Targeting host factors:A novel rationale for the management of hepatitis C virus

Hepatitis C is recognized as a major threat to global public health. The current treatment of patients with chronic hepatitis C is the addition of ribavirin to interferon-based therapy which has limited efficacy, poor tolerability, and significant expense. New treatment options that are more potent and less toxic are much needed. Moreover, more effective treatment is an urgent priority for those who relapse or do not respond to current regimens. A major obstacle in combating hepatitis C virus （HCV） infection is that the fidelity of the viral replication machinery is notoriously low, thus enabling the virus to quickly develop mutations that resist compounds targeting viral enzymes. Therefore, an approach targeting the host cofactors, which are indispensable for the propagation of viruses, may be an ideal target for the development of antiviral agents because they have a lower rate of mutation than that of the viral genome, as long as they have no side effects to patients. Drugs targeting, for example, receptors of viral entry, host metabolism or nuclear receptors, which are factors required to complete the HCV life cycle, may be more effective in combating the viral infection. Targeting host cofactors of the HCV life cycle is an attractive concept because it imposes a higher genetic barrier for resistance than direct antiviral compounds. However the principle drawback of this strategy is the greater potential for cellular toxicity.

Host factors are dominant in the development of post-liver transplant non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease(NAFLD) is a recognized problem in patients after orthotopic liver transplantation and may lead to recurrent graft injury. As the increased demand for liver allografts fail to match the available supply of donor organs, split liver transplantation(SLT) has emerged as an important technique to increase the supply of liver grafts. SLT allows two transplants to occur from one donor organ, and provides a unique model for observing the pathogenesis of NAFLD with respect to the role of recipient environmental and genetic factors. Here we report on two recipients of a SLT from the same deceased donor where only one developed non-alcoholic steatohepatitis(NASH), suggesting that host factors are critical for the development of NASH.

Update on enteroviral protease 2A:Structure,function,and host factor interaction

Enteroviruses(EVs)are human pathogens commonly observed in children aged 0–5 years and adults.EV infections usually cause the common cold and hand-foot-and-mouth disease;however,more severe infections can result in multiorgan complications,such as polio,aseptic meningitis,and myocarditis.The molecular mechanisms by which enteroviruses cause these diseases are still poorly understood,but accumulating evidence points to two enterovirus proteases,2Apro and 3Cpro,as the key players in pathogenesis.The 2Apro performs post-translational proteolytic processing of viral polyproteins and cleaves several host factors to evade antiviral immune responses and promote viral replication.It was also discovered that coxsackievirus-induced cardiomyopathy was caused by 2Apro-mediated cleavage of dystrophin in cardiomyocytes,indicating that cellular protein proteolysis may play a key role in enterovirus-associated diseases.Therefore,studies of 2Apro could reveal additional substrates that may be associated with specific diseases.Here,we discuss the genetic and structural properties of 2Apro and review how the protease antagonizes innate immune responses to promote viral replication,as well as novel substrates and mechanisms for 2Apro.We also summarize the current approaches for identifying the substrates of 2Apro to discover novel mechanisms relating to certain diseases.

Turnip mosaic virus pathogenesis and host resistance mechanisms in Brassica

Turnip mosaic virus(TuMV)is a devastating potyvirus pathogen that infects a wide variety of both cultivated and wild Brassicaceae plants.We urgently need more information and understanding of TuMV pathogenesis and the host responses involved in disease development in cruciferous crops.TuMV displays great versatility in viral pathogenesis,especially in its replication and intercellular movement.Moreover,in the coevolutionary arms races between TuMV and its hosts,the virus has evolved to co-opt host factors to facilitate its infection and counter host defense responses.This review mainly focuses on recent advances in understanding the viral factors that contribute to the TuMV infection cycle and the host resistance mechanism in Brassica.Finally,we propose some future research directions on TuMV pathogenesis and control strategies to design durable TuMV-resistant Brassica crops.

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

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

SNX11 Identified as an Essential Host Factor for SFTS Virus Infection by CRISPR Knockout Screening

Severe fever with thrombocytopenia syndrome virus(SFTSV)is a highly pathogenic tick-borne bunyavirus that causes lethal infectious disease and severe fever with thrombocytopenia syndrome(SFTS)in humans.The molecular mechanisms and host cellular factors required for SFTSV infection remain uncharacterized.Using a genome-wide CRISPR-based screening strategy,we identified a host cellular protein,sorting nexin 11(SNX11)which is involved in the intracellular endosomal trafficking pathway,as an essential cell factor for SFTSV infection.An SNX11-KO HeLa cell line was established,and SFTSV replication was significantly reduced.The glycoproteins of SFTSV were detected and remained in later endosomal compartments but were not detectable in the endoplasmic reticulum(ER)or Golgi apparatus.pH values in the endosomal compartments of the SNX11-KO cells increased compared with the pH of normal HeLa cells,and lysosomal-associated membrane protein 1(LAMP1)expression was significantly elevated in the SNX11-KO cells.Overall,these results indicated that penetration of SFTSV from the endolysosomes into the cytoplasm of host cells was blocked in the cells lacking SNX11.Our study for the first time provides insight into the important role of the SNX11 as an essential host factor in the intracellular trafficking and penetrating process of SFTSV infection via potential regulation of viral protein sorting,membrane fusion,and other endocytic machinery.

Host restriction factors for hepatitis C virus

Host-hepatitis C virus(HCV) interactions have both informed fundamental concepts of viral replication and pathogenesis and provided novel insights into host cell biology. These findings are illustrated by the recent discovery of host-encoded factors that restrict HCV infection. In this review, we briefly discuss these restriction factors in different steps of HCV infection. In each case, we discuss how these restriction factors were identified, the mechanisms by which they inhibit HCV infection and their potential contribution to viral pathogenesis.

The bacterial and host factors associated with extrapulmonary dissemination of Mycobacterium tuberculosis

With high morbidity and mortality worldwide, tuberculosis （TB） is still an important public health threat. The majority of human TB cases are caused by Mycobacterium tuberculosis. Although pulmonary TB is the most common presentation, M. tuberculosis can disseminate into other organs and causes extrapulmonary TB （EPTB）. The dissemination of bacteria from the initial site of infection to other organs can lead to fatal diseases, such as miliary and meningeal TB. Thoroughly understanding the mechanisms and pathways of dissemination would develop therapies to prevent the lethal prognosis of EPTB （miliary and meningeal TB） and vaccines to promote the development of adaptive immunity. This review focuses on risk factors of EPTB, bacterial and host genes involved in EPTB, and potential mechanisms of M. tuberculosis extrapulmonary dissemination.

New insights of Helicobacter pylori host-pathogen interactions: The triangle of virulence factors, epigenetic modifications and non-coding RNAs

Helicobacter pylori(H. pylori) is a model organism for understanding host-pathogen interactions and infection-mediated carcinogenesis. Gastric cancer and H. pylori colonization indicates the strong correlation. The progression and exacerbation of H. pylori infection are influenced by some factors of pathogen and host. Several virulence factors involved in the proper adherence and attenuation of immune defense to contribute the risk of emerging gastric cancer, therefore analysis of them is very important. H. pylori also modulates inflammatory and autophagy process to intensify its pathogenicity. From the host regard, different genetic factors particularly affect the development of gastric cancer. Indeed, epigenetic modifications, Micro RNA and long non-coding RNA received more attention. Generally, various factors related to pathogen and host that modulate gastric cancer development in response to H. pylori need more attention due to develop an efficacious therapeutic intervention. Therefore, this paper will present a brief overview of host-pathogen interaction especially emphases on bacterial virulence factors, interruption of host cellular signaling, the role of epigenetic modifications and non-coding RNAs.

Expressions of Tissue Factor and Tissue Factor Pathway Inhibitor in Patients with Acute Graft-versus-host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

This study examined the expressions of human serum tissue factor （TF） and tissue factor pathway inhibitor （TFPI） in patients with acute graft-versus-host disease （aGVHD） after allogeneic hematopoietic stem cell transplantation （allo-HSCT） and their clinical significance. The serum TF and TFPI levels were detected by ELISA in 28 allo-HSCT recipients before and after the transplanta-tion and the changes of TF and TFPI levels were dynamically monitored at different phases of the disease. No significant differences in the serum TF and TFPI levels were found in allo-HSCT recipi-ents in the absence of aGVHD or with gradeⅠaGVHD before and after the transplantation. The lev-els of serum TF and TFPI were substantially increased in the patients with gradeⅡ aGVHD at the peak of aGVHD （P〈0.05） and they were even higher in the patients with grade Ⅲ–Ⅳ aGVHD （P〈0.01）. When the conditions became stable after treatment with immunosuppressive agents, the serum TFPI level was decreased to the baseline level （P〉0.05） and the TF level was lowered but still higher than the baseline level （P〈0.05）. It was concluded that the levels of serum TF and TFPI were increased significantly in the patients with grade Ⅱ–Ⅳ aGVHD after allo-HSCT and decreased markedly after the treatment. Monitoring the levels of serum TF and TFPI in the patients with allo-HSCT is important to predict the occurrence, outcome and prognosis of aGVHD.

基于蛋白质芯片技术筛选与甲型流感病毒NS1蛋白互作的宿主因子及通路分析

目的筛选出与流感病毒Non-structural protein 1(NS1)蛋白结合的人类宿主蛋白并加以分析,确定这些结合蛋白富集的方向及关键蛋白,为抗流感病毒的新药研发提供思路。方法将NS1样本、Biotin样本分别与HuProt^(TM)人类蛋白质组芯片进行杂交孵育,以两重复均满足Z-Score≥3为筛选条件对与NS1蛋白有结合的宿主蛋白进行筛选得到特异性检出蛋白,实验组(NS1蛋白)与对照组(Biotin)比值I Mean_Ratio≥1.4为条件筛选出显著特异性检出蛋白。用检出的195个蛋白进行GO(Biological Process,Molecular Function,Cellular Component)和KEGG_PATHWAY分析,通过蛋白-蛋白相互作用(PPI)及MCODE分析得到关键蛋白。结果获得显著特异性检出蛋白195个,GO分析结果显示这些蛋白主要参与了mRNA加工、RNA结合、蛋白结合,KEGG分析主要富集到RNA降解、氨基酸的生物合成等通路。得到的4个关键蛋白DDX6、HSPD1、PKLR、MTHFD1中DDX6与RNA的合成、翻译等过程相关,而NS1蛋白可以通过调控流感病毒RNA和宿主RNA促进病毒的感染,推测DDX6可能在该过程发挥作用;其他3个蛋白目前虽然没有明确的研究指明其与流感病毒有关系,但是能在其他RNA病毒的感染过程中发挥作用。结论与NS1结合的人类蛋白主要富集到RNA合成、加工、转录等过程中,MCODE分析得到的关键蛋白有潜力成为抗流感病毒新的靶点,但作用机制需要后续实验进行进一步验证。

卡山保护区核心区璃眼蜱空间格局及成因

璃眼蜱是一类能够传播多种病原体的吸血媒介节肢动物。近年来璃眼蜱在新疆卡拉麦里山有蹄类保护区(简称“卡山保护区”)的泛化,对当地野生动物甚至保护区管护人员构成的威胁日渐突出。于2021、2022年在该保护区核心区设置25km^(2)样地,探究了璃眼蜱的空间分布及其影响因素,重点围绕璃眼蜱与普氏野马及啮齿类动物之间的空间关系展开。通过半方差变异函数分析璃眼蜱空间分布相关性;以双变量空间自相关方法评估璃眼蜱与宿主动物的空间聚集程度;采用结构方程模型拟合璃眼蜱数量与环境因素的关系。结果表明:1)璃眼蜱的块金基台比值大于0.75,显示璃眼蜱具有较低的空间相关性,表明其分布更易受到宿主及所处环境的影响;2)璃眼蜱与宿主的双变量梯度LISA聚集图表明,璃眼蜱与普氏野马之间的空间聚集关系强于璃眼蜱与啮齿类之间的空间聚集关系。3)多元混合结构方程模型的拟合效果较好(R^(2)=0.70),模型发现气候、植被、宿主三种因子均能影响璃眼蜱数量。综上,本研究发现影响卡山保护区核心区的璃眼蜱分布的最主要因素是宿主,其中普氏野马与璃眼蜱的空间聚集关系强于啮齿类动物。璃眼蜱随大型宿主的扩张性分布,对同域,特别是核心区其他野生动物构成了直接威胁。野生动物的重引入可能会对生态链中其他物种产生间接影响。随着普氏野马的重引入,该地区的寄生虫分布发生了变化,可能是因为寄生虫适应了新的环境条件,且这种适应性又依赖于普氏野马的分布。这种现象表明,生态系统中的各个组成部分都会相互关联,生态链的变化可能会导致其他生物适应性发生改变。该问题显示开展濒危野生动物重引入监测工作的重要性,研究结果拓展了野生动物蜱传疾病控制和管理思路。

我国旅游直播地理格局及影响因素研究——以抖音旅游主播为例

选取中国31个省(区、市)为研究单元,以抖音旅游主播为例,采用区位熵、地理空间分析方法对中国旅游主播的空间集聚特征进行了可视化分析,通过回归模型解析了影响旅游直播空间分布的因素。研究表明:(1)我国旅游直播存在空间分布不均的现象,大致以胡焕庸人口线为界,呈现“东南多-西北少”的分布态势;(2)具有独特旅游资源优势的地区对旅游主播吸引力很强,西藏、海南、云南尤为突出;(3)通过回归分析发现,旅游服务设施、电商创业环境、交通便利性、区域旅游收入对旅游直播具有显著正态效应,地区经济发展水平对旅游直播有排挤效应,相比而言,旅游资源禀赋则对旅游主播空间分布贡献较小。

宿主因素对幽门螺杆菌感染患者菌株耐药性的影响

目的分析影响幽门螺杆菌(Helicobacter pylori,Hp)耐药性的宿主因素。方法连续招募2021年11月—2023年10月于南京医科大学附属苏州医院就诊的Hp感染患者为研究对象。取内镜活检标本进行病理诊断、Hp菌株培养和药敏检测,并通过电子病历及问卷收集、纳入19项涉及患者基本资料、生活方式、饮食习惯、健康状况的指标,采用Logistic回归法评估宿主因素与Hp菌株对克拉霉素、左氧氟沙星、阿莫西林、呋喃唑酮、四环素、甲硝唑6种抗菌药物耐药性的相关性。结果共入选符合纳入与排除标准的Hp感染患者115例(Hp菌株115株)。其中男性53例(46.09%)、女性62例(53.91%),平均年龄(45.16±13.39)岁。胃镜病理:浅表性胃炎86例(74.78%),萎缩性胃炎6例(5.22%),肠上皮化生14例(12.17%),低级别上皮内瘤变6例(5.22%),高级别上皮内瘤变/胃癌3例(2.61%)。Hp菌株对抗菌药物的耐药率由高至低分别为甲硝唑(91.30%,105/115)、左氧氟沙星(53.04%,61/115)、克拉霉素(51.30%,59/115),未发现对阿莫西林、呋喃唑酮、四环素耐药菌株。双重耐药:左氧氟沙星+甲硝唑双重耐药率为50.43%(58/115),克拉霉素+甲硝唑双重耐药率为47.83%(55/115),克拉霉素+左氧氟沙星双重耐药率为36.52%(42/115)。多重耐药:克拉霉素+左氧氟沙星+甲硝唑三重耐药率为34.78%(40/115)。多因素Logistic回归分析结果显示(由于无对甲硝唑敏感毒株,多因素分析未纳入该药物),既往Hp根除史(OR=74.782,95%CI:10.377~538.886,P<0.001)、家庭饮用水来源为自来水(OR=4.919,95%CI:1.160~20.859,P=0.031)可增加菌株对克拉霉素的耐药风险,年龄≥50岁可增加菌株对左氧氟沙星的耐药风险(OR=4.261,95%CI:1.420~12.785,P=0.010),既往Hp根除史(OR=5.855,95%CI:2.209~15.517,P<0.001)、年龄40~59岁(OR=3.269,95%CI:1.254~8.520,P=0.015)可增加菌株对克拉霉素+左氧氟沙星双重耐药的风险。结论南京医科大学附属苏州医院Hp感染患者分离培养的菌株对甲硝唑、左氧氟沙星、克拉霉素的耐药率较高,且双重耐药、多重耐药现象突出。年龄、既往Hp根除史、家庭饮用水来源可能与克拉霉素、左氧氟沙星单药或双重耐药具有相关性。临床在进行Hp根除时,应综合考量,合理选择抗菌药物,个体化制订治疗方案。

Understanding the interaction of hepatitis C virus with host DEAD-box RNA helicases

The current therapeutic regimen to combat chronic hepatitis C is not optimal due to substantial side effects and the failure of a significant proportion of patients to achieve a sustained virological response. Recently developed direct-acting antivirals targeting hepatitis C virus (HCV) enzymes reportedly increase the virologic response to therapy but may lead to a selection of drug-resistant variants. Besides direct-acting antivirals, another promising class of HCV drugs in development include host targeting agents that are responsible for interfering with the host factors crucial for the viral life cycle. A family of host proteins known as DEAD-box RNA helicases, characterized by nine conserved motifs, is known to play an important role in RNA metabolism. Several members of this family such as DDX3, DDX5 and DDX6 have been shown to play a role in HCV replication and this review will summarize our current knowledge on their interaction with HCV. As chronic hepatitis C is one of the leading causes of hepatocellular carcinoma, the involvement of DEAD-box RNA helicases in the development of HCC will also be highlighted. Continuing research on the interaction of host DEAD-box proteins with HCV and the contribution to viral replication and pathogenesis could be the panacea for the development of novel therapeutics against HCV.

调控甲型流感病毒感染及复制的酶活性蛋白、宿主调节蛋白和干扰素刺激因子研究进展

甲型流感病毒(Influenza A virus,IAV)给动物和人类健康带来了极大的威胁。IAV感染会引起宿主细胞一系列免疫反应的激活,这一过程由病毒刺激诱导,宿主因子调控完成。由于宿主因子众多,因此会以不同机制影响流感病毒的感染、复制和致病。文章总结了能够调控IAV感染及复制的典型酶类蛋白、宿主调节蛋白和干扰素刺激因子,并归纳了其作用机制,为更好地理解宿主因子抗IAV机制及抗病毒药物靶点的筛选提供一定的理论依据。

Individualization of chronic hepatitis C treatment according to the host characteristics

Hepatitis C virus(HCV)infection is a global health problem that affects more than 170 million people worldwide.It is a major cause of cirrhosis and hepatocellular carcinoma,making the virus the most common cause of liver failure and transplantation.The standardof-care treatment for chronic hepatitis C(CHC)has been changed during the last decade and direct acting antiviral drugs have already been used.Besides,understanding of the pathogenesis of CHC has evolved rapidly during the last years and now several host factors are known to affect the natural history and response to treatment.Recent genome-wide association studies have shown the important role of interleukin-28B and inosine triphosphatase in HCV infection.The present review article attempts to summarize the current knowledge on the role of host factors towards individualization of HCV treatment.

移植物抗宿主病患者营养不良发生的相关因素分析及针对护理策略

目的 探究移植物抗宿主病(GVHD)患者发生营养不良的影响因素,为血液科护理干预策略的制订提供依据。方法 选取2018年9月至2023年2月江苏省淮安市第二人民医院血液科接收的128例GVHD患者作为观察对象,根据营养状态评估标准将其分为正常组(90例)和营养不良组(38例)。使用一般资料调查问卷、主观整体评估定量表、饮食健康知识问卷、心理评估量表等调查工具,对其进行单因素分析、logistic多因素分析。结果 两组饮食健康教育、口腔溃疡、心理状态比较,差异有统计学意义(P<0.05)。logistic回归分析结果显示,口腔溃疡、饮食健康教育、心理状态为GVHD患者发生营养不良的影响因素(OR=2.487、2.378、3.281,P<0.05)。结论 影响GVHD发生营养不良的因素颇多,血液科护理人员需加强口腔清洁干预,树立正确健康饮食知识观念,缓解不良心理情绪等干预,预防营养不良风险发生。

异基因造血干细胞移植后迟发型出血性膀胱炎的危险因素分析

目的:分析异基因造血干细胞移植(allo-HSCT)后并发迟发型出血性膀胱炎(LOHC)的危险因素、LOHC发展为重度LOHC的危险因素及LOHC对生存的影响。方法:对2015年1月-2021年12月在重庆医科大学附属第一医院行allo-HSCT的300例患者的临床资料进行回顾性研究,选择可能影响allo-HSCT后LOHC发生的相关临床参数进行单因素和多因素分析,同时分析组间的总生存期(OS)和无进展生存期(PFS)差异。结果:多因素分析结果显示,患者年龄≤45岁(P=0.039)、强化预处理方案中包含氟达拉滨/克拉屈滨+阿糖胞苷(P=0.002)、移植后d 30白蛋白≤30 g/L(P=0.007)、CMV-DNA+(P=0.028)、移植前有真菌感染(P=0.026)、Ⅱ-Ⅳ度a GVHD的发生(P=0.006)是发生LOHC的独立危险因素;在已发生LOHC的移植患者中,LOHC发生的时间在移植后32 d内(P=0.008)、移植后d 30的白蛋白≤30 g/L(P=0.032)是发展为重度LOHC的独立危险因素。重度LOHC组的OS率显著低于未发生LOHC组(P=0.041)。结论:对于年龄≤45岁、强化预处理或LOHC发生较早的移植患者,需要警惕发生LOHC或发展为重度LOHC,应早期做好防治;定期监测CMV-DNA、白蛋白水平,积极有效地抗病毒、抗真菌治疗及防治a GVHD是预防LOHC发生发展的有效措施。

Identification of druggable host dependency factors shared by multiple SARS-CoV-2 variants of concern

The high mutation rate of SARS-CoV-2 leads to the emergence of multiple variants,some of which are resistant to vaccines and drugs targeting viral elements.Targeting host dependency factors,e.g.cellular proteins required for viral replication,would help prevent the development of resistance.However,it remains unclear whether different SARS-CoV-2 variants induce conserved cellular responses and exploit the same core host factors.To this end,we compared three variants of concern and found that the host transcriptional response was conserved,differing only in kinetics and magnitude.Clustered regularly interspaced short palindromic repeats screening identified host genes required for each variant during infection.Most of the genes were shared by multiple variants.We validated our hits with small molecules and repurposed the US Food and Drug Administration-approved drugs.All the drugs were highly active against all the tested variants,including new variants that emerged during the study(Delta and Omicron).Mechanistically,we identified reactive oxygen species production as a key step in early viral replication.Antioxidants such as N-acetyl cysteine(NAC)were effective against all the variants in both human lung cells and a humanized mouse model.Our study supports the use of available antioxidant drugs,such as NAC,as a general and effective anti-COVID-19 approach.