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 eff icacy, poor tolerability, and signif icant 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 antivira 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 vira 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.

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.

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.

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。

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。

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。

河南省主气时段气象变化周期特征分析——以累计降水量为例

[目的]分析河南省不同主气时段累计降水量变化的周期特征。[方法]基于运气理论,采用小波分析的方法,利用河南省1960年1月21日至2020年1月19日共60年逐日累计降水量资料,分析不同主气时段降水量变化的周期性特征。[结果]河南省初之气累计降水量在8年时间尺度上存在5年的准周期;二之气累计降水量在9年时间尺度上存在6年的准周期;四之气累计降水量在10年时间尺度上存在6年的准周期;五之气累计降水量在17年时间尺度上存在12年的准周期;五之气累计降水量在8年时间尺度上存在5年的准周期;终之气累计降水量在25年时间尺度上存在15~16年的准周期。[结论]河南省不同主气时段累计降水量在多时间尺度存在5、6、12或15年的准周期,初之气、四之气时段实际雨湿变化特征与五运六气理论吻合度较高。

Role of bacterial and genetic factors in gastric cancer in Costa Rica

AIM: To evaluate several risk factors for gastric cancer (GC) in Costa Rican regions with contrasting GC incidence rate (GCIR). METHODS: According to GCIR, 191 Helicobacter pylori (H pylori)-positive patients were classified into groups A (high GCIR, n = 101) and B (low GCIR, n = 90). Human DNA obtained from biopsy specimens was used in the determination of polymorphisms of the genes coding for interleukin (IL)-1β and IL-10 by PCR-RFLP, and IL-1RN by PCR. H pylori DNA extractions obtained from clinical isolates of 83 patients were used for PCR-based genotyping of H pylori cagA, vacA and babA2. Human DNA from gastric biopsies of 52 GC patients was utilized for comparative purposes. RESULTS: Cytokine polymorphisms showed no association with GCIR variability. However, gastric atrophy, intestinal metaplasia and strains with different vacA genotypes in the same stomach (mixed strain infection) were more frequently found in group A than in group B, and cagA and vacA s1b were signif icantly associated with high GCIR (P = 0.026 and 0.041, respectively). IL- 1β+3954_T/C (OR 2.1, 1.0-4.3), IL-1RN*2/L (OR 3.5, 1.7-7.3) and IL-10-592_C/A (OR 3.2, 1.5-6.8) were individually associated with GC, and a combination of these cytokine polymorphisms with H pylori vacA s1b and m1 further increased the risk (OR 7.2, 1.4-36.4). CONCLUSION: Although a proinflammatory cytokine genetic profile showed an increased risk for developing GC, the characteristics of H pylori infection, in particular the status of cagA and vacA genotype distribution seemed to play a major role in GCIR variability in Costa Rica.

异基因造血干细胞移植后短期内死亡的危险因素分析

背景:异基因造血干细胞移植是治愈各种血液病的有效甚至唯一手段,但患者移植后短期内死亡率较高。目的:探讨影响血液病患者异基因造血干细胞移植后短期(100 d)内总体生存的危险因素,旨在降低异基因造血干细胞移植后短期(100 d)内死亡率及有效预防相关危险因素。方法:回顾性分析于2018-01-01/2021-06-30在郑州大学第一附属医院造血干细胞移植中心行异基因造血干细胞移植的585例血液病患者的临床资料,探究影响血液病患者异基因造血干细胞移植后100 d内总体生存的危险因素。结果与结论:共585例血液病患者行异基因造血干细胞移植,92例死于移植后100 d内,死亡率为15.7%(92/585),死亡时中位年龄为26.5岁(1-56岁),死亡病例的中位生存时间为48 d(0-97 d)。单因素分析显示,年龄≥14岁、发生急性移植物抗宿主病、Ⅳ度急性移植物抗宿主病、细菌血流感染及耐碳青霉烯类革兰阴性杆菌血流感染是影响异基因造血干细胞移植后100 d内总体生存的危险因素(P<0.05);多因素分析显示,年龄≥14岁、发生Ⅲ-Ⅳ度急性移植物抗宿主病、细菌血流感染及耐碳青霉烯类革兰阴性杆菌血流感染是影响异基因造血干细胞移植后100 d内总体生存的独立危险因素,相对危险度分别为1.77(95%CI 1.047-2.991),7.926(95%CI 3.763-16.695),2.039(95%CI 1.117-3.722),3.389(95%CI 1.563-7.347)。结果表明:异基因造血干细胞移植后短期内全因死亡率较高,对于移植后短期内合并细菌血流感染、Ⅲ-Ⅳ度急性移植物抗宿主病的患者需及时发现、给予有效治疗,从而改善异基因造血干细胞移植的疗效。

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 directacting antivirals,another promising class of HCV drugs in development include host targeting agents that are responsible for interfering with the host factors crucia 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 DEADbox 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.

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.

冯晓纯教授用主客交病理论治疗小儿腺样体肥大经验

儿童腺样体肥大是儿科常见病、多发病,目前西医多采取有创治疗,但术后易复发、感染,不易被接受。中医药保守治疗可缩小腺样体体积,减轻鼻塞、打鼾、开口呼吸等临证症状,可使部分患儿避免手术、复发患儿避免二次手术,因此被广大患儿及家长接受。冯晓纯教授根据中医经典“主客交病”理论,采用“疏瘀和营,入阴搜邪”法,应用加减三甲散治疗本病,临床取得了显著效果。

Effect of Helicobacter pylori cdrA on interleukin-8 secretions and nuclear factor kappa B activation

AIM:To investigate genetic diversity of Helicobacter pylori (H.pylori) cell division-related gene A (cdrA) and its effect on the host response.METHODS:Inactivation of H.pylori cdrA,which is involved in cell division and morphological elongation,has a role in chronic persistent infections.Genetic property of H.pylori cdrA was evaluated using polymerase chain reaction and sequencing in 128 (77 American and 51 Japanese) clinical isolates obtained from 48 and 51 patients,respectively.Enzyme-linked immunosorbent assay was performed to measure interleukin-8 (IL-8) secretion with gastric biopsy specimens obtained from American patients colonized with cdrA-positive or-negative strains and AGS cells cocultured with wild-type HPK5 (cdrA-positive) or its derivative HPKT510 (cdrA-disruptant).Furthermore,the cytotoxin-associated gene A (cagA) status (translocation and phosphorylation) and kinetics of transcription factors [nuclear factor-kappa B (NF-κB) and inhibition kappa B] were investigated in AGS cells co-cultured with HPK5,HPKT510 and its derivative HPK5CA (cagA disruptant) by western blotting analysis with immunoprecipitation.RESULTS:Genetic diversity of the H.pylori cdrA gene demonstrated that the cdrA status segregated into two categories including four allele types,cdrA-positive (allele types;Ⅰand Ⅱ) and cdrA-negative (allele types;Ⅲ and Ⅳ) categories,respectively.Almost all Japanese isolates were cdrA-positive (Ⅰ:7.8% and Ⅱ:90.2%),whereas 16.9% of American isolates were cdrA-positive (Ⅱ) and 83.1% were cdrA-negative (Ⅲ:37.7% and Ⅳ:45.5%),indicating extended diversity of cdrA in individual American isolates.Comparison of each isolate from different regions (antrum and corpus) in the stomach of 29 Americans revealed that cdrA status was identical in both isolates from different regions in 17 cases.However,12 cases had a different cdrA allele and 6 of them exhibited a different cdrA category between two regions in the stomach.Furthermore,in 5 of the 6 cases possessing a different cdrA category,cdrA-negative isolate existed in the corpus,suggesting that cdrA-negative strain is more adaptable to colonization in the corpus.IL-8 secretions from AGS revealed that IL-8 levels induced by a cdrA-disrupted HPKT510 was significantly lower (P < 0.01) compared to wildtype HPK5:corresponding to 50%-60% of those of wild-type HPK5.These data coincided with in vivo data that an average value of IL-8 in biopsy specimens from cdrA-positive and cdrA-negative groups was 215.6 and 135.9 pg/mL,respectively.Western blotting analysis documented that HPKT510 had no effect on CagA translocation and phosphorylation,however,nuclear accumulation of NF-κB was lower by HPKT510 compared to HPK5.CONCLUSION:Colonization by a cdrA-negative or cdrA-dysfunctional strain resulted in decreased IL-8 production and repression of NF-κB,and hence,attenuate the host immunity leading to persistent infection.