Epigenetic dysregulation of virulence gene expression in severe Plasmodium falciparum malaria

Chronic infections with the human malaria parasite Plasmodium falciparum depend on antigenic variation. P. falciparum erythrocyte membrane protein 1 (PfEMP1), the major erythrocyte surface antigen mediating parasite sequestration in the microvasculature, is encoded in parasites by a highly diverse family of var genes. Antigenic switching is mediated by clonal variation in var expression, and recent in vitro studies have demonstrated a role for epigenetic processes in var regulation. Expression of particular PfEMP1 variants may result in parasite enrichment in different tissues, a factor in the development of severe disease. Here, we study in vivo human infections and provide evidence that infection-induced stress responses in the host can modify PfEMP1 expression via the perturbation of epigenetic mechanisms. Our work suggests that severe disease may not be the direct result of an adaptive virulence strategy to maximize parasite survival but that it may indicate a loss of control of the carefully regulated process of antigenic switching that maintains chronic infections.     

Helicobacter pylori virulence genes

Helicobacter pylori(H.pylori)is one of the most important human pathogens,infecting approximately half of the global population.Despite its high prevalence,only a subset of H.pylori infected individuals develop serious gastroduodenal pathology.The pathogenesis of H.pylori infection and disease outcome is thus thought to be mediated by an intricate interplay between host,environmental and bacterial virulence factors.H.pylori has adapted to the harsh milieu of the human stomach through possession of various virulence genes that enable survival of the bacteria in the acidic environment,movement towards the gastric epithelium,and attachment to gastric epithelial cells.These virulence factors enable successful colonization of the gastric mucosa and sustain persistent H.pylori infection,causing chronic inflammation and tissue damage,which may eventually lead to the development of peptic ulcers and gastric cancer.Numerous studies have focused on the prevalence and role of putative H.pylori virulence genes in disease pathogenesis.While several virulence factors with various functions have been identified,disease associations appear to be less evident,especially among different study populations.This review presents key findings on the most important H.pylori virulence genes,including several bacterial adhesins and toxins,in children and adults,and focuses on their prevalence,clinical significance and potential relationships.     

疟疾免疫记忆最新研究进展

抗原特异性的免疫记忆是获得性免疫的重要特征.初次感染后免疫系统对特异性抗原建立免疫记忆,再次遇到同种抗原后能够产生更快速和高强度的免疫应答.构建疫苗的理想目标是诱导长效免疫记忆的产生.目前,疟疾的预防和治疗策略不断受阻于耐药疟原虫虫株出现等问题.免疫记忆难以长期有效维持是疟疾感染的主要特征.然而,诱导、维持和活化免疫记...     

骨硬化症致病基因研究进展

骨硬化症(osteopetrosis)是一种以骨密度增高、破骨细胞缺乏或功能缺陷导致骨吸收障碍为特点的代谢性骨病,可分为常染色体隐性遗传(autosomal recessive osteopetrosis,ARO)和常染色体显性遗传(autosomal dominant osteopetrosis,ADO)。近年来,越来越多的骨硬化症相关致病基因被发现,本文就有关进展作一综述。     

Parasite virulence and disease patterns in Plasmodium falciparum malaria.

Heterogeneity in parasite virulence is one of several factors that have been proposed to contribute to the wide spectrum of disease severity in Plasmodium falciparum malaria. We used observed age-structured patterns of disease to define a population structure of P. falciparum, where the latter contains several independently transmitted antigenic types or "strains" that each induce some degree of strain-specific antidisease immunity upon infection. Patterns of incidence of severe and mild disease may be explained by assuming that a majority of these strains are associated with mild disease and that although severe malarial anemia is a complication occurring in a certain proportion of early infections with "mild" parasites, cerebral malaria is caused by a few distinct highly virulent strains. Considerable variation in parasite virulence, as a major factor of disease severity in malaria, is made possible by the absence of competition between the various parasite strains, arising from weak shared immune responses. The theoretical framework presented in this paper can explain other epidemiological observations, such as the results of interventions with insecticide-impregnated bednets.     

Epigenetic regulation of key vascular genes and growth factors

The role of small RNAs in epigenetic regulation is an emerging field. This research may also open novel treatment strategies based on manipulation of the epigenetic status of the target tissues. Our objective is to review epigenetic regulation of key vascular genes and growth factors. Vascular endothelial growth factor A (VEGF-A) is one of the key players in regulating and maintaining cardiovascular functions and pathology. Although its epigenetic regulation is still not completely understood, expression of the VEGF gene can be manipulated by epigenetic mechanisms using small RNAs that are targeted to the gene promoter which results in the alteration of histone code. VEGF exerts its effects mostly through two receptors, VEGFR1 and VEGFR2, and their expression is also regulated by promoter DNA methylation in various cancer cells. These findings suggest the importance of epigenetic mechanisms in the regulation of vascular functions.     

Erythrocyte binding ligands in malaria parasites: Intracellular trafficking and parasite virulence

The intracellular trafficking of an Erythrocyte Binding Like (EBL) ligand has recently been shown to dramatically affect the multiplication rate and virulence of the rodent malaria parasite Plasmodium yoelii yoelii. In this review, we describe the current understanding of the role of EBL and other erythrocyte binding ligands in erythrocyte invasion, and discuss the mechanisms by which they may control multiplication rates and virulence in malaria parasites.     

Characterization of mycobacterial virulence genes through genetic interaction mapping

We have previously shown that approximately 5% of the genes encoded by the genome of Mycobacterium tuberculosis are specifically required for the growth or survival of this bacterium during infection. This corresponds to hundreds of genes, most of which have no identifiable function. As a unique approach to characterize these genes, we developed a method to rapidly delineate functional pathways by identifying mutations that modify each other's phenotype, i.e., "genetic interactions". Using this method, we have defined a complex set of interactions between virulence genes in this pathogen, and find that the products of unlinked genes associate to form multisubunit transporters that are required for bacterial survival in the host. These findings implicate a previously undescribed family of transport systems in the pathogenesis of tuberculosis, and identify genes that are likely to function in the metabolism of their substrates. This method can be readily applied to other organisms at either the single pathway level, as described here, or at the system level to define quantitative genetic interaction networks.     

Epigenetic regulation of hematopoietic stem cell self-renewal by polycomb group genes

Polycomb group (PcG) genes are involved in the maintenance of cellular memory through epigenetic chromatin modifications. Recent studies have implicated a role for PcG genes in the self-renewal of hematopoietic stem cells (HSCs), a process in which cellular memory is maintained through cell division. Among the PcG genes, Bmi-1 plays a central role in the inheritance of stemness, and its forced expression promotes HSC self-renewal. These findings highlight the importance of epigenetic regulation in HSC self-renewal and identify PcG genes as potential targets for therapeutic HSC manipulation.     

1996～1998年四川省不同疟区疟疾监测

经过多年的防治 ,四川省的疟疾发病人数逐年减少 ,已由 1990年的 39746人降至 1995年的 80 44人 ,减少79.76 % ,发病率由 3.7 下降至 1.0 以下。流行程度大大降低 ,疟区范围不断缩小 [1 ] ,全省疟疾流行县中已有半数以上达到了卫生部颁布的基本消灭疟疾标准。为了更准确地掌握四川省疟疾流行的动态和防治效果 ,指导全省疟疾防治工作 ,于 1996～ 1998年 ,按照疟疾流行程度及媒介类型等不同特点 ,对沐川县等 9个县进行了疟疾流行病学和媒介按蚊生物学监测。内容与方法1　监测县选择疟疾发病率 >5 的沐川县、名山县、宜宾县和发病率 <1 的岳…     

Signatures of malaria vaccine efficacy in ageing murine immune memory

Malaria transmission occurs by mosquito bite. Thereafter, Plasmodium sporozoites specifically invade the liver, where they develop into thousands of merozoites that initiate blood‐stage infection and clinical malaria. The pre‐erythrocytic phase of a Plasmodium infection is the target of experimental whole‐parasite vaccines against malaria. Repeated immunizations with high doses of live, metabolically active sporozoites can induce protracted protection against Plasmodium reinfection. Parasites lacking a Plasmodium‐specific apicoplast protein, termed PALM, arrest very late during intrahepatic development just prior to liver merozoite release and can elicit sterile protection with two immunization doses only. In this report, we show in the robust Plasmodium berghei‐C57BL/6 model that partial protection extends beyond 1 year after the last immunization. In ageing mice, intracellular cytokine staining of Plasmodium peptide‐stimulated intrahepatic CD8⁺ T cells revealed elevated levels of interferon gamma in vaccinated mice. We conclude that antigen‐specific T cells persist in the target organ and are critical signatures of lasting protection. Our data also support the notions that memory T‐cell responses generated early in life remain largely intact well into old age and that murine Plasmodium vaccination and infection models are suitable to study the mechanisms of maintenance and efficiency of adaptive immunity during immunosenescence.     

Requirements for effective malaria control with homing endonuclease genes

Malaria continues to impose a substantial burden on human health. We have previously proposed that biological approaches to control the mosquito vector of disease could be developed using homing endonuclease genes (HEGs), a class of selfish or parasitic gene that exists naturally in many microbes. Recent lab studies have demonstrated that HEGs can function in mosquitoes. We constructed and analyzed a model of mosquito population genetics and malaria epidemiology to determine how well HEGs need to function in order to have a significant effect on the burden of disease. Our model, combined with currently available data, indicates that populations of Anopheles gambiae could be eliminated by releasing 2-3 HEGs targeting female fertility genes, or a driving-Y chromosome that is transmitted to 75-96% of progeny. Combinations of fertility-targeting HEGs and Y drive may also be effective. It is possible to eliminate the disease without eliminating the vector, but the parameter space producing this outcome appears to be small. HEGs causing a quantitative reduction in adult survival can be more effective than those targeting female fertility, but the selection coefficients that need to be imposed are still large, unless many HEGs are to be released. Simulations show that HEG-based strategies can be effective over socially relevant time frames. Important limiting assumptions of the models are that there is only a single vector species, and we model a homogeneous population, not a landscape. Nevertheless, we conclude that HEG-based approaches could have a transformational effect on malaria control efforts.     

Epigenetic aberrant methylation of tumor suppressor genes in small cell lung cancer

Small cell lung cancer (SCLC), a special type of lung cancer, is reputed to carry a poor prognosis. The morbidity of SCLC is increasing in China and other countries. A variety of DNA alterations associated with non-small cell lung cancer (NSCLC) have been described. However, genetic and epigenetic changes of SCLC are not well established. Few studies have demonstrated that epigenetic silencing of key tumor suppressor genes (TSGs) is pivotal to initiation and development of SCLC. Recently, promoter methylation of many TSGs have been identified in SCLC. These novel TSGs are potential tumor biomarkers for early diagnosis and prognostic prediction. Moreover, epigenetic promoter methylation of TSGs could be a target of intervention with a wide prospect of clinical application. This review summarizes recent studies on promoter methylation of TSGs in SCLC and aims to provide better understanding of the promoter methylation in tumorigenesis and progression of SCLC.KEY WORDS : Small cell lung cancer (SCLC), tumor suppressor gene (TSG), promotor methylation, hypermethylation     

食源性单增李斯特菌14种潜在毒力基因的检测

目的 了解新疆生产建设兵团食源性单核细胞增生性增李斯特菌(Listeria monocytogenes,LM)潜在毒力基因分布情况。方法 以54株食源性LM DNA为模板,针对14个潜在毒力基因设计特异性引物并利用PCR技术检测潜在毒力基因。结果 54株分离株均携带潜在毒力基因,其中5563分离株携带率最高,为57.14%(8/14),21L662分离株携带率最低,为21.43%(3/14),其余分离株携带率在28.57%(4/14) ~50%(7/14)之间。潜在毒力基因检出率不同,其中寡肽转运蛋白、内化素样蛋白、细胞壁表面锚定家族蛋白、单价阳离子/H+逆向转运蛋白、肽聚糖结合蛋白、组氨酸代谢系统、合成致死KAR3样蛋白、精氨酸/鸟氨酸逆向转运蛋白、ABC转运蛋白、Ⅱ型限制酶修饰系统Sau3 Al,磷酸葡萄糖转移酶系统基因的检出率分别是98.15%、81.48%、77.78%、64.81%、59.26%、53.70%、51.85%、35.19%、12.96%、9.26%、9.26%,芳香族氨基酸合成因子,EsaC蛋白类似物,差向异构酶/脱水酶家族蛋白和转录调控因子3种潜在毒力基因未检出。结论 检测食品源LM分离株14种潜在毒力基因的分布,为研究LM致病性和食品LM的溯源奠定了基础。     

DNA repeats identify novel virulence genes in Haemophilus influenzae.

The whole genome sequence (1.83 Mbp) of Haemophilus influenzae strain Rd was searched to identify tandem oligonucleotide repeat sequences. Loss or gain of one or more nucleotide repeats through a recombination-independent slippage mechanism is known to mediate phase variation of surface molecules of pathogenic bacteria, including H. influenzae. This facilitates evasion of host defenses and adaptation to the varying microenvironments of the host. We reasoned that iterative nucleotides could identify novel genes relevant to microbe-host interactions. Our search of the Rd genome sequence identified 9 novel loci with multiple (range 6-36, mean 22) tandem tetranucleotide repeats. All were found to be located within putative open reading frames and included homologues of hemoglobin-binding proteins of Neisseria, a glycosyltransferase (IgtC gene product) of Neisseria, and an adhesin of Yersinia. These tetranucleotide repeat sequences were also shown to be present in two other epidemiologically different H. influenzae type b strains, although the number and distribution of repeats was different. Further characterization of the IgtC gene showed that it was involved in phenotypic switching of a lipopolysaccharide epitope and that this variable expression was associated with changes in the number of tetranucleotide repeats. Mutation of IgtC resulted in attenuated virulence of H. influenzae in an infant rat model of invasive infection. These data indicate the rapidity, economy, and completeness with which whole genome sequences can be used to investigate the biology of pathogenic bacteria.