鼠疫的流行病学概述

鼠疫是由鼠疫耶尔森菌(Yersinia pestis)引起严重危害人类健康的烈性传染病。本文介绍了鼠疫病原体——鼠疫耶尔森菌的一般特性及生物学特性, 并对国内、外鼠疫疫情现状进行总结。目前鼠疫在全球范围内的流行已进入新的活跃期,世界卫生组织将鼠疫列为近20年来重新流行的急性传染病之一。当前,全球疫区主要分布在非洲、亚洲和南美洲。我国人间鼠疫自20世纪80年代开始处于明显回升势态,近10年流行逐渐下降,但防控形势依然艰巨。     

鼠疫的发病机制研究进展

鼠疫是由鼠疫耶尔森菌(Yersinia pestis，Y. pestis)感染引起的一种人畜共患病。鼠疫在世界范围内出现过3次大流行，均引起致命的瘟疫。由于自然疫源面积不断扩大和人口流动愈加频繁，我国的鼠疫防治形势依旧严峻。本文就鼠疫耶尔森菌的毒力因子、对宿主细胞的黏附和侵袭、胞内繁殖、宿主内播散等机制的研究进展进行总结，有助于揭示鼠疫独特的致病和传播机制，为精准防治鼠疫提供工作基础。     

鼠疫减毒活疫苗研究现状与展望

鼠疫(plague)是由鼠疫耶尔森氏菌(Yersinia pesits)引起的烈性传染病,在人类历史上曾造成约2亿人的死亡,在我国被列为甲类传染病。由于鼠疫菌具有高度致病性、传染性,被列为最具潜力的生物战剂和生物恐怖剂。在面临鼠疫威胁时,疫苗是最为有力的武器。鼠疫疫苗研究中,减毒活疫苗是重要的研究方向,现就鼠疫减毒活疫苗的研究现状进行综述,为新疫苗的研制提供参考。     

鼠疫溶菌疫苗免疫小鼠的体液免疫应答

为选择以F1抗原为主要有效成分的鼠疫溶菌疫苗(Whole cell lysate of Yersinia pestis vaccine,WCLY)的免疫程序,设计了这组试验。在37℃培养鼠疫EV菌,通过超声波裂解法制备鼠疫溶菌疫苗。设计(0,2周)、(0,4周)、(0,2,4周)三种免疫程序,以每剂总蛋白量7.9μg、31.5μg和126.0μg三个剂量皮下接种NIH小鼠。分别在第一针免疫后2、4、8、12周采集血清,通过间接ELISA检测抗鼠疫菌F1抗原和总抗原抗体。结果显示:免疫后血清抗体上升很快,2周内即可测出;无论哪种免疫程序,至12周时抗体滴度仍保持高水平;加强免疫后,抗体水平在4周或8周达到较高,可与活疫苗免疫者相比;溶菌疫苗的接种剂量为7.9μg时,动物只出现轻度不良反应。提示鼠疫溶菌疫苗需要两剂免疫,最短可间隔2周,接种剂量应不超过7.9μg,疫苗中应富含F1抗原。     

鼠疫及其预防

鼠疫及其预防梁秀梅（内蒙古呼伦贝尔大学０２１００８）于潜（内蒙古呼伦贝尔盟教研室０２１００８）鼠疫俗名“黑死病”（死于鼠疫的人一般都有皮下出血，全身呈青黑色），是一种严重威胁人类生命的急性传染病，是我国法定的甲类传染病，又称“一号病”。１当前世界上流...     

鼠疫耶尔森氏菌环二鸟苷酸代谢及生物被膜形成调控研究进展

鼠疫耶尔森氏菌(Yersinia pestis,以下简称"鼠疫菌")是烈性传染病鼠疫的病原菌,以鼠蚤作为传播媒介。鼠疫菌在其传播媒介鼠蚤的前胃中形成生物被膜从而促进其在宿主间传播。鼠疫菌生物被膜的形成受第二信使分子环二鸟苷酸(c-di-GMP)的正向调控。鼠疫菌中c-di-GMP由二鸟苷酸环化酶(DGC)HmsT和HmsD合成,由磷酸二酯酶(PDE)HmsP降解。文中主要介绍影响鼠疫菌环二鸟苷酸代谢及生物被膜形成的调控因子,并对其作用机制进行讨论和总结。     

用提呈载体构建鼠疫肽疫苗

鼠疫菌是肺、腺鼠疫病原因子。由于当前注册的疫苗有局限性,需要更合理有效的亚单位疫苗战胜各型鼠疫。结合佐剂的新方法使形成新疫苗有了新方案。为了开发新一代鼠疫疫苗,我们选择了一个免疫主基,鼠疫菌荚膜蛋白F1。已知此肽具有B(3个序列B1,     

鼠疫耶尔森氏菌LcrV基因的克隆及序列分析

为了研究鼠疫耶尔森氏菌（Y.pestis）保护性抗原V蛋白,从基因库中查得Y.pestis LcrV基因DNA序列,针对序列设计合成了一对PCR扩增引物,以本所保存的Y.pestis菌种为模板进行基因扩增,结果获得长约980bp的DNA片段。将扩增产物回收纯化,克隆至pGEM-T载体,构建重组载体pGEN-T/ypV,经过PCR,酶切鉴定,并对pGEM-T/ypV中的V基因片段进行测序,分析测序结果与己知序列相同,表明获得了LcrV基因。     

鼠疫耶尔森菌F1抗原的性质研究

鼠疫菌F1抗原是鼠疫亚单位新疫苗最重要的候选抗原,对其性质的充分认识,将有助于抗原制造工艺和新疫苗的开发。F1抗原的性质研究包括:微观结构,一级核苷酸、氨基酸序列,二级结构,高分子聚集形态,以及F1抗原的理化性质。     

鼠疫新疫苗的研究进展

鼠疫传统疫苗包括死疫苗和活疫苗存在不少缺陷,特别是安全和效果不够理想,接种反应率高,对肺鼠疫不能保护。近些年来开展的鼠疫亚单位疫苗研究,证明能产生保护性抗体,并且对鼠疫毒菌皮下注射和气溶胶攻击均有较好保护效果。本文综述了鼠疫当前流行态势,传统疫苗再评价和鼠疫亚单位疫苗的研究进展。     

The plague

The plague has been one of the most devastating diseases of human history. Despite major advances in diagnosis, prevention, and treatment, it has not been possible to eradicate this infection. Plague is still active in Africa, in Asia and in the Americas, and is classified as a currently re-emerging disease. The plague is mainly a disease of rodents, which is transmitted by fleabites. Humans develop two main clinical forms: bubonic plague (following bites of infected fleas, lethal in 50-70% of the cases in less than a week if an appropriate treatment is not started rapidly), and pneumonic plague (after inhalation of infected droplets, lethal in less than three days in 100% of cases without immediate treatment). Y. pestis, the causative agent of plague, is usually sensitive to most antibiotics, but the first multi-resistant strain was recently described. No efficient and safe vaccines are currently available. The plague bacillus is one of the few organisms that could be used for biological warfare.     

Burkholderia mallei and Burkholderia pseudomallei. Study of immuno- and pathogenesis of glanders and melioidosis. Heterologous vaccines]

Parameters of the infectious activity of B.mallei and B.pseudomallei for animals of various species were determined. Pathomorphological characteristics of the process of malleus and melioidosis were studied on golden hamsters, mice, guinea pigs, rats and monkeys. Tularemia, plague and salmonellosis vaccines were shown to have protective effects in experimental malleus and melioidosis. An insignificant cross immune response between the malleus and melioidosis pathogens was observed.     

Protective efficacy of a recombinant plague vaccine when co-administered with another sub-unit or live attenuated vaccine

Vaccines against bioterrorism agents offer the prospect of providing high levels of protection against airborne pathogens. However, the diversity of the bioterrorism threat means that it may be necessary to use several vaccines simultaneously. In this study we have investigated whether there are changes to the protective immune response to a recombinant sub-unit plague vaccine when it is co-administered with other sub-unit or live attenuated vaccines. Our results indicate that the co-administration of these vaccines did not influence the protection afforded by the plague vaccine. However, the co-administration of the plague sub-unit vaccine with a live vaccine resulted in markedly increased levels of IgG2a subclass antibodies, and markedly reduced levels of IgG1 subclass antibodies, to the plague sub-unit vaccine. This finding might have implications when considering the co-administration of other vaccine combinations.     

我国小鹅瘟研究进展及成就

小鹅瘟是导致雏鹅死亡的常见疾病之一,可造成巨大经济损失,严重危害养鹅业的发展。为了科学认识和积极防控小鹅瘟,我国同行进行了长期不懈的研究,取得了一系列原创性成果。在全世界率先发现并鉴定了小鹅瘟病毒,并对其变异特点进行了遗传进化分析,基本调研清楚了小鹅瘟在我国的发生区域和流行规律。在传统检测技术的基础上,引入免疫学技术和分子生物学技术,建立了一系列快速检测新方法;研制成功高免血清、种鹅用弱毒疫苗、雏鹅用弱毒疫苗和细胞适应弱毒株培育的新型疫苗,使我国小鹅瘟得到了有效的控制。这些成果和进展为我国小鹅瘟的研究与防治奠定了基础。     

Sylvatic plague management and prairie dogs – a meta‐analysis

Yersinia pestis, a bacterial pathogen that causes sylvatic plague, is present in the prairie dogs (Cynomys spp.) of North America. Epizootics of sylvatic plague through transmission in vectors (fleas) commonly completely extirpate colonies of prairie dogs. Wildlife managers employ a wide variety of insecticidal treatments to suppress plague and conserve prairie dog colonies. I compiled and statistically compared the available literature describing methods of plague control and their relative effectiveness in managing plague outbreaks by using meta‐analyses. Natural log response ratios were used to calculate insecticide‐induced vector mortality and vaccine‐conferred survival increases in prairie dogs in 37 publications. Further, subgroupings were used to explore the most effective of the available vector suppression insecticides and plague suppression vaccines. After accounting for the type of treatment used and the method by which it was applied, I observed plague reduction through use of both insecticides and vaccines. Insecticides resulted in a significant reduction of the abundance of vectors by 91.34% compared to non‐treated hosts (p<0.0001). Vaccines improved survival of prairie dog hosts by 4.00% (p<0.0001) compared to control populations. The use of insecticides such as deltamethrin and carbaryl is recommended to stop actively spreading epizootics, and dual antigen oral vaccines to initially suppress outbreaks.     

Yersinia pestis YopE contains a dominant CD8 T cell epitope that confers protection in a mouse model of pneumonic plague

Septic bacterial pneumonias are a major cause of death worldwide. Several of the highest priority bioterror concerns, including anthrax, tularemia, and plague, are caused by bacteria that acutely infect the lung. Bacterial resistance to multiple antibiotics is increasingly common. Although vaccines may be our best defense against antibiotic-resistant bacteria, there has been little progress in the development of safe and effective vaccines for pulmonary bacterial pathogens. The Gram-negative bacterium Yersinia pestis causes pneumonic plague, an acutely lethal septic pneumonia. Historic pandemics of plague caused millions of deaths, and the plague bacilli's potential for weaponization sustains an ongoing quest for effective countermeasures. Subunit vaccines have failed, to date, to fully protect nonhuman primates. In mice, they induce the production of Abs that act in concert with type 1 cytokines to deliver high-level protection; however, the Y. pestis Ags recognized by cytokine-producing T cells have yet to be defined. In this study, we report that Y. pestis YopE is a dominant Ag recognized by CD8 T cells in C57BL/6 mice. After vaccinating with live attenuated Y. pestis and challenging intranasally with virulent plague, nearly 20% of pulmonary CD8 T cells recognize this single, highly conserved Ag. Moreover, immunizing mice with a single peptide, YopE(69-77), suffices to confer significant protection from lethal pulmonary challenge. These findings suggest YopE could be a valuable addition to subunit plague vaccines and provide a new animal model in which sensitive, pathogen-specific assays can be used to study CD8 T cell-mediated defense against acutely lethal bacterial infections of the lung.     

Mutated and Bacteriophage T4 Nanoparticle Arrayed F1-V Immunogens from Yersinia pestis as Next Generation Plague Vaccines

Pneumonic plague is a highly virulent infectious disease with 100% mortality rate, and its causative organism Yersinia pestis poses a serious threat for deliberate use as a bioterror agent. Currently, there is no FDA approved vaccine against plague. The polymeric bacterial capsular protein F1, a key component of the currently tested bivalent subunit vaccine consisting, in addition, of low calcium response V antigen, has high propensity to aggregate, thus affecting its purification and vaccine efficacy. We used two basic approaches, structure-based immunogen design and phage T4 nanoparticle delivery, to construct new plague vaccines that provided complete protection against pneumonic plague. The NH₂-terminal β-strand of F1 was transplanted to the COOH-terminus and the sequence flanking the β-strand was duplicated to eliminate polymerization but to retain the T cell epitopes. The mutated F1 was fused to the V antigen, a key virulence factor that forms the tip of the type three secretion system (T3SS). The F1mut-V protein showed a dramatic switch in solubility, producing a completely soluble monomer. The F1mut-V was then arrayed on phage T4 nanoparticle via the small outer capsid protein, Soc. The F1mut-V monomer was robustly immunogenic and the T4-decorated F1mut-V without any adjuvant induced balanced T_H1 and T_H2 responses in mice. Inclusion of an oligomerization-deficient YscF, another component of the T3SS, showed a slight enhancement in the potency of F1-V vaccine, while deletion of the putative immunomodulatory sequence of the V antigen did not improve the vaccine efficacy. Both the soluble (purified F1mut-V mixed with alhydrogel) and T4 decorated F1mut-V (no adjuvant) provided 100% protection to mice and rats against pneumonic plague evoked by high doses of Y. pestis CO92. These novel platforms might lead to efficacious and easily manufacturable next generation plague vaccines.     

A New Approach to Bacterial Vaccines

Immunizing antigens against only 10 bacterial diseases—cholera, diphtheria, paratyphoid, pertussis, plague, scarlet fever, staphylococcal disease, tetanus, tuberculosis and typhoid—have been licensed for sale in Canada and the United States. Convincing evidence of efficacy is available for only four of these—diphtheria and tetanus toxoids, and pertussis and typhoid vaccines.The principles which determine the efficacy of different immunizing antigens are not always the same. Toxoids, for example, stimulate the formation of antitoxin-producing mechanisms which can neutralize toxins produced by invading organisms, thereby rendering them harmless. Conversely, vaccines stimulate the formation of antibacterial mechanisms which stop the growth of organisms before they can produce disease.Use of enzyme-lysed vaccines for prevention of staphylococcal disease represents a new approach in vaccine research. Animal tests have shown lysed vaccines to be 10 to 100 times less toxic, and about eight times more effective, than whole bacterial vaccines. Studies with lysed vaccines for other diseases are now in progress.