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IMB-0523 Inhibits Enterovirus 71 Replication by Activating Signal Transducer and Activator of Transcription 3 Signaling to Upregulate Interferon-Stimulated Genes Expression IMB-0523通过激活信号转导子和转录激活子3信号上调干扰素刺激基因表达抑制肠道病毒71复制
Pub Date : 2022-09-22 DOI: 10.1097/ID9.0000000000000072
Hui-qiang Wang, Miao Ge, Yanping Li, Yuhuan Li, Zhuorong Li
Abstract Background Hand, foot, and mouth disease caused by enterovirus 71 (EV71) infection is prevalent in the Asia-Pacific region in recent years. Currently, no drug is available for the prevention and treatment of EV71 infection. IMB-0523, a N-phenylbenzamide derivative, inhibits hepatitis B virus replication by upregulating the expression of APOBEC3G. In the present study, the effect of IMB-0523 on EV71 replication and related mechanism were investigated. Methods The cytotoxicity of IMB-0523 was determined by cell counting kit. Quantitative real-time polymerase chain reaction and Western blot assay were used to detect the effect of IMB-0523 on EV71 replication and related mechanism. Cytopathic effect assay was used to investigate the effect of IMB-0523 on different EV71 strains, coxsackievirus A16, and coxsackieviruses of group B. Results The results showed that IMB-0523 could dose-dependently inhibit EV71 replication. Preliminary mechanism studies showed that IMB-0523 could activate STAT3 signaling to upregulate the expression of interferon-stimulated genes to play an antiviral role. In addition, IMB-0523 inhibited the replication of different EV71 strains, coxsackievirus A16, and coxsackieviruses of group B. Conclusions IMB-0523 inhibits EV71 replication by activating the STAT3 signaling pathway to upregulate interferon-stimulated gene expression. IMB-0523 has broad-spectrum antiviral potential and may be used as a lead compound for the development of broad spectrum antiviral drugs.
摘要背景近年来,由肠道病毒71型(EV71)感染引起的手足口病在亚太地区流行。目前,没有药物可用于预防和治疗EV71感染。IMB-0523是一种N-苯基苯甲酰胺衍生物,通过上调APOBEC3G的表达来抑制乙型肝炎病毒的复制。在本研究中,研究了IMB-0523对EV71复制的影响及其相关机制。方法用细胞计数试剂盒测定IMB-0523的细胞毒性。采用实时定量聚合酶链反应和蛋白质印迹法检测IMB-0523对EV71复制的影响及其相关机制。采用细胞病变效应分析法研究IMB-0523对不同EV71株、B组柯萨奇病毒A16和柯萨奇毒株的影响。初步机制研究表明,IMB-0523可以激活STAT3信号,上调干扰素刺激基因的表达,发挥抗病毒作用。此外,IMB-0523抑制了不同EV71菌株、B组的柯萨奇病毒A16和柯萨奇病毒的复制。结论IMB-052通过激活STAT3信号通路上调干扰素刺激的基因表达来抑制EV71的复制。IMB-0523具有广谱抗病毒潜力,可作为开发广谱抗病毒药物的先导化合物。
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引用次数: 0
Pre-treatment Drug Resistance Could Impact the 96-Week Antiretroviral Efficacy in Treatment-Naive HIV-1–Infected Patients in Guangdong, China 在中国广东,治疗前的耐药性可能会影响初治hiv -1感染患者96周抗逆转录病毒治疗的疗效
Pub Date : 2022-09-09 DOI: 10.1097/ID9.0000000000000069
P. Guo, Y. Lan, Quanmin Li, X. Ling, Junbin Li, Xiaoping Tang, F. Hu, W. Cai, Linghua Li
Abstract Background With the high prevalence of pre-treatment drug resistance (PDR) and the potential impact to the virological inhibition, the detection of PDR was particularly necessary. This study aimed to determine the prevalence of PDR in Guangdong, China, and its impact on antiretroviral therapy (ART) in treatment-naive HIV patients. Methods A retrospective cohort study was conducted. A total of 1936 HIV-1–infected treatment-naive patients in the clinic of the infectious department, Guangzhou Eighth People’s Hospital, between August 2018 and December 2019 were assayed for PDR mutations before initiating ART. Patients with PDR mutations (PDR arm) were screened and compared with those without drug-resistant mutations (non-PDR arm). The rate of HIV-1 virologic failure (VF) and CD4+ T-cell counts of the 2 arms were compared at the 96th week after ART to evaluate the impact of PDR on the efficacy of ART. Results Pretreatment drug resistance was detected in 125 cases (6.46%) from the 1936 enrolled participants, most of which were resistant to non-nucleoside reverse transcriptase inhibitors (64.00%, 80/125). One hundred and eight of 125 completed the follow-up of 96 weeks (PDR arm). In this cohort, 52 patients whose ART regimen containing the resistant drug were grouped as con-PDR arm, and the remaining 56 patients whose ART regimen did not contain the resistant drug were grouped as non- con-PDR arm. A total of 125 patients without PDR were randomly selected as the control group (non-PDR arm), 112 of whom had completed the 96-week follow-up. At the 96th week after ART initiation, 7 patients (6.5%, 7/108) in the PDR arm and 1 patient (0.9%, 1/112) in the non-PDR arm developed VF, exhibiting a significant difference (χ2 = 4.901, P = 0.029). Meanwhile, 3 patients (5.8%, 3/52) in the con-PDR arm developed VF; the rate was also higher than that in the non-PDR arm, but without a significant difference (χ2 = 3.549, P = 0.095). The CD4+ T-cell count in the non-PDR arm increased more than the PDR arm (386.6 vs. 319.1 cells/μL, t = 2.448, P = 0.015) or the con-PDR arm (386.6 vs. 325.1 cells/μL, t = 1.821, P = 0.070) at 12 weeks after ART. However, no significant differences were observed in the CD4+ T-cell count from the 24th week after ART onward. Conclusions Pretreatment drug resistance was moderately prevalent in Guangdong, China, and could affect the antiretroviral efficacy during a 96-week observation period, indicating the need to closely monitor PDR before ART initiation.
摘要背景治疗前耐药(pre- drug resistant, PDR)的高发及对病毒学抑制的潜在影响,使得PDR的检测显得尤为必要。本研究旨在确定PDR在中国广东的流行情况及其对初次接受治疗的HIV患者抗逆转录病毒治疗(ART)的影响。方法采用回顾性队列研究。对2018年8月至2019年12月在广州第八人民医院感染科门诊接受治疗的1936例hiv -1感染患者在开始抗逆转录病毒治疗前进行了PDR突变检测。筛选PDR突变患者(PDR组)并与无耐药突变患者(非PDR组)进行比较。在ART治疗后第96周比较两组患者HIV-1病毒学失败率(VF)和CD4+ t细胞计数,以评价PDR对ART疗效的影响。结果1936例受试者中有125例(6.46%)检测到预处理耐药,其中大部分对非核苷类逆转录酶抑制剂耐药(64.00%,80/125)。125例中有108例完成了96周的随访(PDR组)。在该队列中,52例ART方案中含有耐药的患者被分为con-PDR组,其余56例ART方案中不含有耐药的患者被分为non- con-PDR组。随机选择125例无PDR的患者作为对照组(非PDR组),其中112例完成了96周的随访。开始ART治疗后第96周,PDR组7例(6.5%,7/108)、非PDR组1例(0.9%,1/112)发生VF,差异有统计学意义(χ2 = 4.901, P = 0.029)。非pdr组3例(5.8%,3/52)发生VF;P = 0.095,差异无统计学意义(χ2 = 3.549)。在ART治疗后12周,非PDR组CD4+ t细胞计数高于PDR组(386.6 vs. 319.1 cells/μL, t = 2.448, P = 0.015)或con-PDR组(386.6 vs. 325.1 cells/μL, t = 1.821, P = 0.070)。然而,从抗逆转录病毒治疗后第24周开始,CD4+ t细胞计数没有明显差异。结论在96周的观察期内,广东地区预处理耐药普遍存在,并可能影响抗逆转录病毒治疗的疗效,提示在开始抗逆转录病毒治疗前应密切监测PDR。
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引用次数: 0
Chimeric Antigen Receptor-Modified Immune Cells for Eradication of HIV Reservoirs 嵌合抗原受体修饰的免疫细胞根除HIV病毒库
Pub Date : 2022-09-01 DOI: 10.1097/ID9.0000000000000066
Guo-fen Re, Beibei Tang, Jing Kou, Chen Hong, Yi‐Qun Kuang
Abstract Host immune surveillance can achieve powerful clearance of infectious pathogens. Acute human immunodeficiency virus type I (HIV-1) infection can establish viral reservoirs in humans, and persistent chronic activation by the virus exhausts the immune system and ultimately causes acquired immunodeficiency syndrome. Although antiretroviral therapy (ART) can reduce the viral load and viremia in patients, latent HIV-1 reservoirs are still the biggest challenge that needs to be overcome to eradicate the virus. However, the low or absent viral antigen expression and epitope mutation caused during durable ART result in host immune escape and reservoir cell inaccessibility. In addition, durable ART accompanied by inflammation and persistent activation of immune cells, especially dysfunction and/or exhaustion of T cells. With the development of immunology, genetics, and genetic engineering technology, researchers can construct chimeric antigen receptors (CARs) to modify immune cells to enhance HIV clearance. The important research goals of creating CARs to modify natural killer (NK) and T cells are an attempt to enhance the functional effects of immune cells and restore the function of the immune system. This article reviews the latent characteristics of HIV, the development of CAR molecules, and the strategies for reprogramming T cells and NK cells with CARs, and aims to clear the HIV reservoirs and related potential problems.
宿主免疫监测可以实现对感染性病原体的强力清除。急性人类免疫缺陷病毒I型(HIV-1)感染可以在人体内建立病毒库,病毒的持续慢性激活耗尽免疫系统,最终导致获得性免疫缺陷综合征。尽管抗逆转录病毒疗法(ART)可以减少患者体内的病毒载量和病毒血症,但潜伏的HIV-1病毒库仍然是根除这种病毒需要克服的最大挑战。然而,在持续抗逆转录病毒治疗过程中,病毒抗原表达低或缺失和表位突变导致宿主免疫逃逸和库细胞不可接近。此外,持久的抗逆转录病毒治疗伴有炎症和免疫细胞的持续激活,特别是T细胞功能障碍和/或衰竭。随着免疫学、遗传学和基因工程技术的发展,研究人员可以构建嵌合抗原受体(CARs)来修饰免疫细胞以增强对HIV的清除能力。利用car修饰自然杀伤细胞(NK)和T细胞的重要研究目标是增强免疫细胞的功能效应,恢复免疫系统的功能。本文综述了HIV的潜在特征、CAR分子的发展以及用CAR对T细胞和NK细胞进行重编程的策略,旨在清除HIV储库和相关潜在问题。
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引用次数: 0
The Arms Race in the War Between Virus and Host: Implications for Anti-Infection Immunity. 病毒和宿主战争中的军备竞赛:对抗感染免疫的启示。
Pub Date : 2022-07-20 eCollection Date: 2022-07-01 DOI: 10.1097/ID9.0000000000000062
William J Liu, Jianqing Xu
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引用次数: 0
Highly Prevalent SARS-CoV-2 Antigenemia in COVID-19 Patients. 新冠肺炎患者中高度流行的SARS-CoV-2抗基因血症。
Pub Date : 2022-07-20 eCollection Date: 2022-07-01 DOI: 10.1097/ID9.0000000000000057
Wenyan Zhang, Wei Liu, Jiawang Lin, Jing Jin, Kefu Zhao, Liwei Zhu, Xiuzhen Wang, Lijie Wang, Renshu Tang, Yindi Zhu, Wei Zhou, Enqing You, Lei Zhang, Xuxiang Liu, Jinju Wu, Lili Chen, Wenjing Wang, Qiang Zhang, Rongbao Gao

Background: Many issues, such as severity assessment and antibody responses, remain to be answered eagerly for evaluation and understanding of COVID-19. Immune lesion is one of key pathogenesis of the disease. It would be helpful to understand the disease if an investigation on antigenemia and association was conducted in the patients with SARS-CoV-2 infection.

Methods: A total of 156 patients admitted to the First People's Hospital of Hefei or Anhui Provincial Hospital on January to February 2020 were involved in this study. SARS-CoV-2 nucleocapsid (NP) antigen, specific IgM/IgG antibodies, and RNA were detected in sequential sera from three COVID-19 patients, and additional 153 COVID-19 patients by means of NP-antigen capture enzyme-linked immunosorbent assay, colloidal gold quick diagnosis, and real-time RT-PCR, respectively. The clinical types of COVID-19 patients were classified into asymptomatic, mild, moderate, severe, and critical, following on the Chinese guideline of COVID-19 diagnosis and treatment. The demographic and clinical data of patients were obtained for comparable analysis.

Results: NP antigen was detected in 5 of 20 sequential sera collected from three COVID-19 patients with typically clinical symptoms, and 60.13% (92/153) expanded samples collected within 17 days after illness onset. No SARS-CoV-2 RNA segment was detected in these sera. The NP positive proportion reached a peak (84.85%, 28/33) on 6 to 8 days after illness onset. Both NP concentration and positive proportion were increased with the increase of clinical severity of COVID-19. Compared to NP negative patients, NP positive patients had older age [years, medians (interquartile ranges (IQR)), 49 (6) vs. 31 (11)], lower positive proportion of NP specific IgM [27.17% (25/92) vs. 59.02% (36/61)], and IgG [21.74% (20/92) vs. 59.02% (36/61)] antibodies, and longer duration [days, medians (IQR), 24 (10) vs. 21 (13)] from illness to recovery.

Conclusions: SARS-CoV-2 NP antigenemia occurred in COVID-19, and presented highly prevalent at early stage of the disease. The antigenemia was related to clinical severity of the disease, and may be responsible for the delay of detectable SARS-Cov-2 IgM.

背景:许多问题,如严重程度评估和抗体反应,仍有待于评估和理解新冠肺炎。免疫损伤是该病的主要发病机制之一。如果对严重急性呼吸系统综合征冠状病毒2型感染患者进行抗原血症和相关性调查,将有助于了解该疾病。方法:共有156名患者于2020年1月至2月入住合肥市第一人民医院或安徽省立医院。通过NP-抗原捕获酶联免疫吸附试验、胶体金快速诊断和实时RT-PCR,分别在3名新冠肺炎患者和另外153名新冠肺炎患者的连续血清中检测了SARS-CoV-2核衣壳(NP)抗原、特异性IgM/IgG抗体和RNA。根据中国新冠肺炎诊断和治疗指南,将新冠肺炎患者分为无症状、轻度、中度、重度和危重症。获得患者的人口统计学和临床数据进行比较分析。结果:从3名具有典型临床症状的新冠肺炎患者采集的20份连续血清中,有5份检测到NP抗原,60.13%(92/153)的扩展样本在17 发病后几天。在这些血清中未检测到严重急性呼吸系统综合征冠状病毒2型核糖核酸片段。NP阳性率在6至8日达到峰值(84.85%,28/33) 发病后几天。NP浓度和阳性率均随新冠肺炎临床严重程度的增加而增加。与NP阴性患者相比,NP阳性患者的年龄较大[年,中位数(四分位数间距(IQR)),49(6)对31(11)],NP特异性IgM的阳性率较低[27.17%(25/92)对59.02%(36/61],IgG的阳性率[21.74%(20/92)对5.902%(36%)],从患病到康复的持续时间较长[天,中位数(IQR,24(10)对21(13)]。结论:严重急性呼吸系统综合征冠状病毒2型NP抗原血症发生于新冠肺炎,并在疾病早期表现为高度流行。抗原血症与疾病的临床严重程度有关,可能是可检测到的严重急性呼吸系统综合征冠状病毒2型IgM延迟的原因。
{"title":"Highly Prevalent SARS-CoV-2 Antigenemia in COVID-19 Patients.","authors":"Wenyan Zhang,&nbsp;Wei Liu,&nbsp;Jiawang Lin,&nbsp;Jing Jin,&nbsp;Kefu Zhao,&nbsp;Liwei Zhu,&nbsp;Xiuzhen Wang,&nbsp;Lijie Wang,&nbsp;Renshu Tang,&nbsp;Yindi Zhu,&nbsp;Wei Zhou,&nbsp;Enqing You,&nbsp;Lei Zhang,&nbsp;Xuxiang Liu,&nbsp;Jinju Wu,&nbsp;Lili Chen,&nbsp;Wenjing Wang,&nbsp;Qiang Zhang,&nbsp;Rongbao Gao","doi":"10.1097/ID9.0000000000000057","DOIUrl":"10.1097/ID9.0000000000000057","url":null,"abstract":"<p><strong>Background: </strong>Many issues, such as severity assessment and antibody responses, remain to be answered eagerly for evaluation and understanding of COVID-19. Immune lesion is one of key pathogenesis of the disease. It would be helpful to understand the disease if an investigation on antigenemia and association was conducted in the patients with SARS-CoV-2 infection.</p><p><strong>Methods: </strong>A total of 156 patients admitted to the First People's Hospital of Hefei or Anhui Provincial Hospital on January to February 2020 were involved in this study. SARS-CoV-2 nucleocapsid (NP) antigen, specific IgM/IgG antibodies, and RNA were detected in sequential sera from three COVID-19 patients, and additional 153 COVID-19 patients by means of NP-antigen capture enzyme-linked immunosorbent assay, colloidal gold quick diagnosis, and real-time RT-PCR, respectively. The clinical types of COVID-19 patients were classified into asymptomatic, mild, moderate, severe, and critical, following on the Chinese guideline of COVID-19 diagnosis and treatment. The demographic and clinical data of patients were obtained for comparable analysis.</p><p><strong>Results: </strong>NP antigen was detected in 5 of 20 sequential sera collected from three COVID-19 patients with typically clinical symptoms, and 60.13% (92/153) expanded samples collected within 17 days after illness onset. No SARS-CoV-2 RNA segment was detected in these sera. The NP positive proportion reached a peak (84.85%, 28/33) on 6 to 8 days after illness onset. Both NP concentration and positive proportion were increased with the increase of clinical severity of COVID-19. Compared to NP negative patients, NP positive patients had older age [years, medians (interquartile ranges (IQR)), 49 (6) <i>vs.</i> 31 (11)], lower positive proportion of NP specific IgM [27.17% (25/92) <i>vs.</i> 59.02% (36/61)], and IgG [21.74% (20/92) <i>vs.</i> 59.02% (36/61)] antibodies, and longer duration [days, medians (IQR), 24 (10) <i>vs.</i> 21 (13)] from illness to recovery.</p><p><strong>Conclusions: </strong>SARS-CoV-2 NP antigenemia occurred in COVID-19, and presented highly prevalent at early stage of the disease. The antigenemia was related to clinical severity of the disease, and may be responsible for the delay of detectable SARS-Cov-2 IgM.</p>","PeriodicalId":73371,"journal":{"name":"Infectious diseases & immunity","volume":"2 3","pages":"193-199"},"PeriodicalIF":0.0,"publicationDate":"2022-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/34/5e/id9-2-193.PMC9295937.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9963341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A COVID-19 Patient Discharged According to Strict Discharge Standards: Viral Negativity in Both Nasopharynx and Feces. 1例新冠肺炎患者严格出院:鼻咽部和粪便均呈病毒阴性。
Pub Date : 2022-07-01 DOI: 10.1097/ID9.0000000000000040
Enqiang Chen, Lichun Wang, Guangming Tang, Menglan Wang, Yachao Tao, Ping Feng, Hong Tang

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) currently has spread all over the world. However, the dynamic characteristics of SARS-CoV-2 infections have not previously been described in detail. Here, we report a cured patient in West China Hospital, and describe the dynamic detection of SARS-CoV-2-RNA in different specimens and viral specific IgM and IgG antibodies in blood. The findings suggest that the fecal SARS-CoV-2-RNA negativity may be considered as a new standard for de isolation. Serum IgM and IgG antibodies detection were helpful for early diagnosis of SARS-CoV-2 infection and judgment of patients in recovery stage, respectively.

目前,严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)已在全球蔓延。然而,SARS-CoV-2感染的动态特征以前没有详细描述。在这里,我们报告了一名华西医院的治愈患者,并描述了不同标本中sars - cov -2 rna和血液中病毒特异性IgM和IgG抗体的动态检测。研究结果提示,粪便SARS-CoV-2-RNA阴性可作为分离的新标准。血清IgM抗体和IgG抗体检测分别有助于SARS-CoV-2感染的早期诊断和患者康复期的判断。
{"title":"A COVID-19 Patient Discharged According to Strict Discharge Standards: Viral Negativity in Both Nasopharynx and Feces.","authors":"Enqiang Chen,&nbsp;Lichun Wang,&nbsp;Guangming Tang,&nbsp;Menglan Wang,&nbsp;Yachao Tao,&nbsp;Ping Feng,&nbsp;Hong Tang","doi":"10.1097/ID9.0000000000000040","DOIUrl":"https://doi.org/10.1097/ID9.0000000000000040","url":null,"abstract":"<p><p>Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) currently has spread all over the world. However, the dynamic characteristics of SARS-CoV-2 infections have not previously been described in detail. Here, we report a cured patient in West China Hospital, and describe the dynamic detection of SARS-CoV-2-RNA in different specimens and viral specific IgM and IgG antibodies in blood. The findings suggest that the fecal SARS-CoV-2-RNA negativity may be considered as a new standard for de isolation. Serum IgM and IgG antibodies detection were helpful for early diagnosis of SARS-CoV-2 infection and judgment of patients in recovery stage, respectively.</p>","PeriodicalId":73371,"journal":{"name":"Infectious diseases & immunity","volume":"2 3","pages":"210-212"},"PeriodicalIF":0.0,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/74/d5/id9-2-210.PMC9295935.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9963342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
MHC Class I Assembly Function and Intracellular Transport Routes for Hepatitis B Virus Antigen Cross-presentation by Heat Shock Protein gp96 热休克蛋白gp96对乙型肝炎病毒抗原交叉呈递的MHC I类组装功能和细胞内转运途径
Pub Date : 2022-07-01 DOI: 10.1097/ID9.0000000000000058
Lijuan Qin, Yongai Liu, Yuxiu Xu, Yang Li, Jun Hu, Y. Ju, Yu Zhang, Shuo Wang, Zihai Li, Changfei Li, Xin Li, S. Meng
Abstract Background: During hepatitis B virus (HBV) infection, virus-infected hepatocytes directly cross-present viral antigens and regulate T cell response within the liver microenvironment. However, little is known regarding the regulatory pathways involved in viral antigen presentation in HBV-infected hepatocytes. This study investigated the underlying mechanism of antigen assembly and the HBV antigen-presenting function of major histocompatibility complex (MHC) class I molecules using heat shock protein gp96. Methods: First, western blotting, flow cytometry, co-immunoprecipitation, GST pull-down, and confocal microscopic assays were performed to determine whether endogenous gp96 affects MHC-I levels via an antigen presentation pathway. Second, the B3Z assay and an AAV/HBV-infected hepatocyte-specific gp96-deficient mouse model were used to determine whether gp96 knockout functionally impaired peptide cross-presentation and produced a weakened antiviral cytotoxic T cell (CTL) response both in vivo and in vitro. Finally, confocal microscopic analysis and the B3Z assay were employed to show that exogenous gp96-associated peptide was present in MHC-I molecules via the endoplasmic reticulum (ER)-Golgi secretory pathway. Results: Compared with the control, gp96 knockdown significantly reduced the cell surface levels of MHC-I by approximately 75% (P < 0.01). Endogenous gp96 interacts with MHC-I and is involved in antigen presentation. Moreover, a weakened antiviral CTL response (34% compared to control mice) has been observed in hepatocyte-specific gp96-deficient mice following HBV infection. gp96 directed exogenous antigen to the ER, and the exogenous gp96-chaperoned peptide was endosome- and proteasome-dependent but not transporter associated with antigen processing dependent. Conclusions: Cellular gp96 promotes the assembly and antigen presentation of MHC class I molecules. In addition, extracellular gp96 served as a natural adjuvant to induce a CTL response in a concerted and regulated manner within different cellular compartments. Our results elucidate the mechanism of assembly of MHC class I molecules by gp96, which may be beneficial for the design of immunotherapy and vaccines.
摘要背景:在乙型肝炎病毒(HBV)感染过程中,病毒感染的肝细胞直接在肝脏微环境中交叉呈递病毒抗原并调节T细胞反应。然而,关于HBV感染肝细胞中病毒抗原呈递的调控途径知之甚少。本研究利用热休克蛋白gp96研究了抗原组装的潜在机制和主要组织相容性复合体(MHC)I类分子的HBV抗原呈递功能。方法:首先,进行蛋白质印迹、流式细胞术、共免疫沉淀、GST下拉和共聚焦显微镜分析,以确定内源性gp96是否通过抗原呈递途径影响MHC-I水平。其次,使用B3Z测定法和AAV/HBV感染的肝细胞特异性gp96缺陷小鼠模型来确定gp96敲除是否在体内和体外功能受损肽交叉呈递并产生减弱的抗病毒细胞毒性T细胞(CTL)反应。最后,共聚焦显微镜分析和B3Z分析表明,外源性gp96相关肽通过内质网(ER)-高尔基体分泌途径存在于MHC-I分子中。结果:与对照组相比,gp96的敲除使MHC-I的细胞表面水平显著降低约75%(P < 0.01)。内源性gp96与MHC-I相互作用并参与抗原呈递。此外,在HBV感染后肝细胞特异性gp96缺陷小鼠中观察到抗病毒CTL反应减弱(与对照小鼠相比为34%)。gp96将外源性抗原导向ER,并且外源性gp96伴侣肽是内体和蛋白酶体依赖性的,但不是与抗原处理相关的转运蛋白依赖性的。结论:细胞gp96促进MHC I类分子的组装和抗原呈递。此外,细胞外gp96作为一种天然佐剂,在不同的细胞区室中以协同和调节的方式诱导CTL反应。我们的研究结果阐明了gp96组装MHC I类分子的机制,这可能有助于免疫疗法和疫苗的设计。
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引用次数: 2
Severe Acute Hepatitis of Unknown Etiology in Children: Is It Caused by Pathogens or Non-infectious Factors? 病因不明的儿童严重急性肝炎:是病原体引起的还是非感染性因素引起的?
Pub Date : 2022-07-01 DOI: 10.1097/ID9.0000000000000060
Wei Hu, Min Zhang, Zhe Xu, Jing Li, Fu-Sheng Wang, Tong Li

Recently, an outbreak of severe acute hepatitis of unknown etiology in children has been reported in more than 27 countries worldwide. However, information on its prevalence in different countries and regions is still lacking. The evidence is suggestive of a potential viral infection, but this has not been fully confirmed. Cases of this disease have been reported in children, mainly in those younger than 5 years old. The reason for the age range of the disease requires further investigation.

最近,在全世界超过27个国家报告了一次病因不明的儿童严重急性肝炎暴发。然而,关于其在不同国家和地区的流行情况的信息仍然缺乏。有证据表明可能是病毒感染,但尚未得到充分证实。据报道,这种疾病的病例发生在儿童中,主要是5岁以下的儿童。发病年龄范围的原因有待进一步研究。
{"title":"Severe Acute Hepatitis of Unknown Etiology in Children: Is It Caused by Pathogens or Non-infectious Factors?","authors":"Wei Hu,&nbsp;Min Zhang,&nbsp;Zhe Xu,&nbsp;Jing Li,&nbsp;Fu-Sheng Wang,&nbsp;Tong Li","doi":"10.1097/ID9.0000000000000060","DOIUrl":"https://doi.org/10.1097/ID9.0000000000000060","url":null,"abstract":"<p><p>Recently, an outbreak of severe acute hepatitis of unknown etiology in children has been reported in more than 27 countries worldwide. However, information on its prevalence in different countries and regions is still lacking. The evidence is suggestive of a potential viral infection, but this has not been fully confirmed. Cases of this disease have been reported in children, mainly in those younger than 5 years old. The reason for the age range of the disease requires further investigation.</p>","PeriodicalId":73371,"journal":{"name":"Infectious diseases & immunity","volume":"2 3","pages":"200-203"},"PeriodicalIF":0.0,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/92/e0/id9-2-200.PMC9295934.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10276633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Innate Immune Response in Respiratory System: A Double-edged Sword Against Virus Infection. 呼吸系统先天免疫反应:对抗病毒感染的双刃剑。
Pub Date : 2022-07-01 DOI: 10.1097/ID9.0000000000000031
Ang Li, Jianqing Xu
Respiratory virus infection, as a leading cause of newly emerging or re-emerging infectious diseases, is undoubtedly a primary threat for global public health. Nevertheless, among various respiratory viruses, namely adenovirus, influenza virus, rhinovirus, respiratory syncytial virus as well as coronavirus, most of them cause self-limited diseases with mild symptoms. However, a fewmay progress into severe morbidity and evenmortality. For example, a-coronavirus HCoV-229E, HCoV-NL63 and ßcoronavirus HCoV-OC43, HCoV-HKU1 only cause mild common cold, whereas the b-coronavirus SARS-CoV, MERSCoV, and SARS-CoV-2 could result in fatal infection and pose great threat to human public health with global pandemics. Similar observations exist for influenza viruses, as low pathogenic seasonal influenza (H3N2) versus high pathogenic avian influenza (H5N1 and H7N9) and 1918 pandemic influenza (H1N1). The mechanisms underlying the nature of different respiratory viral infections should be urgently explored to develop effective intervention approaches.
{"title":"Innate Immune Response in Respiratory System: A Double-edged Sword Against Virus Infection.","authors":"Ang Li,&nbsp;Jianqing Xu","doi":"10.1097/ID9.0000000000000031","DOIUrl":"https://doi.org/10.1097/ID9.0000000000000031","url":null,"abstract":"Respiratory virus infection, as a leading cause of newly emerging or re-emerging infectious diseases, is undoubtedly a primary threat for global public health. Nevertheless, among various respiratory viruses, namely adenovirus, influenza virus, rhinovirus, respiratory syncytial virus as well as coronavirus, most of them cause self-limited diseases with mild symptoms. However, a fewmay progress into severe morbidity and evenmortality. For example, a-coronavirus HCoV-229E, HCoV-NL63 and ßcoronavirus HCoV-OC43, HCoV-HKU1 only cause mild common cold, whereas the b-coronavirus SARS-CoV, MERSCoV, and SARS-CoV-2 could result in fatal infection and pose great threat to human public health with global pandemics. Similar observations exist for influenza viruses, as low pathogenic seasonal influenza (H3N2) versus high pathogenic avian influenza (H5N1 and H7N9) and 1918 pandemic influenza (H1N1). The mechanisms underlying the nature of different respiratory viral infections should be urgently explored to develop effective intervention approaches.","PeriodicalId":73371,"journal":{"name":"Infectious diseases & immunity","volume":"2 3","pages":"132-134"},"PeriodicalIF":0.0,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/29/7a/id9-2-132.PMC9295932.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9963343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Diagnosis and Clinical Management of Acute Severe Hepatitis of Unknown Origin: Operational Recommendation of Peking Union Medical College Hospital. 不明原因急性重型肝炎的诊断与临床处理:北京协和医院手术建议。
Pub Date : 2022-07-01 DOI: 10.1097/ID9.0000000000000061
Wei Cao, Zhenghong Li, Huadong Zhu, Xiang Zhou, Qiwen Yang, Yang Han, Jihai Liu, Qing Chang, Taisheng Li

Around 450 cases of acute severe hepatitis of unknown origin in children have been reported in 21 countries and region globally since April 2022, which has exceeded the past annual incidences of related regions, and has aroused wide concern. Affected patients were predominantly children under 16 years of age, presented with symptoms of acute hepatitis with markedly elevated liver enzymes, and had been ruled out of common viral infections such as hepatitis A, B, C, D, and E. Similar cases have not been reported in China yet. However, considering that the severe acute hepatitis has involved worldwide areas, still with unknown origin, and incidences of severity is relatively high, we formulated this recommendation to standardize diagnosis and treatment of acute severe hepatitis of unknown origin in Peking Union Medical College Hospital, to get fully prepared to the possible public health events.

自2022年4月以来,全球已有21个国家和地区报告了约450例来源不明的儿童急性重型肝炎病例,超过了过去相关地区的年发病率,引起了广泛关注。受影响的患者主要是16岁以下的儿童,表现为急性肝炎症状,肝酶明显升高,并已排除常见的病毒性感染,如甲型、乙型、丙型、丁型和戊型肝炎。但考虑到重症急性肝炎已波及世界范围,病因不明,严重程度发生率较高,为规范北京协和医院不明原因急性重型肝炎诊疗,为可能发生的公共卫生事件做好充分准备,我们制定了本建议。
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引用次数: 1
期刊
Infectious diseases & immunity
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