protein protein, which disappeared from the membrane structure fraction. Finally, a liposome leakage assay showed that EV71 myristoylation mediates the permeability of the model membrane. Hence, the amino-terminal myristoylation of VP4 is pivotal to EV71 infection and capsidmembrane structure interaction. This study provides novel molecular mechanisms regarding EV71 infection and potential molecular targets for antiviral drug design.
Molecular Epidemiology and Vaccine Compatibility Analysis of Seasonal Influenza Viruses in Wuhan, 2016–2019
Liang-Jun Chen, Jing-Jing Guo, Wei-Wei Guo, E-Xiang Shen, Xin Wang, Kai-Ji Li, Jie Yan, Mang Shi, Yi-Rong Li, Wei Hou
当前状态: , doi: 10.1007/s12250-020-00225-2
收稿日期: 2019-12-15 录用日期: 2020-03-07 出版日期: 2020-05-11
[摘要] [PDF] Springerlink
Influenza viruses (FLUV) cause high morbidity and mortality annually in the world and pose a serious threat to the public health. Wuhan, as an important transportation hub in China, has a dense population and suitable climate, which also lays a major hidden danger for the outbreak of influenza. To survey and characterize the seasonal FLUV in Wuhan during 2016–2019, we collected 44,738 throat swabs, among which 15.5% were influenza A (FLUAV) positive, 6.1% influenza B (FLUBV) and 0.3% co-infection. By monitoring FLUV in each month from June 2016 to May 2019, different with the previously seasonality pattern, only a single influenza peak was appeared in winter of 2017–2018 and 2018–2019, respectively. These data indicated that the complex circulation pattern of seasonal influenza in Wuhan. In addition, we found the age group was skewed towards 5–14 years group whose activity were mostly school based, which suggested school may be an important place for influenza outbreaks. Meanwhile, phylogenic analysis revealed that two subtypes (subclade 3C.2a2 and 3C.2a1b) of A(H3N2) were circulating in Wuhan and there was an obvious transition in 2018 because the two subclades were detected simultaneously. Furthermore, by estimating the vaccine effectiveness, we found that the vaccine strain of FLUAV didn’t seem to match very well the current epidemic strain, especially A(H3N2). Hence, more accurate prediction of seasonal outbreak is essential for vaccine design. Taken together, our results provided the current information about seasonal FLUV in Wuhan which form the basis for vaccine updating.
Phylogeography of Highly Pathogenic H5 Avian Influenza Viruses in China
Xiaowen Li, Xueying Li, Bing Xu
当前状态: , doi: 10.1007/s12250-020-00193-7
收稿日期: 2019-05-26 录用日期: 2019-12-17 出版日期: 2020-05-08
[摘要] [PDF] Springerlink
The spread of H5 highly pathogenic avian influenza viruses poses serious threats to the poultry industry, wild bird ecology and human health. Circulation of H5 viruses between poultry and wild birds is a significant public health threat in China. Thus, viral migration networks in this region need to be urgently studied. Here, we conducted molecular genetic analyses of the hemagglutinin genes of H5 highly pathogenic avian influenza viruses in multiple hosts from 2000 to 2018 in China. Our aim was to clarify the roles of different hosts in the evolution of H5 viruses. We used a flexible Bayesian statistical framework to simulate viral space diffusion and continuous-time Markov chains to infer the dynamic evolutionary process of spatiotemporal dissemination. Bayesian phylogeographic analysis of H5 viruses showed for the first time that H5 viruses in poultry and wild birds were present in Guangdong Province. Furthermore, Guangdong, Jiangsu, Shanghai and Hunan acted as the epicenters for the spread of various H5 subtypes viruses in poultry, and Henan, Shanghai, Hong Kong and Inner Mongolia acted as epicenters for the spread of various H5 subtypes viruses in wild birds. Thus, H5 viruses exhibited distinct evolutionary dynamics in poultry and wild birds. Our findings extend our understanding of the transmission and spread of highly pathogenic H5 avian influenza viruses in China.
A Comprehensive Review on Human Aichi Virus
Enrique Rivadulla, Jesús L. Romalde
当前状态: , doi: 10.1007/s12250-020-00222-5
收稿日期: 2019-09-21 录用日期: 2020-02-28 出版日期: 2020-04-27
[摘要] [PDF] Springerlink
Although norovirus, rotavirus, adenovirus and Astrovirus are considered the most important viral agents transmitted by food and water, in recent years other viruses, such as Aichi virus (AiV), have emerged as responsible for gastroenteritis outbreaks associated with different foods. AiV belongs to the genus Kobuvirus of the family Picornaviridae. It is a virus with icosahedral morphology that presents a single stranded RNA genome with positive sense (8280 nucleotides) and a poly (A) chain. AiV was first detected from clinical samples and in recent years has been involved in acute gastroenteritis outbreaks from different world regions. Furthermore, several studies conducted in Japan, Germany, France, Tunisia and Spain showed a high prevalence of AiV antibodies in adults (between 80% and 99%), which is indicative of a large exposure to this virus. The aim of this review is to bring together all the discovered information about the emerging pathogen human Aichi virus (AiV), discussing the possibles routes of transmission, new detection techniques and future research. Although AiV is responsible for a low percentage of gastroenteritis outbreaks, the high seroprevalence shown by human populations indicates an evident role as an enteric agent. The low percentage of AiV detection could be explained by the fact that the pathogen is more associated to subclinical infections. Further studies will be needed to clarify the real impact of AiV in human health and its importance as a causative gastroenteritis agent worldwide.
IP10, KC and M-CSF is Remarkably Increased in the Brains from the Various Strains of Experimental Mice Infected with Different Scrapie Agents
Jia Chen, Cao Chen, Chao Hu, Lian Liu, Ying Xia, Lin Wang, Wei Yang, Hai-Yan Wu, Wei Zhou, Kang Xiao, Qi Shi, Yuezhang Wu, Zhi-Bao Chen, Xiao-Ping Dong
当前状态: , doi: 10.1007/s12250-020-00216-3
收稿日期: 2019-09-17 录用日期: 2019-11-27 出版日期: 2020-04-20
[摘要] [PDF] Springerlink
Activation of inflammatory cells and upregulations of a number of cytokines in the central nervous system (CNS) of patients with prion diseases are frequently observed. To evaluate the potential changes of some brain cytokines that were rarely addressed during prion infection, the levels of 17 different cytokines in the brain homogenates of mice infected with different scrapie mouse-adapted agents were firstly screened with Luminex assay. Significant upregulations of interferon gamma-induced protein 10 (IP10), keratinocyte chemoattractant (KC) and macrophage colony stimulating factor (M-CSF) were frequently detected in the brain lysates of many strains of scrapie infected mice. The upregulations of those three cytokines in the brains of scrapie infected mice were further validated by the individual specific ELISA and immunohistochemical assay. Increased specific mRNAs of IP10, M-CSF and KC in the brains of scrapie infected mice were also detected by the individual specific qRT-PCRs and IP10-specific digital PCR. Dynamic analyses of the brain samples collected at different time points post infection revealed the time-dependent increases of those three cytokines, particularly IP10 during the incubation period of scrapie infection. In addition, we also found that the levels of IP10 in cerebral spinal fluid (CSF) of 45 sporadic Creutzfeldt–Jakob disease (sCJD) patients were slightly but significantly higher than those of the cases who were excluded the diagnosis of prion diseases. These data give us a better understanding of inflammatory reaction during prion infection and progression of prion disease.
Cutaneous Dengue Virus Inoculation Triggers Strong B Cell Reactions but Contrastingly Poor T Cell Responses
Edith Marcial-Juárez, Julio García-Cordero, Raúl Antonio Maqueda-Alfaro, Rafael Eduardo Saucedo-López, Luvia Enid Sánchez-Torres, Leticia Cedillo-Barrón, Leopoldo Flores-Romo
当前状态: , doi: 10.1007/s12250-020-00213-6
收稿日期: 2019-10-16 录用日期: 2019-12-24 出版日期: 2020-04-20
[摘要] [PDF] Springerlink
Dengue is a global health problem without current specific treatment nor safe vaccines available. While severe dengue is related to pre-existing non-neutralizing dengue virus (DENV) antibodies, the role of T cells in protection or pathology is unclear. Using cutaneous DENV infection in immunocompetent mice we previously showed the generation of PNA+ germinal centers (GCs), now we assessed the activation and proliferation of B and T cells in draining lymph nodes (DLNs). We found a drastic remodelling of DLN compartments from 7 to 14 days post-infection (dpi) with greatly enlarged B cell follicles, occupying almost half of the DLN area compared to ~24% in naïve conditions. Enormous clusters of proliferating (Ki-67+) cells inside B follicles were found 14 dpi, representing ~33% of B cells in DLNs but only ~2% in noninfected mice. Inside GCs, we noticed an important recruitment of tingle body macrophages removing apoptotic cells. In contrast, the percentage of paracortex area and total T cells decreased by 14–16 dpi, compared to controls. Scattered randomly distributed Ki-67+ T cells were found, similar to non-infected mice. CD69 expression by CD4+ and CD8+ T cells was minor, while it was remarkable in B cells, representing 1764.7% of change from basal levels 3 dpi. The apparent lack of T cell responses cannot be attributed to apoptosis since no significant differences were observed compared to noninfected mice. This study shows massive B cell activation and proliferation in DLNs upon DENV infection. In contrast, we found very poor, almost absent CD4+ and CD8+ T cell responses.
Effect of Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 Alpha Variants on Spontaneous Clearance and Fibrosis Progression during Hepatitis C Virus Infection in Moroccan Patients
Raouia ElFihry, Mohcine Elmessaoudi-Idrissi, Fatima-Zahra Jadid, Imane Zaidane, Hajar Chihab, Mohamed Tahiri, Mostafa Kabine, Wafaa Badre, Isabelle Chemin, Agnes Marchio, Pascal Pineau, Sayeh Ezzikouri, Soumaya Benjelloun
当前状态: , doi: 10.1007/s12250-020-00220-7
收稿日期: 2019-10-04 录用日期: 2020-02-08 出版日期: 2020-04-15
[摘要] [PDF] Springerlink
Hepatitis C virus (HCV) is still one of the main causes of liver disease worldwide. Metabolic disorders, including nonalcoholic fatty liver disease (NAFLD), induced by HCV have been shown to accelerate the progression of fibrosis to cirrhosis and to increase the risk of hepatocellular carcinoma. An optimal peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) activity is crucial to prevent NAFLD installation. The present study aims to investigate the associations between two common PPARGC1A polymorphisms (rs8192678 and rs12640088) and the outcomes of HCV infection in a North African context. A series of 592 consecutive Moroccan subjects, including 292 patients with chronic hepatitis C (CHC), 100 resolvers and 200 healthy controls were genotyped using a TaqMan allelic discrimination assay. PPARGC1A variations at rs8192678 and rs12640088 were not associated with spontaneous clearance of HCV infection (adjusted ORs = 0.76 and 0.79 respectively, P >0.05, for both). Furthermore, multivariable logistic regression analysis showed that both SNPs were not associated with fibrosis progression (OR = 0.71; 95% CI 0.20–2.49; P = 0.739; OR = 1.28; 95% CI 0.25–6.54; P = 0.512, respectively). We conclude that, in the genetic context of South Mediterranean patients, rs8192678 and rs12640088 polymorphisms of PPARGC1A are neither associated with spontaneous clearance nor with disease progression in individuals infected with HCV.
Potential m6A and m5C Methylations within the Genome of A Chinese African Swine Fever Virus Strain
Lijia Jia, Jianjun Chen, Haizhou Liu, Wenhui Fan, Depeng Wang, Jing Li, Di Liu
当前状态: , doi: 10.1007/s12250-020-00217-2
收稿日期: 2020-01-05 录用日期: 2020-03-07 出版日期: 2020-04-08
[摘要] [PDF] Springerlink
It has been more than 1 year since China reported the first case of African swine fever (ASF) infection in August 2018, and the epidemic situation remains severe (China News Service 2019). According to reports from the Ministry of Agriculture and Rural Affairs, China has reported 160 cases of ASF, which resulted in nearly 1.2 million pigs being killed, as of November 21, 2019 (China News Service 2019). ASF is an acute febrile, hemorrhagic and fulminating infectious disease, and would reach 100% case fatality rate to pigs (Gallardo et al. 2015). The causative pathogen, African swine fever virus (ASFV), is a doublestranded DNA virus with a genome of 170–193 kb belonging to the Asfarviridae family (Galindo and Alonso 2017; Gallardo et al. 2015). A recent study has revealed that ASFV maintains a core genome of 102 ORFs and has 168 dispensable genes (Wang et al. 2019). Thus, the complexed genomic features of ASFV require more attentions. By using the next generation sequencing (NGS) and the single molecule real-time sequencing (SMRT-seq), a couple of Chinese ASFV genomes have been uncovered (Bao et al. 2019; Wen et al. 2019; Jia et al. 2019). Compared to NGS, SMRT-seq has the advantage of long read length and can generate sequencing data containing the original single base modification information, which can be identified through the state-of-art bioinformatic procedures (Senol Cali et al. 2019; Simpson et al. 2017). DNA methylation is a chemical modification common in animal and plant genomes. It refers to the catalytic transfer of methyl groups on active methyl compounds (such as s-adenosine methionine) to other compounds under the catalysis of DNA methyltransferase (DNMT), mainly forming 5-methylcytosine (5-mC), 6-methyladenine (6-mA), 5-hydroxymethylcytosine (5-hmC), etc. DNA methylation, which triggers the epigenetic regulatory mechanism, has been proved to play important roles in gene expression and regulation, embryonic development, and disease-related aspects (Gouil and Keniry 2019). Whether ASFV genome has DNA methylation and epigenetic regulation is to be discerned.
Development of an MCA-Based Real Time RT-qPCR Assay for the Simultaneous Detection and Differentiation of Duck Hepatitis A Virus Types 1 and 3
Chunchun Meng, Yunxiu Huang, Zaib Ur Rehman, Wen Hu, Chuanfeng Li, Ruiying Liang, Zongyan Chen, Kaijie Song, Tianchao Wei, Guangqing Liu
当前状态: , doi: 10.1007/s12250-020-00211-8
收稿日期: 2019-10-16 录用日期: 2020-03-03 出版日期: 2020-04-08
[摘要] [PDF] Springerlink
Duck virus hepatitis (DVH) is a significant concern in the duck industry as the disease causes a highly contagious infection in young ducklings that is often associated with liver necrosis, hemorrhage, and high mortality (Yugo et al. 2016). Duck hepatitis virus (DHV) was first described in 1949 on Long Island in the United States. Subsequent, outbreaks have been reported in England, Canada, Germany, Japan and elsewhere (Toth 1969). DHV is associated with at least two RNA viruses, duck hepatitis A virus (DHAV) and duck astrovirus (DAstV); however, no antigenic relationships have been identified between these two viruses (Yugo et al. 2016). DHAV is the primary causative agent of DVH. As the only member of the genus Avihepatovirus, in the Picornaviridae family, DHAV has a linear, single-stranded positive-sense RNA genome. The genomic organization of DHAV is analogous to that of other picornaviruses with one large open reading frame (ORF) that encodes a polyprotein precursor, that is preceded by a 50-untranslated-terminal-region (UTR) and followed by 30- UTR (Tseng et al. 2007). Based on systematic phylogenetic analyses and neutralization assays, DHAVs have been classified into three serotypes: the classical serotype 1 (DHAV-1) (Kim et al. 2006; Ding and Zhang 2007; Tseng et al. 2007), the second serotype that has only been reported in Taiwan Province of China (DHAV-2) (Tseng and Tsai 2007), and the third serotype that was first reported in South Korea (DHAV-3) (Kim et al. 2007). DHAV-3 also accounts for an increasing proportion of DHV pathogens in China (Liu et al. 2011; Zhang et al. 2017; Wen et al. 2018), South Korea (Cha et al. 2013; Soliman et al. 2015) and Vietnam (Doan et al. 2016).
Characterization of the First Genome of Porcine mastadenovirus B (HNU1 Strain) and Implications on Its Lymphoid and Special Origin
Shu-Jing Liu, Qiong Wang, Ting-Ting Li, Si-Hua Zhang, Jin-Yan Li, Li-Jun Wu, Ye Qiu, Xing-Yi Ge
当前状态: , doi: 10.1007/s12250-020-00210-9
收稿日期: 2019-12-05 录用日期: 2020-02-04 出版日期: 2020-03-31
[摘要] [PDF] Springerlink
Porcine adenoviruses (PAdVs) are classified into three species, PAdV-A, PAdV-B, and PAdV-C. The genomes of PAdV-A and PAdV-C have been well characterized. However, the genome of PAdV-B has never been completely sequenced, and the epidemiology of PAdV-B remains unclear. In our study, we have identified a novel strain of PAdV-B, named PAdV-BHNU1, in porcine samples collected in China by viral metagenomic assay and general PCR. The genome of PAdV-BHNU1 is 31,743 bp in length and highly similar to that of California sea lion adenovirus 1 (C. sea lion AdV-1), which contains typical mastadenoviral structures and some unique regions at the carboxy-terminal end. Especially, PAdV-BHNU1 harbors a dUTPase coding region not clustering with other mastadenoviruses except for C. sea lion AdV-1 and a fiber coding region homologous with galectin 4 and 9 of animals. However, the variance of GC contents between PAdV-BHNU1 (55%) and C. sea lion AdV-1 (36%) indicates their differential evolutionary paths. Further epidemiologic study revealed a high positive rate (51.7%) of PAdV-B-HNU1 in porcine lymph samples, but low positive rates of 10.2% and 16.1% in oral swabs and rectal swabs, respectively. In conclusion, this study characterized a novel representative genome of a lymphotropic PAdV-B with unique evolutionary origin, which contributes to the taxonomical and pathogenic studies of PAdVs.
Pan-Genomic Analysis of African Swine Fever Virus
Ziming Wang, Lijia Jia, Jing Li, Haizhou Liu, Di Liu
当前状态: , doi: 10.1007/s12250-019-00173-6
收稿日期: 2019-09-10 录用日期: 2019-10-17 出版日期: 2019-12-11
[摘要] [PDF] Springerlink
African swine fever (ASF) is a severe haemorrhagic fever in domestic pigs and wild boar with extremely high mortality rate. It is cataloged as a notifiable disease by the World Organization for Animal Health (OIE). The etiological agent that causes the highly lethal disease is the African swine fever virus (ASFV) (Sanchez-Vizcaino et al. 2015). ASFV is the only known member of the genus Asfivirus and family Asfarviridae. The family Asfarviridae belongs to the member of nucleocytoplasmic large DNA viruses (NCLDV) superfamily (Iyer et al. 2006; Costard et al. 2009). Overall, the ASFV virion presents an icosahedral morphology with a multilayered structure (Wang et al. 2019). The genome of ASFV is a large doublestranded DNA (dsDNA) molecule that varies in length from about 170 to 193 kilobase pairs and encodes between 150 and 167 open reading frames (ORFs) depending on the isolate (Dixon et al. 2013). In addition, ASFV also infects African wild suids, including warthogs (Phacochoerus africanus) and bushpigs (Potamochoerus larvatus), which act as asymptomatic carriers. Soft ticks of the Ornithodoros moubata complex also serve as a natural reservoir and transmit the disease to suids. In East Africa, ASFV is maintained in an ancient sylvatic cycle involving warthogs and soft ticks (Ornithodoros genus) that inhabit their burrows (Jori et al. 2013).
Isolation and Characterization of A Novel Fowl Adenovirus Serotype 8a Strain from China
Li Chen, Lijuan Yin, Peng Peng, Qingfeng Zhou, Yunping Du, Yun Zhang, Chunyi Xue, Yongchang Cao
当前状态: , doi: 10.1007/s12250-019-00172-7
收稿日期: 2019-06-04 录用日期: 2019-08-05 出版日期: 2019-12-02
[摘要] [PDF] Springerlink
Since 2012, the clinical cases of inclusion body hepatitis showed an increasing trend in China, causing considerable economic losses to the poultry industry. In this study, a fowl adenovirus strain CH/GDLZ/201801 was isolated from a chicken flock experiencing inclusion body hepatitis and analyzed by complete genome sequencing. The pathogenicity of the new virus strain was examined by experimental infection of specific pathogen free chickens. The isolate was identified by immunofluorescence and the virions presented typical icosahedral particles under transmission electron microscopy. The full genome of the isolate was 44,329 nucleotides in length with 58% G+C content. Phylogenetic analysis, based on the whole genome, revealed that the new isolate was closest to serotype 8a from the species Fowl aviadenovirus E (FAdVE). Recombination analysis and phylogenetic analysis showed that the new isolate is a recombinant strain between FAdV- 8a and FAdV-8b. In infection experiments, three infected chickens showed clinical signs and one chicken died on day 7 post infection, corresponding to 5% mortality. Macroscopic and microscopic lesions in the liver were observed, and viral antigen could be detected in the livers by immunohistochemical staining and TEM. Taken together, our study describes the genomic characteristics and pathogenicity of a FAdV-8a strain in China. It would lay a solid foundation for further study of the pathogenic mechanism and vaccine development of the virus.

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Review
The Restrictome of Flaviviruses
Lionel Berthoux
2020, 35(4): 363-377.   doi: 10.1007/s12250-020-00208-3
收稿日期: 2019-11-30 录用日期: 2020-02-03 出版日期: 2020-03-09
[HTML全文] [PDF 558KB] Springerlink
Flaviviruses are a genus of mostly arthropod-borne RNA viruses that cause a range of pathologies in humans. Basic knowledge on flaviviruses is rapidly expanding, partly due to their status as frequent emerging or re-emerging pathogens. Flaviviruses include the dengue, Zika, West Nile, tick-borne encephalitis and yellow fever viruses (DENV, ZIKV, WNV, TBEV and YFV, respectively). As is the case with other families of viruses, the success of productive infection of human cells by flaviviruses depends in part on the antiviral activity of a heterogeneous group of cellular antiviral proteins called restriction factors. Restriction factors are the effector proteins of the cell-autonomous innate response against viruses, an immune pathway that also includes virus sensors as well as intracellular and extracellular signal mediators such as type Ⅰ interferons (IFN-I). In this review, I summarize recent progress toward the identification and characterization of flavivirus restriction factors. In particular, I focus on IFI6, Schlafen 11, FMRP, OAS-RNase L, RyDEN, members of the TRIM family of proteins (TRIM5α, TRIM19, TRIM56, TRIM69 and TRIM79α) and a new mechanism of action proposed for viperin. Recent and future studies on this topic will lead to a more complete picture of the flavivirus restrictome, defined as the ensemble of cellular factors with demonstrated anti-flaviviral activity.
Research Article
与慢性HBV感染风险相关的新基因变异
范梦洁, 王晶, 王飒, 李腾龑, 潘虹, 刘汉奎, 徐惠芳, Daria V. Zhernakova, Stephen J. O'Brien, 冯珍如, 常乐, 戴二黑, 卢建华, 席宏丽, 于岩岩, 张建国, 王彬彬, 曾争
2020, 35(4): 378-387.   doi: 10.1007/s12250-020-00200-x
收稿日期: 2019-03-05 录用日期: 2020-01-16 出版日期: 2020-04-15
[HTML全文] [PDF 1402KB] Springerlink ESM
一些慢性乙肝病毒(HBV)感染者在表达抗乙肝病毒表面抗体(anti-HBs)后仍未能清除HBV,其机理未清楚。本研究采用两阶段病例对照研究,旨在发现影响HBV感染结局的新基因变异。在第一阶段,用Illumina Hiseq x-10对101例HBsAg和anti-HBs同时阳性的病例组和102例anti-HBs阳性但HBsAg阴性的对照组进行全外显子测序。在第二阶段,用飞行时间质谱法对579例慢性HBV感染者(病例组)和439例HBV清除者(对照组)进行候选基因检测。使用ARCHITECT I2000、Roche Cobas Taqman和商用试剂盒进行HBV病毒学和血清学检查。应用基因组分析工具GATK、ExAC数据库、SPSS和PLINK进行生物信息学分析。在第一阶段,没有发现显著的功能性基因变异,但结合第二阶段的结果发现,慢性HBV感染组细胞分裂因子8 (DOCK8)基因rs506121位点的T等位基因频率(P = 0.002, OR = 0.77, 95%CI [0.65, 0.91])和碳酐酶9 (CA9)基因rs2071676位点的A等位基因频率(P = 0.0003, OR = 1.35, 95%CI [1.15, 1.58])高于病毒清除组。故DOCK8基因rs506121位点的T等位基因和CA9基因rs2071676位点的A等位基因可能是影响HBV持续感染的潜在危险遗传因素。
乙型肝炎病毒前C与C基因在免疫耐受期内的进化高度保守
骆予倩, 张乐, 戴毅敏, 胡娅莉, 许碧云, 周乙华
2020, 35(4): 388-397.   doi: 10.1007/s12250-020-00194-6
收稿日期: 2019-08-02 录用日期: 2019-12-06 出版日期: 2020-03-02
[HTML全文] [PDF 440KB] Springerlink ESM
乙型肝炎病毒(HBV)具有高突变性特征,这通常归因于HBV病毒逆转录酶缺乏校正功能及宿主的免疫压力。本研究中,为研究相同来源的HBV在不同宿主中的进化,纳入了来自于14个家庭的31位HBV慢性携带者。第一组为纵向分析(取样间隔6~7.2年):8对母亲与其配对子女(5.5~6.7岁)血清中HBV前C与C基因(pre-C/C)序列;第二组来自6个已知存在家族内HBV感染家庭的15位成年人(21~78岁)的血清中HBV pre-C/C序列。在6~7.2年间,第一组的8位母亲及其孩子处于免疫耐受期,其所携带的HBV pre-C/C基因序列几乎没有改变。第二组的15位成年人绝大多数处于免疫清除期或病毒低复制期,HBV pre-C/C基因序列在家庭内每位个体间存在多样的突变。与来源于临近城市所报道的HBV序列(GQ205441)相比,第一组HBV pre-C/C在核苷酸水平具98.56-99.52%同源性,在氨基酸水平具99.5-100%同源性。然而第二组HBV pre-C/C与GQ205441相比具有多个突变,主要分布于免疫细胞识别表位和precore基因的G1896位点。上述结果提示,HBV基因组进化中的高突变性特征与宿主免疫压力密切相关。
中国不同家养动物蜱虫病毒基因组的比较
赵婷婷, 龚海燕, 沈小娟, 张文, 单同领, 余向前, 王胜晋, 崔立
2020, 35(4): 398-406.   doi: 10.1007/s12250-020-00197-3
收稿日期: 2019-05-08 录用日期: 2019-12-11 出版日期: 2020-03-10
[HTML全文] [PDF 665KB] Springerlink
蜱虫能传播多种虫媒病毒。蜱传病毒对人类或牲畜的健康构成了重大威胁。本研究旨在调查中国中东部地区蜱类及蜱相关病毒的地理分布。2017年,我们收集了来源自狗、羊以及牛身上的蜱虫573只,主要包括两种蜱类:扇头蜱和血蜱。测序显示,来自四个采样点的蜱虫病毒体包括19个不同的病毒家族。13,640 reads中有超过37.74%的病毒reads是RNA病毒。通过比较它们的病毒体,发现不同蜱属之间携带的病毒体存在着显著的差异。其中,扇头蜱属的病毒体表现出了更多的多样性和更高的丰度。此外,在不同的两个属之间还观察到病毒种类的大量重叠。相比之下,我们没有发现自然宿主在形成病毒多样性方面起主要作用的证据。地理位置对病毒科也有显著影响。系统进化分析表明,本研究发现的新型负意义RNA病毒与蜱病毒1型和3型亲缘关系近。综上所述,本研究为根据物种、自然宿主和地理位置比较蜱虫携带病毒奠定了基础。
基于量子点单病毒示踪技术研究猪繁殖与呼吸综合征病毒在细胞内的转运
梁振普, 李鹏娟, 王彩平, Deepali Singh, 张小霞
2020, 35(4): 407-416.   doi: 10.1007/s12250-019-00187-0
收稿日期: 2019-08-20 录用日期: 2019-10-09 出版日期: 2019-12-23
[HTML全文] [PDF 1825KB] Springerlink ESM
基于量子点的单粒子示踪技术能较长时间地示踪病毒在活细胞内的侵染情况。猪繁殖与呼吸综合征病毒(PRRSV)是一种大小约40-60纳米的小尺寸病毒,该病毒给全世界的生猪产业造成了巨大的经济损失。弄清病毒的侵染机制对开发有效的抗病毒策略至关重要。本研究利用链霉亲和素-生物素系统对PRRSV实现了量子点标记,检测了该病毒在活细胞内的感染过程。结果显示,量子点标记对病毒的感染性几乎没有影响。在进入细胞之前,PRRSV会在细胞膜上振动,并通过细胞内体介导的入胞途径进入细胞。PRRSV以慢-快-慢的振动运动模式最终聚集在核周区域。PRRSV一旦入胞,就沿着微管、微丝、波形蛋白这三种细胞骨架蛋白进行转运。另外,荧光共定位研究显示,在运输过程中PRRSV粒子与非肌肉肌球蛋白NMHC Ⅱ-A发生了互作。本研究可以促进量子点在病毒尤其是较小尺寸病毒的可视化研究,对PRRSV的侵染机制解析也提供了重要的研究结果。
HIV-1感染的B-NSG人源化小鼠模型的建立
樊天娇, 孙丽, 杨献光, 金侠, 孙玮玮, 王建华
2020, 35(4): 417-425.   doi: 10.1007/s12250-019-00181-6
收稿日期: 2019-07-12 录用日期: 2019-12-02 出版日期: 2019-12-21
[HTML全文] [PDF 855KB] Springerlink
人免疫缺陷病毒1型(HIV-1)感染的动物模型可用于阐述病毒致病机理和评价抗病毒策略。本文利用重度免疫缺陷的B-NSG (NOD-PrkdcscidIl2rgtm1/Bcge) 小鼠建立HIV-1感染的动物模型。健康人外周血单核细胞 (PBMCs)通过尾静脉注射移植入B-NSG小鼠,3周后可在小鼠外周血及部分组织中检测到重建的人T淋巴细胞;该人源化小鼠可被HIV-1感染,并且HIV-1感染诱导的T淋巴细胞动态变化可模拟人体内急性感染特性;联合抗逆转录病毒治疗(cART) 可抑制病毒复制,恢复T淋巴细胞的异常变化。该HIV-1感染的人源化B-NSG小鼠模型,不但可用于阐述HIV-1与T细胞相互作用机制,还可为评价抗病毒策略提供有效的工具。
建立柯萨奇病毒A10型的感染性克隆和单轮感染性颗粒
王敏, 闫静静, 朱流垚, 王萌, 刘丽珍, 喻锐, 陈明, 荀静娜, 张玉玲, 易志刚, 章树业
2020, 35(4): 426-435.   doi: 10.1007/s12250-020-00198-2
收稿日期: 2019-09-27 录用日期: 2019-12-24 出版日期: 2020-03-06
[HTML全文] [PDF 8738KB] Springerlink ESM
柯萨奇病毒A10型(Coxsackievirus A10, CVA10)是手足口病的主要病原之一。目前尚无控制CVA10感染的疫苗和抗病毒药物。CVA10反向遗传学工具将有助于其机制研究及其疫苗和抗病毒药物研发。本研究中,我们构建了CVA10原型和带Myc标签的感染性克隆。将病毒mRNA转染人横纹肌肉瘤(RD)细胞,获得存活的CVA10病毒。二代测序技术和病毒学实验进一步证实了拯救的CVA10特性。进而构建带有荧光素酶报告基因的CVA10亚基因组复制子和带有EGFP报告基因的病毒衣壳蛋白表达载体。在人胚肾293T细胞(HEK293T)中,共转染病毒复制子RNA和衣壳蛋白表达载体可获得单轮感染性颗粒(Single round infectious particles, SRIPs)。基于CVA10复制子RNA,制备带有肠道病毒A71(EVA71)衣壳或CVA10衣壳的SRIPs。EVA71型SRIPs感染依赖SCARB2,而CVA10型SRIPs则不需要。发现在5'-非翻译区(UTR)之前插入cis-active hammerhead ribozyme(HHRib)可以显著提高复制子的活性和SRIPs的生产。综上所述,我们成功建立并优化了CVA10原型毒株的反向遗传学工具,包括感染性克隆和SRIPs系统,这些工具将有助于CVA10的基础和转化研究。
丙型肝炎病毒NS2蛋白抑制在细胞内RNA干扰
周惠, 钱齐, 舒婷, 许久月, 孔静, 穆敬芳, 邱洋, 周溪
2020, 35(4): 436-444.   doi: 10.1007/s12250-019-00182-5
收稿日期: 2019-10-12 录用日期: 2019-11-01 出版日期: 2019-11-27
[HTML全文] [PDF 1117KB] Springerlink ESM
RNA干扰(RNAi)作为一种进化上保守的转录后基因沉默机制,被认为是真核生物中一种重要的抗病毒免疫。许多病毒已被证明编码RNAi抑制因子(VSR)来拮抗RNAi抗病毒免疫。丙型肝炎病毒(HCV)是引起急慢性肝炎的重要病原体。在本研究中,我们筛选了HCV所有的非结构蛋白,发现HCV NS2可以在哺乳动物细胞中抑制由小发卡RNA(shRNA)或siRNA诱导的RNAi。此外,通过一系列的点突变分析,我们证明NS2可以通过与双链RNA(dsRNA)和siRNA直接相互作用来抑制RNAi,并进一步确定NS2的半胱氨酸184(C184)是其VSR活性必须。综上所述,我们的发现揭示了HCV NS2在体外可以作为VSR,从而为HCV的生命周期和病毒-宿主相互作用提供了新的见解。
HRV-C 3C蛋白酶与芦平曲韦(Rupintrivir)复合物的三维结构为抑制剂设计提供新思路
袁帅, 樊凯悦, 陈中豪, 孙瑶, 侯海, 朱玲
2020, 35(4): 445-454.   doi: 10.1007/s12250-020-00196-4
收稿日期: 2019-08-21 录用日期: 2019-12-25 出版日期: 2020-02-26
[HTML全文] [PDF 2683KB] Springerlink
人鼻病毒(HRVs)是引起感冒的最主要病原体,而HRV-C能在儿童中导致更严重的疾病,并且与哮喘的急性加重紧密相关。3C蛋白酶高度保守,不仅在病毒复制时切割病毒的多聚蛋白,还能协助病毒逃逸宿主免疫系统,因此,它是一个重要的药物靶点。已有部分病毒的3C蛋白酶与芦平曲韦的复合物结构被解析,这些结构为药物特异性的决定因素提供了信息。我们分别解析了HRV-C15的3C蛋白酶的三维结构以及其与芦平曲韦复合物的三维结构。HRV-C15的3C蛋白酶结构里含有更小体积的亚结合位点S1’和半闭合的亚结合位点S2,而它们曾被认为是A型肠道病毒(EV-A)特有的构象。芦平曲韦在复合物结构里呈现出“中间态”构象,或能为高效抗病毒抑制剂的设计提供更多的思路。我们对3C蛋白酶三维结构和氨基酸序列的进一步分析提示现有的药物或许还能有新的应用方法。
DCpep修饰的新城疫-H9N2亚型禽流感嵌合病毒样颗粒的构建及免疫原性研究
徐小洪, 钱晶, 秦岭松, 李金斗, 薛聪, 丁佳欣, 王玮琦, 丁伟, 尹仁福, 金宁一, 丁壮
2020, 35(4): 455-467.   doi: 10.1007/s12250-020-00199-1
收稿日期: 2019-02-03 录用日期: 2019-11-18 出版日期: 2020-04-09
[HTML全文] [PDF 1530KB] Springerlink
新城疫病毒(NDV)和H9N2亚型禽流感病毒(AIV)是两种重要的禽呼吸道病原,给养禽业造成了巨大的经济损失。针对这两种病原的现有疫苗主要有两种,其中灭活疫苗难于诱导有效的黏膜免疫,而弱毒疫苗则存在毒力返强的风险。DCpep是一种能辅助活化树突状细胞(Dendritic cell, DC)的多肽。而DC是连接天然免疫和适应性免疫的纽带,对呼吸道相关适应性免疫反应具有重要的作用。因此,在本研究中,我们构建了一种包含NDV HN蛋白和H9N2亚型AIV H9蛋白的、DCpep修饰的嵌合型新城疫病毒样颗粒(cVLP)。经检测,该疫苗可有效活化DC、诱导高水平的免疫反应、促进分泌型IgA(sIgA)的分泌、加强脾脏T细胞的分化。同时,它还可以有效保护SPF鸡不受NDV和H9N2的攻击。除此之外,相比于肌肉注射,经呼吸道免疫的cVLP还能诱导产生更加强烈的sIgA分泌和更短的排毒时间。综上,这种cVLP是一种良好的疫苗候选株,为NDV和AIV的防控奠定了基础。
A Mother-to-Child Transmission Study in Nigeria: The Impact of Maternal HIV Infection and HAART on Plasma Immunoglobulins, Cytokine Profiles and Infant Outcome
Chinwe O. Ewenighi-Amankwah, Charles Chinedum Onyenekwe, Ogochukwu Udemba, Patience Muogbo, Lijun Rong
2020, 35(4): 468-477.   doi: 10.1007/s12250-020-00202-9
收稿日期: 2019-10-09 录用日期: 2019-12-24 出版日期: 2020-03-10
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Prevention of mother-to-child transmission (PMTCT) of HIV with highly active antiretroviral therapy (HARRT) allows the HIV+ pregnant mothers to have vaginal delivery and breastfeed. Here we investigated the maternal plasma immunoglobulin, cytokine secretion and the outcome of the exposed infants among the HIV+ HAART treated pregnant women in Nigeria. In this study, different plasma immunoglobulins and cytokines were measured in the HIV+ HAART treated pregnant mothers. Pooled culture supernatants of B and T lymphocytes showed lower levels of IFN-c, IL-10 and IL-4. There were lower IFN-c and IL-10 secretions at 1st trimester; however, IL-10 continued to be lower throughout 2nd and 3rd trimesters. TNF-a secretion significantly decreased as pregnancy progressed to term. There were high plasma IgG and low IgM in the HIV+ HAART treated pregnant women. Plasma IgG was high during 1st and 3rd trimesters. After one year of follow up, all the exposed children were seronegative for HIV-1 and HIV-2. Vaginal delivery and breastfeeding among HIV+ HAART treated mothers have shown to be safe. The use of HAART by the infected mothers and the use of septrin and niverapin by the exposed infants prevented mother to-child transmission of HIV.
Letter
登革病毒快速诊断方法在诊断特殊免疫状态感染者的局限性
庾蕾, 温莺芬, 向梦蓉, 洪文昕, 赵令斋, 张复春
2020, 35(4): 478-480.   doi: 10.1007/s12250-019-00183-4
收稿日期: 2019-04-25 录用日期: 2019-11-18 出版日期: 2020-01-14
[HTML全文] [PDF 413KB] Springerlink ESM
非结构蛋白1(NS1)快速检测是临床常用的登革病毒(DENV)感染筛查方法之一。但该诊断试验的敏感性会受到患者免疫状况和感染的DENV血清型的影响。在本研究中,我们报道了一例DENV感染疑似病例。实验室采用胶体金法检测NS1在连续两天血清样品均为阴性,同时IgM也呈阴性。该病人以DENV核酸检测确诊为DENV2感染。然而,在另外14例DENV-2感染病例中,若同时做NS1快速检测和病毒RNA检测,其结果是一致的。进一步采用ELISA法可在该病例血清中检测到非常低水平的NS1蛋白。此外,采用商业化ELISA试剂盒(PanBio dengue IgM and IgG capture ELISA)检测该病例血清中抗体显示延迟的IgM反应和缺陷的IgG反应。血清样本中E和NS1基因的序列分析显示没有突变,因此该患者NS1分泌减少和抗体反应缺陷并非所感染的病毒株变异所致。这些结果表明,DENV感染者个体差异可能导致临床误诊,对高度怀疑的病例应进行多诊断策略和连续样本检测。
中国不常见暴露引起的丙型肝炎病毒感染应引起重视
覃新程, 钟丽华, 朱丽影, 亚历山大·普柳斯宁, 张永振
2020, 35(4): 481-485.   doi: 10.1007/s12250-019-00191-4
收稿日期: 2019-04-26 录用日期: 2019-12-02 出版日期: 2020-02-21
[HTML全文] [PDF 299KB] Springerlink ESM
来自黑龙江省的两姐妹分别在半年前和3年前常规检查中发现丙型肝炎病毒(HCV)IgG阳性,直到她们感到虚弱和疲劳才去一同去医院接受治疗。门诊初步诊断结果表明HCV-IgG阳性,入院检查证实她们都感染了2a基因型的丙型肝炎病毒。在他们直系亲属血液样本中未检测到HCV,排除了家庭中的垂直传播或水平传播。HCV基因组序列的系统发育分析表明,这两名妇女感染了具有不同遗传特征的HCV病毒株,排除了同一来源的可能性。随后的调查没有发现确凿的能表明她们的感染途径的证据。该研究的结果支持以往的观点,即不常见暴露引起的HCV感染可能导致HCV传播,因此这类感染应予以重视。
Sero-Epidemiological Survey of Crimean-Congo Hemorrhagic Fever among the Human Population of the Punjab Province in Pakistan
Muhammad Furqan Shahid, Muhammad Zubair Shabbir, Kamran Ashraf, Muzaffar Ali, Saima Yaqub, Aziz Ul-Rahman, Nageen Sardar, Nadia Mukhtar, Zarfishan Tahir, Tahir Yaqub
2020, 35(4): 486-489.   doi: 10.1007/s12250-020-00195-5
收稿日期: 2019-04-18 录用日期: 2019-11-07 出版日期: 2020-02-26
[HTML全文] [PDF 422KB] Springerlink ESM
朊蛋白表达与神经胶质瘤等级相关
罗乔荔, 王一松, 范东瀛, 王士杰, 王培刚, 安静
2020, 35(4): 490-493.   doi: 10.1007/s12250-020-00209-2
收稿日期: 2019-10-08 录用日期: 2020-02-17 出版日期: 2020-03-31
[HTML全文] [PDF 830KB] Springerlink
脑胶质瘤是最常见的原发性中枢神经系统(CNS)肿瘤。迄今为止,神经胶质瘤发病原因仍不明确,当前治疗方案效果并不理想。高级别神经胶质瘤(HGG)比低级别神经胶质瘤(LGG)更具侵略性,且中位生存期更短。阮蛋白(PrP)是在CNS中最丰富的保守表达的糖蛋白。多项研究表明PrP与细胞粘附、抗凋亡,迁移,信号转导、病毒复制、免疫调节和细胞分化等相关(Sarnataro等,2017)。与此同时,PrP的表达水平在包括神经胶质瘤在内的多种肿瘤中被上调。本研究采用免疫组织化学方法研究了不同级别胶质瘤中PrP的表达,结果表明HGG和LGG之间PrP的阳性率和表达水平存在显著差异,PrP染色的阳性程度与胶质瘤级别呈线性关系。这些结果表明PrP可能在神经胶质瘤的进展中起重要作用,并且可能是影响神经胶质瘤预后的生物靶标。这些结果表明PrP可能在神经胶质瘤的进展中起重要作用,并且可能是影响神经胶质瘤预后的生物靶标。
Re-emergence of Highly Pathogenic Avian Influenza H5N1 in Nigeria, 2014–2016: Role of Social Network and Value Chain Forces in Interstate Transmission
Daniel Oladimeji Oluwayelu, Clement Adebajo Meseko, Adekunle Bamidele Ayinmode, Adebowale Idris Adebiyi, Mike Aneshimi Lawani, Florence Omonele Kakulu
2020, 35(4): 494-498.   doi: 10.1007/s12250-020-00201-w
收稿日期: 2019-08-07 录用日期: 2020-01-17 出版日期: 2020-03-31
[HTML全文] [PDF 992KB] Springerlink
Correction
Correction to: Development of a Novel Reverse Transcription Loop-Mediated Isothermal Amplification Method for Rapid Detection of SARS-CoV-2
Renfei Lu, Xiuming Wu, Zhenzhou Wan, Yingxue Li, Lulu Zuo, Jianru Qin, Xia Jin, Chiyu Zhang
2020, 35(4): 499-499.   doi: 10.1007/s12250-020-00223-4
出版日期: 2020-04-23
[HTML全文] [PDF 171KB] Springerlink