chapter 5 Bacterial Infection and Immunity
第七章细菌感染与免疫PPT课件
入院时体检
T39℃，P120次/分，R27次/分，BP100/70mmHg
急性病容、烦躁、神志尚清，对答准确 右眼结膜及全身皮肤有帽针头至绿豆大小不等的红色 出血点，表面稍隆起，边缘不整，压之不褪色 双侧瞳孔等圆，对光反射存，咽微红，双侧扁桃体肿 大，外耳道无流脓。颈硬，心肺无特殊发现。腹软， 肝脾未触及。膝反射存在，屈膝牵伸征+。屈颈缩腿征 +。未引出病理神经反射。
问题：
患者患的是什么病？是由什么细菌引起的？
对该病进行微生物检查时主要注意什么问
题？
怎样进行防治？
内容：
正常菌群与机会致病菌
细菌的致病作用 感染的发生与发展
宿主的免疫防御机制
第一节
正常菌群与条件致病菌
1g
10g 20g 20g 1000g (80%)
一、正常菌群及其分布
微生态平衡与失调
•微生态平衡 •微生态失调的主要原因:
使用抗生素 正常菌群寄居部位改变 免疫功能改变
细菌的感染与免疫
Bacterial infection & Immunity
•微生态失调的防治
内容：
第二节
致病性
细菌的致病作用
（质）
细菌引起疾病的性质
毒力:病原菌致病性的强弱程度
免疫功能下降
菌群失调（flora disequilibrium）
寄生在正常人体某个部位的正常菌群，
各菌间的比例发生较大幅度的改变，超出
正常范围的现象，称为菌群失调。由此产
生的疾病称为菌群失调症。
菌群失调的重要原因是滥用抗生素
细菌的感染与免疫
Bacterial infection & Immunity
医学微生物学英语
医学微生物学英语Microbiology is a fascinating field that delves into the intricate world of microscopic organisms, playing a pivotal role in the realm of medicine. From the study of bacteria, viruses, and other microbes, to the understanding of their impact on human health, microbiology has been at the forefront of scientific advancements.One of the primary focuses of medical microbiology is the identification and characterization of pathogenic microorganisms. These are the microbes that can cause various diseases and infections in the human body. By understanding the unique features and behaviors of these microbes, medical professionals can develop effective strategies for diagnosis, treatment, and prevention of infectious diseases.The field of medical microbiology encompasses a wide range of specialized areas. Bacteriology, for instance, involves the study of bacteria, their structure, metabolism, and the ways in which they can either benefit or harm human health. Virology, on the other hand, focuses on the study of viruses, their genetic composition, and their ability to infect and replicate within host cells.Another important aspect of medical microbiology is the study of the human microbiome. The human body is home to a vast and diverse community of microorganisms, collectively known as the microbiome. These microbes play a crucial role in maintaining a healthy immune system, aiding in the digestion of food, and even influencing the development of the brain and nervous system.Understanding the delicate balance of the microbiome and how it can be disrupted by factors such as diet, antibiotic use, and environmental exposures is a critical area of research in medical microbiology. Imbalances in the microbiome have been linked to a variety of health conditions, including inflammatory bowel diseases, obesity, and even certain mental health disorders.In the realm of diagnosis and treatment, medical microbiologists play a vital role. They develop and refine techniques for the rapid and accurate identification of infectious agents, allowing healthcare providers to make informed decisions about the most appropriate course of action. This can include the use of advanced laboratory techniques, such as polymerase chain reaction (PCR) and next-generation sequencing, to detect the presence of specific microbes.Moreover, medical microbiologists contribute to the development of new antimicrobial agents, such as antibiotics and antiviral drugs, to combat the growing threat of drug-resistant microbes. As pathogensevolve and become more resilient, the need for innovative and effective therapies becomes increasingly urgent.Beyond the clinical setting, medical microbiologists also play a crucial role in public health and epidemiology. They investigate outbreaks of infectious diseases, tracing the sources and transmission patterns of microbes, and implementing strategies to control and prevent the spread of these diseases within communities.The field of medical microbiology is constantly evolving, with new discoveries and advancements being made every day. From the development of cutting-edge diagnostic tools to the exploration of the human microbiome, the contributions of medical microbiologists have a profound impact on the health and well-being of individuals and populations worldwide.As we continue to navigate the complex and ever-changing landscape of infectious diseases, the expertise and dedication of medical microbiologists will remain essential in our efforts to maintain and improve global health.。
细菌的感染与免疫InfectionandImmunityofBacteria
感染的类型(结局)
显性感染apparent infection ( 传染病) 宿主细胞受到不同程度的损害，生理功能发生改变，并出现一系列的临床症状和体征 急性感染（acute infection） 慢性感染（chronic infection） ．局部感染（local infection） ．全身感染（generalized infection； systemic infection）
发热反应 白细胞反应 内毒素血症与内毒素休克 Shwartzman现象与DIC
”
发热反应
白细胞反应
内毒素血症与内毒素休克
Shwartzman现象与DIC
内毒素毒性作用
人体内存在着较完善的免疫系统。
01
免疫器官 免疫细胞 免疫分子
02
天然免疫 获得性免疫
03
宿主的免疫防御机制
01
02
03
04
生物拮抗——作屏障
营养作用——产营养
免疫作用—— 有免疫
抗衰老作用——除废物
正常菌群生理学意义：
条件致病菌（conditioned pathogen) 机会致病菌（opportunitistic pathogen) 有些细菌在正常情况下并不致病，在某些条件改变的特殊情况下可以致病。 致病条件 寄居部位的改变 免疫功能低下 菌群失调（dysbacteriosis） 菌群失调症或菌群交替症（microbial selection and substitution） 二重感染：金黄色葡萄球菌、白假丝酵母菌等
第5章细菌感染与免疫
知识要领
致病菌毒力的物质基础 细菌感染的发生与发展 机体抗细菌免疫的组成及特点
感染
细菌的感染(bacterial infection)：细菌侵入 宿主体内后，在生长繁殖过程中不仅释放出毒 性产物，同时还与宿主细胞之间发生相互作用， 引起宿主出现病理变化的过程。
非菌毛黏附素来自于细菌表面的其他组分，如G-外 膜蛋白（OMP）、G+细胞壁
黏附机制
细菌和宿主：静电吸引及疏水作用、阳离子桥联作用和配 体-受体相互结合
黏附素受体多为靶细胞表面的糖类或糖蛋白。 细菌黏附素与宿主细胞表面黏附素受体结合的特异性决定
了感染的组织特异性。
3.侵袭性物质
（1）侵袭素：细菌的侵袭由基因控制,称为侵袭基因(inv基 因) inv基因编码产生的蛋白,介导细菌能够侵入敏感细 胞内，主要是黏膜上皮细胞。
荚膜在免疫逃逸现象中起重要作用，避免了被宿主 细胞的免疫防御机制杀灭。
如肺炎链球菌
2.黏附素（adhensin）
黏附作用需要两个条件：黏附素和宿主细胞表面的 黏附素受体
黏附素是一类细菌表面与黏附相关的蛋白质，按其 来源分为菌毛黏附素和非菌毛黏附素
菌毛黏附素由菌毛分泌并存在于菌毛顶端如E.coli的 菌毛黏附素
病原菌(pathogen)：能引起感染或宿主疾病的细 菌。
非病原菌（nonpathogen）：不能造成宿主感染 的细菌。
条件致病菌（conditional pathogen）：正常条件 下不致病，在某些条件改变的特殊机会下可以致 病的细菌。
第一节 细菌的致病作用
细菌
体外
毒病
细菌细菌 性
Bacterial Infections
Staphylococcal Scalded Skin Syndrome
Furuncle/Carbuncle
Abscess: inflamed walled-off collection of pus; Not limited to hair follicles;
Furuncle
Carbuncle
Abcess
Furuncle/Carbuncle
• Involve the entire follicle and surrounding tissue; • Typically due to S . Aureus;
Furuncle/Carbuncle
• Treatment – Simple furuncle (no fluctuance): warm compresses – Fluctuant furuncle or abscess: incision and drainage – Oral antibiotics if:
Folliculitis • Superficial infection of hair follicle usually due to S . Aureus; • Presents with pustules in follicular distribution associated with hairs;
Bullous Impetigo
• Cleavage at granular layer due to ET (A/B) binding to desmoglein 1 ;
细菌感染及其致病性
31
细菌外毒素和内毒素特性比较
特性 外毒素
内毒素
来源 释放
G+及少数G-菌 活菌分泌
G-菌 死亡裂解后释放
成分 蛋白质
脂多糖
抗原性 强，甲醛处理后形成类毒素 弱，甲醛处理后不能形成类毒 素
稳定性 60~80℃，30min可被破坏 160℃，2~4h才被破坏
毒性 强，有选择性，引起独特临 较弱，不同菌可引起类似的全
Many: potentially pathogenic
Most: never pathogenic
-外源性感染
(exogenous infection) 病原菌来源于机体外，如发 病或带菌的人 (动物) ，土 壤、污水或被污染的食品， 多为寄生菌，少数为腐生菌
/blog/Bacterial-Time-Share
细菌感染是指细菌侵入宿 主机体内，并感染宿主细 胞引起机体不同程度上的 病理性损伤，及引起机体 免疫应答等一系列的过程
/wiki/Bacteria 4
细菌感染的来源 (Sources of Infection)
Few: always pathogenic
悬浮体系) (飞沫传播>1m距离)
经水传播 (water-borne transmission)： 饮用水、河水
肺炭疽、肺结核
霍乱、空肠弯曲杆菌感染、 伤寒
经食物传播 (food-borne transmission)： 肉、蛋、奶、海鲜
病媒传播 (vector-borne transmission)： 虱子、跳蚤、蚊子、螨虫
细菌外毒素 (Bacterial Exotoxin)
外毒素 (exotoxin)：主要由G+菌和少数G-菌产生并 分泌到菌体外的毒性蛋白质
大肠杆菌文献
1Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK 2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA 3Broad Institute of MIT and Harvard, Cambridge,Massachusetts, USA 4Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands 5Division ofGastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA 6Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA 7Cedars-Sinai F.Widjaja Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, California, USA 8Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA9Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA10Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, University ofCambridge, Cambridge, UK 11Department of Health Studies, University of Chicago, Chicago,Illinois, USA 12Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA 13Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA 14University of Maribor,Faculty of Medicine, Center for Human Molecular Genetics and Pharmacogenomics, Maribor,Slovenia 15University Medical Center Groningen, Department of Genetics, Groningen, TheNetherlands 16Department of Pathophysiology, Gastroenterology section, KU Leuven, Leuven,Belgium 17Unit of Animal Genomics, Groupe Interdisciplinaire de Genoproteomique Appliquee (GIGA-R) and Faculty of Veterinary Medicine, University of Liege, Liege, Belgium 18Division of Gastroenterology, Centre Hospitalier Universitaire, Universite de Liege, Liege, Belgium19Department of Medical and Molecular Genetics, King’s College London School of Medicine,Guy’s Hospital, London, UK 20Division of Rheumatology Immunology and Allergy, Brigham and Women’s Hospital, Boston, Massachusetts, USA 21Program in Medical and Population Genetics,Broad Institute, Cambridge, Massachusetts, USA 22Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts, USA 23Université de Montréal and the Montreal Heart Institute,Research Center, Montréal, Québec, Canada 24Department of Computer Science, New Jersey Institute of Technology, Newark, NJ 07102, USA 25Department of Gastroenterology &Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio 26Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA 27Peninsula College of Medicine and Dentistry, Exeter, UK 28Erasmus Hospital, Free University of Brussels,Department of Gastroenterology, Brussels, Belgium 29Massachusetts General Hospital, Harvard Medical School, Gastroenterology Unit, Boston, Massachusetts, USA 30Viborg Regional Hospital,Medical Department, Viborg, Denmark 31Inflammatory Bowel Disease Service, Department ofGastroenterology and Hepatology, Royal Adelaide Hospital, and School of Medicine, University of Adelaide, Adelaide, Australia 32Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany 33Department of Gastroenterology and Hepatology, Flinders Medical Centre and School of Medicine, Flinders University, Adelaide, Australia 34Division ofGastroenterology, McGill University Health Centre, Royal Victoria Hospital, Montréal, Québec,Canada 35Department of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University, Munich, Germany 36Department of Gastroenterology, Charit, Campus Mitte, UniversitŠtsmedizin Berlin, Berlin, Germany 37Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York City, New York, USA 38Department of Genomics, Life & Brain Center, University Hospital Bonn, Bonn, Germany 39Department ofBiosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden 40Department of Pediatrics,Cedars Sinai Medical Center, Los Angeles, California, USA 41Torbay Hospital, Department ofGastroenterology, Torbay, Devon, UK 42School of Medical Sciences, Faculty of Medical & Health Sciences, The University of Auckland, Auckland, New Zealand 43University of Groningen,University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands 44Department of Medicine, University of Otago, Christchurch, New Zealand 45Department of $watermark-text $watermark-text $watermark-textGastroenterology, Christchurch Hospital, Christchurch, New Zealand 46Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for EnvironmentalHealth, Neuherberg, Germany 47St Mark’s Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ 48Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham NG7 1AW, UK 49Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway 50Kaunas University of Medicine, Department of Gastroenterology, Kaunas, Lithuania51Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA 52Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo dellaSofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo, Italy 53Ghent University Hospital,Department of Gastroenterology and Hepatology, Ghent, Belgium 54School of Medicine andPharmacology, The University of Western Australia, Fremantle, Australia 55Gastrointestinal Unit,Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK 56Department of Gastroenterology, The Townsville Hospital, Townsville, Australia 57Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK 58Department of Medicine,Ninewells Hospital and Medical School, Dundee, UK 59Genetic Medicine, MAHSC, University of Manchester, Manchester, UK 60Academic Medical Center, Department of Gastroenterology,Amsterdam, The Netherlands 61University of Maribor, Faculty for Chemistry and Chemical Engineering, Maribor, Slovenia 62King’s College London School of Medicine, Guy’s Hospital,Department of Medical and Molecular Genetics, London, UK 63Royal Hospital for Sick Children,Paediatric Gastroenterology and Nutrition, Glasgow, UK 64Guy’s & St. Thomas’ NHS Foundation Trust, St. Thomas’ Hospital, Department of Gastroenterology, London, UK 65Department ofGastroenterology, Hospital Cl’nic/Institut d’Investigaci— Biomdica August Pi i Sunyer (IDIBAPS),Barcelona, Spain 66Centro de Investigaci—n Biomdica en Red de Enfermedades Hep‡ticas y Digestivas (CIBER EHD), Barcelona, Spain 67Christian-Albrechts-University, Institute of Clinical Molecular Biology, Kiel, Germany 68Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany 69Inflammatory Bowel Diseases, Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia 70Norfolk and Norwich University Hospital 71Department of Gastroenterology, Leiden University Medical Center, Leiden,The Netherlands 72Child Life and Health, University of Edinburgh, Edinburgh, Scotland, UK 73Institute of Human Genetics and Department of Neurology, Technische Universität München,Munich, Germany 74Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA 75Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany 76Department of Biostatistics, School of Public Health, Yale University, New Haven, Connecticut, USA 78Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario, Canada 79Azienda Ospedaliero Universitaria (AOU) Careggi, Unit of Gastroenterology SOD2, Florence, Italy 80Center for Applied Genomics,The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA 81Department of Pediatrics, Center for Pediatric Inflammatory Bowel Disease, The Children’s Hospital ofPhiladelphia, Philadelphia, Pennsylvania, USA 82Meyerhoff Inflammatory Bowel Disease Center,Department of Medicine, School of Medicine, and Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA 83Department of Gastroenterology, Royal Brisbane and Womens Hospital, and School of Medicine, University of Queensland, Brisbane, Australia 84Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK 85Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium AbstractCrohn’s disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory boweldisease (IBD), affect over 2.5 million people of European ancestry with rising prevalence in otherpopulations 1. Genome-wide association studies (GWAS) and subsequent meta-analyses of CD and UC 2,3 as separate phenotypes implicated previously unsuspected mechanisms, such as autophagy 4,$watermark-text $watermark-text $watermark-textin pathogenesis and showed that some IBD loci are shared with other inflammatory diseases 5.Here we expand knowledge of relevant pathways by undertaking a meta-analysis of CD and UC genome-wide association scans, with validation of significant findings in more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional and balancing selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe striking overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.We conducted an imputation-based association analysis using autosomal genotype level data from 15 GWAS of CD and/or UC (Supplementary Table 1, Supplementary Figure 1). We imputed 1.23 million SNPs from the HapMap3 reference set (Supplementary Methods),resulting in a high quality dataset with reduced genome-wide inflation (Supplementary Figures 2, 3) compared with previous meta-analyses of subsets of these data 2,3. The imputed GWAS data identified 25,075 SNPs that had association p < 0.01 in at least one of the CD,UC or all IBD analyses. A meta-analysis of GWAS data with Immunochip 6 validation genotypes from an independent, newly-genotyped set of 14,763 CD cases, 10,920 UC cases,and 15,977 controls was performed (Supplementary Table 1, Supplementary Figure 1).Principal components analysis resolved geographic stratification, as well as Jewish and non-Jewish ancestry (Supplementary Figure 4), and significantly reduced inflation to a level consistent with residual polygenic risk, rather than other confounding effects (from λGC =2.00 to λGC = 1.23 when analyzing all IBD samples, Supplementary Methods,Supplementary Figure 5).Our meta-analysis of the GWAS and Immunochip data identified 193 statistically independent signals of association at genome-wide significance (p < 5×10−8) in at least one of the three analyses (CD, UC, IBD). Since some of these signals (Supplementary Figure 6)probably represent associations to the same underlying functional unit, we merged thesesignals (Supplementary Methods) into 163 regions, of which 71 are reported here for the first time (Table 1, Supplementary Table 2). Figure 1A shows the relative contributions of each locus to the total variance explained in UC and CD. We have increased the total disease variance explained (variance being subject to fewer assumptions than heritability 7) from8.2% to 13.6% in CD and from 4.1% to 7.5% in UC (Supplementary Methods). Consistent with previous studies, our IBD risk loci seem to act independently, with no significantevidence of deviation from an additive combination of log odds ratios.Our combined genome-wide analysis of CD and UC enables a more comprehensive analysis of disease specificity than was previously possible. A model selection analysis(Supplementary Methods 1d) showed that 110/163 loci are associated with both disease phenotypes; 50 of these have an indistinguishable effect size in UC and CD, while 60 show evidence of heterogeneous effects (Table 1). Of the remaining loci, 30 are classified as CD-specific and 23 as UC-specific. However, 43 of these 53 show the same direction of effect in the non-associated disease (Figure 1B, overall p=2.8×10−6). Risk alleles at two CD loci,PTPN22 and NOD2, show significant (p < 0.005) protective effects in UC, exceptions that may reflect biological differences between the two diseases. This degree of sharing ofgenetic risk suggests that nearly all the biological mechanisms involved in one disease play some role in the other.The large number of IBD associations, far more than reported for any other complexdisease, increases the power of network-based analyses to prioritize genes within loci. We investigated the IBD loci using functional annotation and empirical gene network tools$watermark-text$watermark-text$watermark-text(Supplementary Table 2). Compared with previous analyses which identified candidate genes in 35% of loci 2,3 our updated GRAIL 8 -connectivity network identifies candidates in 53% of loci, including increased statistical significance for 58 of the 73 candidates from previous analyses. The new candidates come not only from genes within newly identified loci, but also integrate additional genes from previously established loci (Figure 1C). Only 29 IBD-associated SNPs are in strong linkage disequilibrium (r 2 > 0.8) with a missense variant in the 1000 Genomes Project data, which reinforces previous evidence that a large fraction of risk for complex disease is driven by non-coding variation. In contrast, 64 IBD-associated SNPs are in linkage disequilibrium with variants known to regulate gene expression (Supplementary Table 2). Overall, we highlighted a total of 300 candidate genes in 125 loci, of which 39 contained a single gene supported by two or more methods.Seventy percent (113/163) of the IBD loci are shared with other complex diseases or traits,including 66 among the 154 loci previously associated with other immune-mediated diseases 9, which is 8.6 times the number that would be expected by chance (Figure 2A, p <10−16, Supplementary Figure 7). Such enrichment cannot be attributed to the immune-mediated focus of the Immunochip, (Supplementary Methods 4a(i), Supplementary Figure 8), since the analysis is based on our combined GWAS-Immunochip data. Comparing overlaps with specific diseases is confounded by the variable power in studies of different diseases. For instance, while type 1 diabetes (T1D) shares the largest number of loci (20/39,10-fold enrichment) with IBD, this is partially driven by the large number of known T1D associations. Indeed, seven other immune-mediated diseases show stronger enrichment of overlap, with the largest being ankylosing spondylitis (8/11, 13-fold) and psoriasis (14/17,14-fold).IBD loci are also markedly enriched (4.9-fold, p < 10−4) in genes involved in primary immunodeficiencies (PIDs, Figure 2A), which are characterized by a dysfunctional immune system resulting in severe infections 10. Genes implicated in this overlap correlate with reduced levels of circulating T-cells (ADA , CD40, TAP1/2, NBS1, BLM, DNMT3B ), or of specific subsets such as Th17 (STAT3), memory (SP110), or regulatory T-cells (STAT5B ).The subset of PIDs genes leading to Mendelian susceptibility to mycobacterial disease(MSMD)10–12 is enriched still further; six of the eight known autosomal genes linked to MSMD are located within IBD loci (IL12B , IFNGR2, STAT1, IRF8, TYK2 and STAT3,46-fold enrichment, p = 1.3 × 10−6), and a seventh, IFNGR1, narrowly missed genome-wide significance (p = 6 × 10−8). Overlap with IBD is also seen in complex mycobacterial disease; we find IBD associations in 7/8 loci identified by leprosy GWAS 13, including 6cases where the same SNP is implicated. Furthermore, genetic defects in STAT314–15and CARD916, also within IBD loci, lead to PIDs involving skin infections with staphylococcus and candidiasis, respectively. The comparative effects of IBD and infectious diseasesusceptibility risk alleles on gene function and expression is summarized in Supplementary Table 3, and include both opposite (e.g. NOD2 and STAT3, Supplementary Figure 9) and similar (e.g., IFNGR2) directional effects.To extend our understanding of the fundamental biology of IBD pathogenesis we conducted searches across the IBD locus list: (i) for enrichment of specific GeneOntology (GO) terms and canonical pathways, (ii) for evidence of selective pressure acting on specific variants and pathways, and (iii) for enrichment of differentially expressed genes across immune cell types. We tested the 300 prioritized genes (see above) for enrichment in GO terms(Supplementary Methods) and identified 286 GO terms and 56 pathways demonstrating significant enrichment in genes contained within IBD loci (Supplementary Table 4,Supplementary Figure 10,11). Excluding high-level GO categories such as “immune system processes” (p = 3.5 × 10−26), the most significantly enriched term is regulation of cytokine production (p=2.7×10−24), specifically IFNG-γ, IL-12, TNF-α, and IL-10 signalling.$watermark-text$watermark-text$watermark-textLymphocyte activation was the next most significant (p=1.8 × 10−23), with activation of T-,B-, and NK-cells being the strongest contributors to this signal. Strong enrichment was also seen for response to molecules of bacterial origin (p=2.4 × 10−20), and for KEGG’s JAK-STAT signalling pathway (p = 4.8 × 10−15). We note that no enriched terms or pathways showed specific evidence of CD- or UC-specificity.As infectious organisms are known to be among the strongest agents of natural selection, we investigated whether the IBD-associated variants are subject to selective pressures (Supplementary Methods, Supplementary Table 5). Directional selection would imply that the balance between these forces shifted in one direction over the course of human history,whereas balancing selection would suggest an allele frequency dependent-scenario typified by host-microbe co-evolution, as can be observed with parasites. Two SNPs show Bonferroni-significant selection: the most significant signal, in NOD2, is under balancing selection (p = 5.2 × 10−5), and the second most significant, in the receptor TNFRSF18,showed directional selection (p = 8.9 × 10−5). The next most significant variants were in the ligand of that receptor, TNFSF18 (directional, p = 5.2 × 10−4), and IL23R (balancing, p =1.5 × 10−3). As a group, the IBD variants show significant enrichment in selection (Figure 2B) of both types (p = 5.5 × 10−6). We discovered an enrichment of balancing selection (Figure 2B) in genes annotated with the GO term “regulation of interleukin-17 production”(p = 1.4 × 10−4). The important role of IL17 in both bacterial defense and autoimmunity suggests a key role for balancing selection in maintaining the genetic relationship between inflammation and infection, and this is reinforced by a nominal enrichment of balancing selection in loci annotated with the broader GO term “defense response to bacterium” (p =0.007).We tested for enrichment of cell-type expression specificity of genes in IBD loci in 223distinct sets of sorted, mouse-derived immune cells from the Immunological Genome Consortium 17. Dendritic cells showed the strongest enrichment, followed by weaker signals that support the GO analysis, including CD4+ T, NK and NKT cells (Figure 2C). Notably,several of these cell types express genes near our IBD associations much more specifically when stimulated; our strongest signal, a lung-derived dendritic cell, had p stimulated < 1×10−6compared with p unstimulated = 0.0015, consistent with an important role for cell activation.To further our goal of identifying likely causal genes within our susceptibility loci and to elucidate networks underlying IBD pathogenesis, we screened the associated genes against 211 co-expression modules identified from weighted gene co-expression networkanalyses 18, conducted with large gene expression datasets from multiple tissues 19–21. The most significantly enriched module comprised 523 genes from omental adipose tissuecollected from morbidly obese patients 19, which was found to be 2.9-fold enriched for genes in the IBD-associated loci (p = 1.1 × 10−13, Supplementary Table 6, Supplementary Figure12). We constructed a probabilistic causal gene network using an integrative Bayesian network reconstruction algorithm 22–24 which combines expression and genotype data toinfer the direction of causality between genes with correlated expression. The intersection of this network and the genes in the IBD-enriched module defined a sub-network of genes enriched in bone marrow-derived macrophages (p < 10−16) and is suggestive of dynamic interactions relevant to IBD pathogenesis. In particular, this sub-network featured close proximity amongst genes connected to host interaction with bacteria, notably NOD2, IL10,and CARD9.A NOD2-focused inspection of the sub-network prioritizes multiple additional candidate genes within IBD-associated regions. For example, a cluster near NOD2 (Figure 2D)contains multiple IBD genes implicated in M.tb response, including SLC11A1, VDR and LGALS9. Furthermore, both SLC11A1 (also known as NRAMP1) and VDR have been$watermark-text$watermark-text$watermark-textassociated with M.tb infection by candidate gene studies 25–26, and LGALS9 modulates mycobacteriosis 27. Of interest, HCK (located in our new locus on chromosome 20 at 30.75Mb) is predicted to upregulate expression of both NOD2 and IL10, an anti-inflammatory cytokine associated with Mendelian 28 and non-Mendelian IBD 29. HCK has been linked to alternative, anti-inflammatory activation of monocytes (M2 macrophages)30;while not identified in our aforementioned analyses, these data implicate HCK as the causal gene in this new IBD locus.We report one of the largest genetic experiments involving a complex disease undertaken to date. This has increased the number of confirmed IBD susceptibility loci to 163, most of which are associated with both CD and UC, and is substantially more than reported for any other complex disease. Even this large number of loci explains only a minority of thevariance in disease risk, which suggests that other factors such as rarer genetic variation not captured by GWAS or environmental exposures make substantial contributions topathogenesis. Most of the evidence relating to possible causal genes points to an essential role for host defence against infection in IBD. In this regard the current results focus ever closer attention on the interaction between the host mucosal immune system and microbes both at the epithelial cell surface and within the gut lumen. In particular, they raise the question, in the context of this burden of IBD susceptibility genes, as to what triggers components of the commensal microbiota to switch from a symbiotic to a pathogenic relationship with the host. Collectively, our findings have begun to shed light on thesequestions and provide a rich source of clues to the pathogenic mechanisms underlying this archetypal complex disease.METHODS SUMMARY We conducted a meta-analysis of GWAS datasets after imputation to the HapMap3reference set, and aimed to replicate in the Immunochip data any SNPs with p < 0.01. We compared likelihoods of different disease models to assess whether each locus was associated with CD, UC or both. We used databases of eQTL SNPs and coding SNPs in linkage disequilibrium with our hit SNPs, as well as the network tools GRAIL andDAPPLE, and a co-expression network analysis to prioritize candidate genes in our loci.Gene Ontology, ImmGen mouse immune cell expression resource, the TreeMix selection software, and a Bayesian causal network analysis were used to functionally annotate these genes.Supplementary MaterialRefer to Web version on PubMed Central for supplementary material.AcknowledgmentsWe thank all the subjects who contributed samples and the physicians and nursing staff who helped withrecruitment globally. UK case collections were supported by the National Association for Colitis and Crohn’s disease, Wellcome Trust grant 098051 (LJ, CAA, JCB), Medical Research Council UK, the Catherine McEwan Foundation, an NHS Research Scotland career fellowship (RKR), Peninsular College of Medicine and Dentistry,Exeter, the National Institute for Health Research, through the Comprehensive Local Research Network and through Biomedical Research Centre awards to Guy’s & St. Thomas’ National Health Service Trust, King’s College London, Addenbrooke’s Hospital, University of Cambridge School of Clinical Medicine and to theUniversity of Manchester and Central Manchester Foundation Trust. The British 1958 Birth Cohort DNA collection was funded by Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02, and the UK National Blood Service controls by the Wellcome Trust. The Wellcome Trust Case Control Consortium projects were supported by Wellcome Trust grants 083948/Z/07/Z, 085475/B/08/Z and 085475/Z/08/Z. North American collections and data processing were supported by funds to the NIDDK IBD Genetics Consortium which is funded by the following grants: DK062431 (SRB), DK062422 (JHC), DK062420 (RHD), DK062432 (JDR), DK062423(MSS), DK062413 (DPM), DK076984 (MJD), DK084554 (MJD and DPM) and DK062429 (JHC). Additional$watermark-text$watermark-text$watermark-textfunds were provided by funding to JHC (DK062429-S1 and Crohn’s & Colitis Foundation of America, Senior Investigator Award (5-2229)), and RHD (CA141743). KYH is supported by the NIH MSTP TG T32GM07205training award. Cedars-Sinai is supported by USPHS grant PO1DK046763 and the Cedars-Sinai F. Widjaja Inflammatory Bowel and Immunobiology Research Institute Research Funds, National Center for Research Resources (NCRR) grant M01-RR00425, UCLA/Cedars-Sinai/Harbor/Drew Clinical and Translational Science Institute (CTSI) Grant [UL1 TR000124-01], the Southern California Diabetes and Endocrinology Research Grant (DERC) [DK063491], The Helmsley Foundation (DPM) and the Crohn’s and Colitis Foundation of America (DPM). RJX and ANA are funded by DK83756, AI062773, DK043351 and the Helmsley Foundation. TheNetherlands Organization for Scientific Research supported RKW with a clinical fellowship grant (90.700.281) and CW (VICI grant 918.66.620). CW is also supported by the Celiac Disease Consortium (BSIK03009). This study was also supported by the German Ministry of Education and Research through the National Genome Research Network, the Popgen biobank, through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence‘Inflammation at Interfaces’ and DFG grant no. FR 2821/2-1. S Brand was supported by (DFG BR 1912/6-1) and the Else-Kröner-Fresenius-Stiftung (Else Kröner-Exzellenzstipendium 2010_EKES.32). Italian case collections were supported by the Italian Group for IBD and the Italian Society for Paediatric Gastroenterology, Hepatology and Nutrition and funded by the Italian Ministry of Health GR-2008-1144485. Activities in Sweden were supported by the Swedish Society of Medicine, Ihre Foundation, Örebro University Hospital Research Foundation, Karolinska Institutet, the Swedish National Program for IBD Genetics, the Swedish Organization for IBD, and the Swedish Medical Research Council. DF and SV are senior clinical investigators for the Funds for Scientific Research (FWO/FNRS) Belgium. We acknowledge a grant from Viborg Regional Hospital, Denmark. VA was supported by SHS Aabenraa, Denmark. We acknowledge funding provided by the Royal Brisbane and Women’s Hospital Foundation,National Health and Medical Research Council, Australia and by the European Community (5th PCRDT). We gratefully acknowledge the following groups who provided biological samples or data for this study: theInflammatory Bowel in South Eastern Norway (IBSEN) study group, the Norwegian Bone Marrow Donor Registry (NMBDR), the Avon Longitudinal Study of Parents and Children, the Human Biological Data Interchange and Diabetes UK, and Banco Nacional de ADN, Salamanca. This research also utilizes resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the NIDDK, NIAID, NHGRI, NICHD,and JDRF and supported by U01 DK062418. The KORA study was initiated and financed by the HelmholtzZentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ.References 1. Molodecky NA, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012; 142:46–54. [PubMed: 22001864]2. Anderson CA, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing thenumber of confirmed associations to 47. Nat Genet. 2011; 43:246–252. [PubMed: 21297633]3. Franke A, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010; 42:1118–1125. [PubMed: 21102463]4. Khor BGA, Xavier RJ. Genetics pathogenesis of inflammatory bowel disease. Nature. 2011;474:307–317. [PubMed: 21677747]5. Cho JH, Gregersen PK. Genomics and the multifactorial nature of human autoimmune disease. N Engl J Med. 2011; 365:1612–1623. [PubMed: 22029983]6. Cortes A, Brown MA. Promise and pitfalls of the Immunochip. Arthritis Res Ther. 2011; 13:101.[PubMed: 21345260]7. Zuk O, Hechter E, Sunyaev SR, Lander ES. The mystery of missing heritability: Geneticinteractions create phantom heritability. Proc Natl Acad Sci USA. 2012; 109:1193–1198. [PubMed:22223662]8. Raychaudhuri S, et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 2009; 5:e1000534.10.1371/journal.pgen.1000534 [PubMed: 19557189]9. Hindorff LA, et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA. 2009; 106:9362–9367. [PubMed:19474294]10. International Union of Immunological Societies Expert Committee on Primary I et al. Primaryimmunodeficiencies: 2009 update. J Allergy Clin Immunol. 2009; 124:1161–1178. [PubMed:20004777]$watermark-text $watermark-text$watermark-text。
感染与免疫
• 条件致病性微生物的主要特点
• 1、毒力弱或无明显毒力 • 2、常为耐药菌或多重耐药菌 • 3、新的条件致病性微生物不断出现。如 过去曾认为与医学关系不大的微生物成 为机会性病原体，如阴沟肠杆菌、不动 杆菌、肠球菌、黏质沙雷菌等。
• 常见的条件致病性微生物
• 1、细菌：机会性感染最常见的病原体，常见的阴性 菌有大肠埃希菌、克雷伯菌属、铜绿假单胞菌、沙雷 菌属及变形杆菌；阳性菌主要为凝固酶阴性的葡萄球 菌。 • 2、病毒：常见的机会致病性病毒有水痘-带状疱疹病 毒、巨细胞病毒和单纯疱疹病毒。 • 3、真菌：条件致病性真菌广泛存在，但一般都毒力 低不致病，免疫功能低下者，长期使用广谱抗生素、 糖皮质激素或免疫抑制剂者，长期使用内脏导管或放 置静脉插管者易感染。常见的条件致病性真菌有假丝 酵母菌、隐球菌属及曲霉菌属。
宿主与微生物相互关系
• 在人体的体表及与外界相通腔道的粘膜上，栖 居着种类繁多、数以亿万计的细菌、真菌等微 生物，称为人体相关菌群(body-associated flora)。根据这些微生物与人体的相互关系， 分为 • 有益微生物（benifical microbes）对人体 具有生理作用无致病作用的细菌，是机体自然、 正常生命活动必不可少的组成部分。如阴道中 的乳杆菌、结肠中的厌氧菌、口腔和口咽部的 甲型溶血性链球菌，肠道中的双歧杆菌最典型。
条件致病微生物（opportunistic microbes）：对
健康宿主不致病，可具有生理作用，但能使免疫 力低下或生理功能异常的机体致病，或在特定条 件下产生毒性产物或获得侵袭性而具有致病性。 如肠杆菌科细菌、肠球菌、葡萄球菌、类杆菌、 真菌中的白假丝酵母菌、曲霉菌、隐球菌等。
病的病原，产毒素或（和）具有侵袭性，能使健 康宿主受感染，通过释放毒性产物或诱发超敏反 应引起机体较强烈的结构和功能的变化。常见的 包括病毒如呼吸道病毒、消化道病毒、肝炎病毒 等；革兰阳性菌如白喉棒状杆菌、破伤风梭菌、 肺炎链球菌、A群链球菌等；革兰阴性菌如霍乱 弧菌、伤寒沙门菌、痢疾志贺菌等；真菌中的组 织胞浆菌、孢子丝菌等。
感染免疫ppt课件优选全文
一，抗细菌的固有免疫效应 屏障结构 吞噬细胞 体液因素
41
屏障结构
1．皮肤与粘膜
（1）机械性阻挡与排除作用
如上皮细胞脱落，纤毛运动等 （2）分泌杀菌物质，如乳酸，脂肪酸
（3）正常菌群的拮抗作用
42
2．血脑屏障
血脑屏障： •软脑膜 •脉络膜 •脑毛细血管 •星状胶质细胞
43
吞噬细胞
小吞噬细胞 中性粒细胞 大吞噬细胞 单核/吞噬细胞系统
53
防御素（defensin)
•小分子多肽，位于中性粒细胞中 •作用于胞外菌，破坏细胞膜
54
固有免疫作用：
吞噬细胞 NK细胞 T细胞
55
特异性免疫效应
（1）胞外菌：体液免疫， B细胞介导
• 效应分子：抗体（免疫球蛋白）
• Th2细胞辅助（IL-4,5,6,10)
• 体液免疫的作用机制：
• 抑制病原菌粘附 • 调理吞噬作用 • 中和细菌外毒素 • 与补体联合溶菌作用 • ADCC-抗体依赖性细胞介导的细胞毒作用
如结核杆菌，只被吞噬但不被杀死。引起吞噬 细胞死亡，或扩散感染
3，组织损伤
吞噬过程中溶酶体释放蛋白水解酶，破坏正常 细胞
47
慢性肉芽肿内含有大量感染TB的M
48
体液因素
– 补体(complement)
• 球蛋白, M,肠上皮细胞产生； • 三条途径：经典，凝集素，旁
路途径激活； • 产生生物学活性分子,作用机制：
病毒
HBV EBV EBV HHV-8 HPV亚型 HPV-16、18 HTLV-1
34
（二）病毒感染的免疫病理损伤
✓ 抗体介导的免疫病理损伤
II型超敏反应：激活补体，导致细胞破坏 III型超敏反应：HBV病人，IC沉积于关节滑膜
细菌的感染与免疫(医院感染)
第七章细菌的感染与免疫Infectionand Immunity of Bacterium医学微生物学(Medical Microbiology)学习目标●掌握：细菌的致病机制及机体抗菌感染免疫机制，以及细菌性感染性疾病的发生、发展和结局，培养针对细菌性感染性疾病进行诊、防和治的临床思维能力。
简单地说，针对细菌性感染性疾病，就是要问自己5个问题，简称为5Q，并且要能回答这5QQ1: 什么是细菌性感染？Q2: 哪些类型的细菌可导致细菌性感染?Q3: 细菌性感染从何而来？Q4: 细菌性感染为什么会发生？Q5:细菌性感染的结局是什么？●熟悉：医院感染的定义、主要特点、危险因素及其防控策略第五节医院感染Nosocomial infection主要特点:●医院感染的发生率高达5-20%，是医院面临的一个突出公共卫生问题●三大类微生物均可引起医院感染；细菌占90%以上，且多具有耐药性、甚至多重耐药性●引起医院感染的危险因素, 相对较为明确且可预知●加强医院感染管理和针对危险因素进行早期预防，是降低医院感染发生率最有效的策略住院病人在医院内获得的感染，包括在住院期间发生的感染和在医院内获得出院后发生的感染；医院工作人员在医院内获得的感染也属医院感染。
依据引起医院感染的病原体的来源不同, 可分为:●内源性途径: 人体的微生物群●外源性传染: 病原体的直接或间接传播●病人与病人之间●医护人员与病人之间●病人、医护人员与医院环境如污染的空气、设施之间●医源性感染(iatrogenic infection): 病人在医护人员进行诊疗、诊断和预防过程中，因所使用医疗器械消毒不严而被感染●易感人群:老年人和婴幼儿罹患基础疾病如免疫缺陷或抑制性疾病、代谢性疾病和慢性消耗性疾病等导致免疫功能低下或紊乱的住院病人●侵入性检查与治疗技术:器官移植、血液或腹膜透析等治疗技术支气管镜、胃镜等侵入性检查技术气管切口和插管、留置导尿管和引流管、置入人工心瓣膜等侵入性治疗技术●导致免疫功能低下或紊乱的治疗技术放射治疗肿瘤化疗免疫抑制剂和肾上腺皮质激素的应用●抗生素的不合理应用降低医院感染发生率最有效的策略:●加强医院感染管理●针对危险因素进行早期预防详细内容参见第16章其他细菌: 不动杆菌属。
细菌的感染与免疫
特异性免疫
第三节 感染的发生、发展、与结局
外源性感染 exogenous infection
感染的来源 内源性感染 endogenous infection
经粘膜
感染的途径
经皮肤 多途径
隐性感染 （inapparent infection）
感染的类型
潜伏感染 （latent infection） 显性感染 （apparent infection）
Hospital Acquired Infection
定义：指病人在住院期间所获得的感染。 交叉感染 cross infection 内源性感染 endogenous infection 医源性感染 nosocomial infection
第二节 细菌的致病性
Pathogenicity of Bacteria
酶： 葡萄球菌凝固酶、A群链球菌透明质酸酶 、 链激酶、DNA酶等。 侵袭素： 如伤寒沙门菌、痢疾志贺菌、致病性大肠杆 菌等可通过存在于菌细胞表面的侵袭素入侵肠 上皮细胞，并进一步扩散。
二、毒素 toxin
外毒素 exotoxin 内毒素 endotoxin
外毒素 exotoxin
定义： 由革兰阳性菌和部分革兰阴性菌在生长繁殖 过程中释放至菌体外的毒性蛋白质。
内毒素
存在部位 从活菌分泌出，少数菌 细胞壁组分，菌死亡 死亡后释出 后释出 化学成分 蛋白质 脂多糖
稳定性 60～80℃,30min被破坏 160℃，2～4h被破坏
毒性作用 对组织有特殊的选择性 毒性效应大致相同 免疫原性 强，刺激机体产生抗毒 弱，甲醛处理不能形 素，甲醛处理形成类毒 成类毒素 素 编码基因 多为染色体外基因 染色体基因
Bacterial Pathogens in Human Disease
Bacterial Pathogens in Human DiseaseBacterial pathogens are microorganisms that cause diseases in humans, and they are responsible for a significant proportion of the global disease burden. These pathogens can cause a wide range of illnesses, from mild infections to life-threatening conditions. Some of the most common bacterial pathogens include Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Salmonella, and Mycobacterium tuberculosis. Staphylococcus aureus is a bacterium that is commonly found on the skin and in the nose of healthy individuals. However, it can cause a range of infections, from minor skin infections such as boils and impetigo to more severe infections such as pneumonia, sepsis, and endocarditis. Methicillin-resistant Staphylococcus aureus (MRSA) is a strain of the bacteria that isresistant to many antibiotics and can be difficult to treat. Streptococcus pneumoniae is a bacterium that can cause pneumonia, meningitis, and sepsis. It isa leading cause of death in children under the age of five and in the elderly. Vaccines are available to prevent infections caused by Streptococcus pneumoniae. Escherichia coli is a bacterium that is commonly found in the intestines ofhealthy individuals. However, some strains of the bacteria can cause severe diarrhoea and kidney failure. These infections are often associated with consumption of contaminated food or water. Salmonella is a bacterium that can cause food poisoning. It is commonly found in raw meat, poultry, and eggs. Symptoms of Salmonella infection include diarrhoea, fever, and abdominal cramps. Mycobacterium tuberculosis is a bacterium that causes tuberculosis (TB), a disease that primarily affects the lungs. TB is one of the top 10 causes of death worldwide, and it is estimated that one-third of the world's population isinfected with the bacteria. Treatment for TB involves a combination of antibiotics taken for several months. Bacterial pathogens can be transmitted through avariety of routes, including person-to-person contact, contaminated food or water, and contact with contaminated surfaces. Good hygiene practices, such as washing hands regularly and cooking food thoroughly, can help reduce the risk of infection. Antibiotics are often used to treat bacterial infections, but the overuse and misuse of antibiotics has led to the development of antibiotic-resistant bacteria. This is a major public health concern, as infections caused by antibiotic-resistant bacteria are more difficult to treat and can be more severe. In conclusion, bacterial pathogens are responsible for a significant proportion of human disease. While some bacteria are harmless and even beneficial, others can cause serious illness and death. Preventing the spread of bacterial infections requires good hygiene practices and appropriate use of antibiotics. Continued research into the development of new antibiotics and alternative treatments is also important to combat the growing problem of antibiotic resistance.。
Bacterial Pathogens in Human Disease
Bacterial Pathogens in Human Disease Bacterial pathogens are a significant cause of human disease, posing a threat to public health worldwide. These microscopic organisms have the ability to cause a wide range of illnesses, from mild infections to life-threatening diseases. Understanding the impact of bacterial pathogens on human health is crucial for developing effective prevention and treatment strategies. One of the most common bacterial pathogens that cause human disease is Staphylococcus aureus. This bacterium is a major cause of skin and soft tissue infections, as well as more serious conditions such as pneumonia and bloodstream infections. The emergence of antibiotic-resistant strains, such as methicillin-resistant Staphylococcus aureus (MRSA), has further complicated the treatment of staphylococcal infections, leading to increased morbidity and mortality. Another significant bacterial pathogen is Streptococcus pneumoniae, which is a leading cause of pneumonia, meningitis, and sepsis. The development of effective vaccines has helped reduce the burden of pneumococcal disease, but antibiotic resistance remains a concern. In recent years, there has been an increase in the prevalence of multidrug-resistant strains of Streptococcus pneumoniae, posing a challenge to the treatment of these infections. In addition to causing acute infections, bacterial pathogens can also contribute to the development of chronic conditions. For example, Helicobacter pylori is a bacterium that infects the stomach lining and is a major cause of peptic ulcers and stomach cancer. The eradication of Helicobacter pylori has been shown to prevent the recurrence of peptic ulcers and reduce the risk of stomach cancer, highlighting the importance of understanding the role of bacterial pathogens in chronic diseases. The impact of bacterial pathogens on human health extends beyond the direct effects of infection. These organisms can alsocontribute to the development of autoimmune and inflammatory conditions. For example, some strains of Escherichia coli have been implicated in the pathogenesis of inflammatory bowel disease, while Chlamydia trachomatis has been linked to the development of reactive arthritis. Understanding the mechanisms by which bacterial pathogens trigger these immune-mediated diseases is essential for developing targeted therapies. In addition to the direct impact on human health, bacterial pathogens also impose a significant economic burden. The costs associated withtreating bacterial infections, including hospitalization, antibiotic therapy, and lost productivity, are substantial. Furthermore, the emergence of antibiotic-resistant strains has led to the need for more expensive and prolonged treatment regimens, further exacerbating the economic impact of bacterial pathogens. In conclusion, bacterial pathogens play a significant role in human disease, causing a wide range of infections and contributing to the development of chronic and immune-mediated conditions. The emergence of antibiotic resistance further complicates the treatment of these infections, posing a threat to public health and imposing a substantial economic burden. Understanding the impact of bacterial pathogens on human health is essential for developing effective prevention and treatment strategies, as well as for addressing the broader implications of these organisms on society as a whole.。
- 1、下载文档前请自行甄别文档内容的完整性，平台不提供额外的编辑、内容补充、找答案等附加服务。
- 2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
- 3、如文档侵犯您的权益，请联系客服反馈,我们会尽快为您处理(人工客服工作时间：9:00-18:30)。
3. 正常菌群的作用 physiology effects of normal flora (1)biologic antagonism(生物拮抗) Competition for receptors or binding sites on host cells：biomembrane Synthesize metabolic or toxic products：
内毒素血症与休克：当血液中有大量革兰阴性菌生长繁殖 时，或病灶中的细菌释放大量内毒素进入血循环时，宿主机 体可出现内毒素血症（endotoxemia）。可引起微循环衰竭和 低血压为特征的内毒素休克。
小剂量内毒素有免疫调节作用，增强非特异性免疫功能。
细菌外毒素与内毒素的区别要点
毒素特征 来源 外 毒 素 革兰阳性及阴性菌 革兰阴性菌 细胞壁成分，细菌裂解后释放 脂多糖 内 毒 素
需的最小细菌数。 细菌的毒力主要指侵袭力和毒素，是细菌致病的关键。 1. 侵袭力 致病菌突破机体防御功能，侵入机体在体内定植、
繁殖和扩散的能力，称为侵袭力（invasiveness ）。
构成细菌侵袭力的主要致病物质： （1）黏附素 ①菌毛：主要存在于革兰阴性菌，发
挥黏附作用。
②非菌毛黏附物质：多存在于革兰阳 性菌，菌体表面的成分，起黏附作用。 （2）荚膜：抗吞噬。
normal flora的拮抗作用(antagonistic action ）
皮肤
黏膜
2. blood-brain barrier
3. placental barrier
(二）phagocytosis：
大吞噬细胞：血中的单核细胞 monocyte和各种组织中的巨噬细胞
macrophage； 小吞噬细胞：外周血中的中性粒细胞 Neutrophil 。
嗜酸性粒细胞 嗜碱性粒细胞
1. phagocytosis and bacteriecidal process ： chemotaxis 趋化 touch 接触 phagocytosis 吞入 digestion and lysis of bacteria 杀灭与消化
Phagocytosis,pinocytosis 细菌 线粒体 细胞核 溶酶体
第5章
细菌的感染与免疫
Bacterial Infection and Immunity
细菌的感染( bacterial infection)又称传染，通过外源 或内源性感染方式，细菌突破宿主的免疫防御机制后，在 宿主体内生长繁殖，或产生侵袭性酶和毒素，引起一系列 病理生理的过程。能感染宿主引起疾病的细菌称为致病菌
内质网
2.Outcome of phagocytosis
complete phagocytosis ：Purulent bacteria等被吞噬后， 一般5-10min被杀死，30-60min被破坏，为complete phagocytosis ； noncomplete phagocytosis ：一些胞内寄生菌，在免疫力 缺乏或低下的机体中，虽被吞噬，却不被杀灭。 tissue injury ：lysosome release the lysozyme to injure the tissue
二、条件致病菌
1. 概念 机体正常菌群与宿主间的平衡状态及正常菌 群之间的平衡，在某些特定的条件下被打破，使原来 不致病的细菌成了致病菌，称为条件致病菌
（conditioned pathogen）或机会致病菌
（opportunistic pathogen）。
2. 致病条件
引起机会感染常见的条件或因素：
normal persons. 2. 分布 正常菌群存在于人的皮肤、与外界相杆菌
外耳道
葡萄球菌、类白喉杆菌 绿脓杆菌、非致病性分枝杆菌
鼻咽腔
人 体 内 正 常 菌 群 的 分 布
阴道
大肠杆菌、乳杆菌 白念珠菌、类白喉杆菌
葡萄球菌、甲，丙型链球菌 肺炎球菌、奈氏菌、类杆菌等 表皮葡萄球菌 口腔 甲，丙型链球菌 类白喉杆菌、肺炎球菌 奈氏菌、乳杆菌、梭杆菌 螺旋体、放线菌、白念珠菌
（3）侵袭性物质：促进细菌的扩散。
①侵袭素：由侵袭基因（inv）控制，
②侵袭性酶 （4）细菌生物被摸（bacterial biofilm）: 细菌粘附于接触表面，分泌多糖基质、纤 维蛋白、脂蛋白等，将其自身包绕其中而
形成的大量细菌聚集膜样物。
包被在生物膜中的细菌称被膜菌。
2. 毒素
是细菌合成的对机体组织细胞有损害的毒性物质。毒
③ 根据外毒素对靶细胞的亲和性和作用机制的不同可分为三 大类：神经毒素（neurotoxins）、细胞毒素（cytotoxins）和
肠毒素（enterotoxins）。
细胞膜 A-B 式作用方式
活化 结合
A
B
（2）内毒素（endotoxin） ① 概念：是革兰阴性菌细胞壁中的脂多糖（LPS）组分，只
存在部位 从活菌分泌到细胞外，少数菌崩 解后释放 化学成分 蛋白质
热稳定性 60～80℃，30min
毒性作用 强，作用部位有较强选择性 免疫原性 强，能被甲醛脱毒成类毒素，类 毒素可刺激机体产生抗毒素
250℃，30min
弱，毒性效应大致相同 弱，不能脱毒成为类毒素，刺激 机体产生抗毒素的能力弱
第三节 抗菌免疫
antigen, it is specific and is mediated by either
antibody or lymphocytes cells.
特点： 1、针对性强，只对引发immunity的相同 antigen有作用，对它种antigen无效，称特异性
免疫（specific immunity）；
2、non-hereditable，需个体自身接触 antigen后形成，故需一定时间，一般10-14天； 3、再次接触相同antigen，其免疫强度可增加。
（一）humoral immunity(体液免疫) （1）抗菌抗体（调理素）
（2）抗外毒素抗体（抗毒素） Bioactivities of antibodies: 1)inhibition of adhesion of bacteria to the local membrane. 2)neutralization of exotoxin 3)opsonization of phagocytosis: 4)lysis of bacteria by Ab and C combination. 5)ADCC( antibody dependent cell mediated cytotoxicity): IgG Fc— NKFcR.
菌群失调
机体某些部位正常菌群中各菌种产生较大
幅度的变化而超出了正常范围的状态，称为菌群失调 （dysbacteriosis）。
菌群失调症或菌群交替症 由于菌群失调而导致的病
症称为菌群失调症或菌群交替症（microbial selection and substitution）。菌群失调时，机体易出现二重感 染或重叠感染。
第二节
细菌的致病性
细菌能引起机体产生疾病的性能称为致病性或病原性
（pathogenicity）。致病菌的致病作用与它的毒力、侵入
数量以及侵入途径密切相关。
一、细菌的毒力
致病菌致病力强弱的程度称为毒力（virulence），毒力 的大小用LD50或ID50来表示：在规定时间内，通过指定的
感染途径，使一定体重或年龄的某种动物半数死亡或感染所
人体免疫系统由免疫器官、免疫细胞和免疫分子组成。 根据免疫的特点和作用性质的不同，机体的免疫防御机制可 分为固有性免疫（innate immunity）和适应性免疫（adaptive
immunity）。
一、非特异性免疫
组成：屏障结构、吞噬细胞和体液中的杀菌物质（补体、
溶菌酶、防御素等）。
Immune responses can be innate or acquired. innate immunity（天然免疫) 是人类在长期的种系发育和进化过程中，逐渐建立 起来的一系列防御致病菌等外来抗原的功能。 Innate immunity is nonspecific and includes barriers to infectious agents —for example, skin and mucous membranes, nature killer (NK) cells, phagocytosis, inflammation, and a variety of other nonspecific factors.
Target cell
二、特异性免疫
1. 体液免疫 由特异性抗体起主要作用的免疫应答。如
抗毒素（antitoxin）是细菌在生长繁殖中释放的外毒素
或人工制备的类毒素刺激机体产生的抗体，主要有IgG、 SIgA。 2. 细胞免疫 TDTH细胞。 指以T细胞为主的免疫应答，如Tc、Th和
Mechanisms of specific host defense Adaptive immunity occurs after exposure to an
素按其来源、性质和作用不同可分为外毒素和内毒素两种。 （1）外毒素（exotoxin） ① 概念：由革兰阳性菌和部分革兰阴性菌在生长繁殖过程中 释放至菌体外的毒性蛋白质。 ② 特性：蛋白质成分，具有一般蛋白质的理化特性；毒性强， 具有选择性；种类繁多，作用机制复杂多样；免疫原性强，能
用甲醛处理脱毒成类毒素（toxoid）。
（三）Natural Killer（NK）Cells （四）Humoral factors plement(补体) 2.lysozyme(溶菌酶)
3.defensin(防御素):破坏菌cell membrane的完整性。
cell membrane损伤 bacterium死亡