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分枝桿菌屬M(fèi)ycobacteriumHigher Education PressHigher Education Press分枝桿菌屬（ Mycobacterium）是一類(lèi)細(xì)長(zhǎng)略彎曲的桿菌，有分枝生長(zhǎng)趨勢(shì)，故名。細(xì)胞壁含有大量脂質(zhì)（細(xì)胞壁重量的 60% ，細(xì)菌重量的 20 % ～ 40% ），與其染色特性、抵抗力、致病性等密切相關(guān)，引起的疾病均呈慢性并伴有肉芽腫。致人類(lèi)疾病的主要是：結(jié)核分枝桿菌牛分枝桿菌麻風(fēng)分枝桿菌Higher Education PressHigher Education Press第一節(jié) 結(jié)核分枝桿菌結(jié)核分枝桿菌（ M. tuberculosis） 俗稱(chēng)結(jié)核桿菌，是引起結(jié)核病的病原菌。結(jié)核病至今仍為重要的傳染病，估計(jì)世界人口的 1/3感染結(jié)核分枝桿菌。據(jù) WHO 報(bào)道，每年約有 800萬(wàn)新病例發(fā)生，近 300萬(wàn)人死于結(jié)核。Higher Education PressHigher Education PressHigher Education PressHigher Education Press1882年 3月 24日 Koch發(fā)現(xiàn)結(jié)核分枝桿菌。 1944年以后，由于普遍接種疫苗和應(yīng)用抗結(jié)核藥物進(jìn)行治療，結(jié)核病的蔓延曾一度得到控制，其發(fā)病率和死亡率明顯下降。但 20世紀(jì) 90年代初，結(jié)核病重新在人群中蔓延，為此， 1993年 WHO 宣布：全球處于結(jié)核病緊急狀態(tài)。Robert Koch1843—1910Higher Education PressHigher Education Press中國(guó)是全球 22個(gè)結(jié)核病高負(fù)擔(dān)國(guó)家之一。2000年我國(guó)衛(wèi)生部宣布：中國(guó)處于結(jié)核病的緊急狀態(tài)。Higher Education PressHigher Education PressLeon Charles Albert Calmette 1863–1933, French physician,bacteriologist and immunologist Higher Education PressHigher Education PressJean-Marie Camille Guérin 1872-1961, bacteriologist and immunologistHis father died of tuberculosis in 1882 (as well as his wife, in 1918). In 1897, he joined the Pasteur Institute in Lille and started to work with its director, French physician, bacteriologist and immunologist Albert Calmette (1863-1933). He started as a technician in charge of preparing Calmette's serum (antivenom against snake bites) and the vaccine against smallpox.Higher Education PressHigher Education PressThereafter, from 1905 to 1915, and from 1918 to 1928 he devoted himself to the research on a vaccine against tuberculosis, in closeassociation with Calmette, until his death in 1933. He discovered in 1905 that the bovine tuberculosis bacillum, the Mycobacterium bovis, could immunize the animals without causing the disease. Henceforth, he and Calmette developed ways of attenuate the pathogenic activity of Mycobacterium, using successive transferrals of culture. In 1908, after successfully obtaining an immunologically active preparation that could be use to produce a vaccine, he published with Calmette the results of what was named the BCG.Higher Education PressHigher Education PressThis preparation received the name of its two discoverers (Bacillum Calmette-Guérin, or BCG, for short). Attenuation was achieved by cultivating them in a bile-containing substrate, based on idea given by a Norwegian researcher, Kristian Feyer Andvord (1855-1934). From 1908 to 1921, Guérin and Calmette strived to produce less and less virulent strains of the bacillus, by transferring them to successive cultures. Finally, in 1921, they used BCG to successfully vaccine newborn infants in the Charité in Paris.Stamp Russia 1963Calmette Higher Education PressHigher Education Press一、生物學(xué)性狀1. 形態(tài)與染色 典型的結(jié)核分枝桿菌為細(xì)長(zhǎng)略彎曲的桿菌，分枝狀排列或聚集成團(tuán)。一般染色方法不易著色，常用 齊尼（Ziehl-Neelsen）抗酸染色法 ，結(jié)核分枝桿菌經(jīng)抗酸染色后呈紅色。Higher Education PressHigher Education PressHigher Education PressHigher Education Press2. 培養(yǎng)特性 營(yíng)養(yǎng)要求高，常用的培養(yǎng)基為 羅氏（Lowenstein- Jensen） 固體培養(yǎng)基，專(zhuān)性需氧。生長(zhǎng)緩慢，繁殖一代約需 18 h。典型菌落呈乳白色或米黃色，表面粗糙，顆粒樣或菜花狀。 在液體培養(yǎng)基成團(tuán)或索狀生長(zhǎng)。Higher Education PressHigher Education Press3. 抵抗力抗干燥 8 個(gè)月抗酸堿（ 3% HCl 或 4% NaOH ） 30 min抗染料紫外線敏感乙醇（ 70％～ 75％）敏感濕熱（例如 : pasteurization ）敏感Higher Education PressHigher Education Press結(jié)核分枝桿菌形態(tài)變異4. 變異 結(jié)核分枝桿菌可發(fā)生形態(tài)、菌落、毒力、免疫原性和耐藥性等變異。 卡介苗（ Bacille Calmette-Guerin, BCG） 是毒力變異的典型例子。它是將有毒的牛結(jié)核分枝桿菌在含甘油、膽汁、馬鈴薯的培養(yǎng)基中經(jīng) 13年 230次傳代而獲得的減毒活疫苗株，廣泛用于結(jié)核病的預(yù)防接種。Higher Education PressHigher Education Press二、致病性1. 致病物質(zhì) （ 1）莢膜（ 2）脂質(zhì)① 磷脂：促進(jìn)單核細(xì)胞增生，形成結(jié)核結(jié)節(jié)形成結(jié)核干酪樣壞死。② 脂肪酸：破壞細(xì)胞線粒體膜，抑制白細(xì)胞游走和吞噬能力。③ 硫酸腦苷脂：可抑制吞噬細(xì)胞中吞噬體與溶酶體的融合。④ 蠟脂 D：可激發(fā)機(jī)體產(chǎn)生遲發(fā)型超敏反應(yīng)。（ 3）蛋白質(zhì)：使機(jī)體發(fā)生遲發(fā)型超敏反應(yīng)。（ 4）多糖：引起局部病灶侵潤(rùn)及非特異增強(qiáng)機(jī)體免疫（ 5）核酸Higher Education PressHigher Education PressHigher Education PressHigher Education Press2. 所致疾病 結(jié)核分枝桿菌主要通過(guò)飛沫經(jīng)呼吸道傳播，也可經(jīng)消化道或皮膚黏膜損傷侵入機(jī)體，侵犯肺、腸、腎、骨、神經(jīng)系統(tǒng)等組織器官，引起結(jié)核病，以肺結(jié)核最為常見(jiàn)。 Higher Education PressHigher Education PressHigher Education PressHigher Education Press（ 1）肺部感染① 原發(fā)感染：多發(fā)生于兒童以及成人，是首次感染結(jié)核分枝桿菌引起的病變。一般多見(jiàn)于肺上葉下部或下葉上部。 Higher Education PressHigher Education Press粟粒性結(jié)核原發(fā)綜合征Higher Education PressHigher Education PressResected human lung containing liquefying and cavitary tubercular lesionsHigher Education PressHigher Education Press② 原發(fā)后感染：多見(jiàn)于成人。感染可從呼吸道獲得，即外源性感染?；騺?lái)自病灶內(nèi)潛伏的細(xì)菌，即內(nèi)源性感染。由于機(jī)體已有特異性細(xì)胞免疫，所以病灶一般局限于局部，而不擴(kuò)散至肺門(mén)淋巴結(jié)，常見(jiàn)于供氧充足的肺尖部。 Higher Education PressHigher Education Press（ 2）肺外感染 在部分患者中，結(jié)核分枝桿菌可進(jìn)入血液循環(huán)，引起肺內(nèi)、外播散，如腎、骨、腸結(jié)核以及結(jié)核性腦膜炎等。Higher Education PressHigher Education Press三、免疫性1. 免疫機(jī)制 結(jié)核分枝桿菌是胞內(nèi)感染菌，免疫機(jī)制主要是T細(xì)胞介導(dǎo)的細(xì)胞免疫?？菇Y(jié)核免疫屬于感染性免疫，又稱(chēng)有菌免疫 （ infectant immunity） 。當(dāng)受結(jié)核分枝桿菌感染后，機(jī)體對(duì)該菌的再次入侵有較強(qiáng)的免疫力，而當(dāng)該菌或其成分在體內(nèi)完全消失時(shí)，免疫力也隨之消失。Higher Education PressHigher Education Press2. 免疫與超敏反應(yīng) 機(jī)體對(duì)結(jié)核分枝桿菌產(chǎn)生細(xì)胞免疫的同時(shí)，也產(chǎn)生遲發(fā)型超敏反應(yīng)。在結(jié)核分枝桿菌感染過(guò)程中，感染、免疫和超敏反應(yīng)三者同時(shí)存在。超敏反應(yīng)由結(jié)核菌素蛋白和蠟質(zhì) D引起，免疫反應(yīng)由 TB核糖體 RNA引起。Koch現(xiàn)象 —— 將 TB初次注入豚鼠皮下， 10～ 14天后局部潰爛不愈，附近淋巴結(jié)腫大（原發(fā)感染）； TB再注射， 1～ 2天局部潰爛，附近淋巴結(jié)不腫大（原發(fā)后感染）。Higher Education PressHigher Education Press3. 結(jié)核菌素試驗(yàn) tuberculin test 用結(jié)核菌素作皮膚試驗(yàn)，通過(guò)觀察局部是否出現(xiàn)遲發(fā)型超敏反應(yīng)，判斷機(jī)體有無(wú)結(jié)核分枝桿菌感染和對(duì)該菌的免疫力。（ 1）試劑：舊結(jié)核菌素（ OT） Old Tuberculin， OT或純蛋白衍化物（ PPD） purified protein derivative,PPD（ 2）試驗(yàn)方法：常規(guī)試驗(yàn)用 PPD 5TU前臂掌側(cè)皮內(nèi)注射，48～ 72 h后檢查局部紅腫、硬結(jié)形成及其大小。Higher Education PressHigher Education Press（ 3）結(jié)果：紅腫硬結(jié)＞ 5 mm者為陽(yáng)性≤ 5 mm為陰性≥ 15 mm為強(qiáng)陽(yáng)性Higher Education PressHigher Education PressTuberculin test with positive reaction Higher Education PressHigher Education Press結(jié)果判斷：?陽(yáng)性反應(yīng)提示機(jī)體已感染過(guò)結(jié)核分枝桿菌或 BCG接種成功。?強(qiáng)陽(yáng)性提示有活動(dòng)性結(jié)核病的可能性，應(yīng)作進(jìn)一步檢查證實(shí)。?陰性反應(yīng)提示機(jī)體未感染過(guò)結(jié)核分枝桿菌，但應(yīng)考慮以下情況：① 原發(fā)感染早期，因感染后需 4周以上才能出現(xiàn)超敏反應(yīng)；② 重度結(jié)核病患者，處于免疫無(wú)反應(yīng)狀態(tài)；③ 患有其他疾病，如麻疹導(dǎo)致的細(xì)胞免疫低下、 AIDS或腫瘤患者等。Higher Education PressHigher Education Press四、微生物學(xué)檢查法1. 標(biāo)本 根據(jù)感染部位不同，可取痰、尿、糞、腦脊液、關(guān)節(jié)液、胸腔積液、腹腔積液等。2. 直接涂片鏡檢 標(biāo)本處理，抗酸染色，若找到抗酸性桿菌即可初步診斷。3. 分離培養(yǎng) 將處理材料接種于羅氏培養(yǎng)基，每周觀察生長(zhǎng)情況，一般 3～ 4周長(zhǎng)成肉眼可見(jiàn)的菌落。4. 快速診斷 PCR技術(shù)和核酸探針技術(shù)。Higher Education PressHigher Education Press五、防治原則1. BCG接種，能大大降低結(jié)核病的發(fā)病率。2. 發(fā)現(xiàn)和治療痰菌陽(yáng)性者。3. 結(jié)核病的治療以抗結(jié)核病化療藥物為主，包括異煙肼、利福平、乙胺丁醇和鏈霉素等。治療原則是早期、聯(lián)合、適量、規(guī)則和全程Higher Education PressHigher Education PressPrevention1.Maintain good personal and environmental hygiene.2.Adopt a healthy lifestyle, i.e., have balanced diet, adequate exercise and rest.3.Keep hands clean and wash hands properly.4.Wash hands when they are dirtied by respiratory secretions e.g. after sneezing.5.Cover nose and mouth while sneezing or coughing and dispose of nasal and mouth discharge properly.6.Seek treatment promptly if symptoms similar to tuberculosis appear, particularly persistently cough for more than one month.7.Receive BCG immunization according to immunization schedule. Higher Education PressHigher Education Press第二節(jié) 非結(jié)核分枝桿菌非結(jié)核分枝桿菌是指結(jié)核分枝桿菌、牛分枝桿菌與麻風(fēng)分枝桿菌以外的分枝桿菌，原稱(chēng)非典型分枝桿菌 ( atypical mycobacteria)，分為 4組：第 Ⅰ 組：光產(chǎn)色菌第 Ⅱ 組：暗產(chǎn)色菌第 Ⅲ 組：不產(chǎn)色菌第 Ⅳ 組：快速生長(zhǎng)菌Higher Education PressHigher Education Press第三節(jié) 麻風(fēng)分枝桿菌一、生物學(xué)性狀麻風(fēng)分枝桿菌（ M. leprae） 的形態(tài)、染色與結(jié)核分枝桿菌相似，常呈束狀排列，抗酸染色陽(yáng)性。是一種典型的細(xì)胞內(nèi)寄生菌，患者病灶滲出物涂片或病理切片中可見(jiàn)大量麻風(fēng)桿菌成束、成團(tuán)在吞噬細(xì)胞內(nèi)，細(xì)胞質(zhì)呈泡沫狀，這種細(xì)胞稱(chēng)麻風(fēng)細(xì)胞。Higher Education PressHigher Education Press二、致病性麻風(fēng)的傳染源主要是麻風(fēng)患者，可通過(guò)皮膚黏膜接觸或由飛沫傳播。根據(jù)機(jī)體的免疫狀態(tài)、病理變化和臨床表現(xiàn)可將大多數(shù)患者分為瘤型和結(jié)核型兩型。 少數(shù)患者處于兩型之間的界線類(lèi)或未定類(lèi)。 Higher Education PressHigher Education Press三、防治原則麻風(fēng)病目前尚無(wú)特異性預(yù)防方法，預(yù)防措施主要靠全面普查，早發(fā)現(xiàn)、早隔離和早治療。治療藥物主要有砜類(lèi)、利福平、氯法齊明及丙硫異煙胺等。