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Mycobacterium MYCOBACTERIUM THIS GENUS IS COMPOSED OF: Strictly aerobic, acid-fast rods, does not Stain well (gram stain indeterminant), DNA has high g+c content, unique cell wall, Mycolic acid carbon chain length > c60 Relatively slow growth (two groups) A. RAPID GROWERS (Visible colonies in <5 days) B. SLOW GROWERS (Visible colonies in > 5 days) TYPE SPECIES: Mycobacterium tuberculosis THE GENUS MYCOBACTERIUM CAN BE DIVIDED INTO FOUR BROAD GROUPS 1. THE TUBERCULOSIS COMPLEX 2. SLOW GROWING MYCOBACTERIA OTHER THAN TUBERCULOSIS (MOTT) 3. RAPIDLY GROWING MYCOBACTERIA 4. MYCOBACTERIUM LEPRAE Acid Fastness Stain (Ziehl-Neelsen stain) • flood the slide with basic fuchsin (a red dye) in 5% phenol as a mordant. • heat gently for few minutes to melt the wax. • wash with 3% HCl in ethanol. • counter-stain with methylene blue. Mycobacterium stains red and other bacteria and the background are blue. The mycolic acid and its derivatives are responsible for the acid f THE TUBERCULOSIS COMPLEX (Organisms that resemble M. tuberculosis; Causing a similar type of disease in humans) 1. M. tuberculosis 2. M. bovis Mycobacterium tuberculosis M. tuberculosis General Features • It is a causative agent for human tuberculosis. • It grows very slow with a generation time of 12-15 hours. • On solid media the colonies are raised and rough with a wrinkled surface. • M. tuberculosis cells grow either as discrete rods or as aggregates. Virulent strains tend to grow as an aggregated long arrangement called serpentine cord. Cord COLONIAL MORPHOLOGY OF THE TUBERCULOSIS COMPLEX MYCOBACTERIA EUGONIC GROWTH 14 DAYS Mycobacterium tuberculosis DYSGONIC GROWTH 14 DAYS Mycobacterium bovis Resistance: Not sensitive Sensitive Dry (highly) Wet Chemical disinfectants (more) Heat(62-63℃,15min) 3%HCL, 6%H2SO4, 4%NaOH (15min) Alcohol (to nonsporeforming bacteria) Malachite green(1:13000) UV Transmission Through respiratory tract, alimentary tract, injured skin。 TB in the lungs or throat can be infectious. This means that the bacteria can be spread to other people. TB in other parts of the body, such as the kidney or spine, is usually not infectious. Who is at risk: Primary infection: children Secondary infection: age>25 Virulence factors No spore, no flagellum, no exotoxin,no endotoxin, no invasive enzyme Capsule:polysaccharide;CR3;enzy me; protect Lipid/Lipo arabinomannan Heat-shock protein/Tuberculin protein: antigenicity, old tuberculin; associate with wax D can cause hypersensitivity and form tubercle Lipid Lipid: closely related to virulence a. Phospholipid monocytes proliferate,cause tubercles b. Wax D adjuvent(not only to TB), delayed-type hypersensitivity c. Sulfatide硫酸脑苷脂 suppress phagosome combine with lysosome d. Cord factor (trehalose-6,6-dimycolate) destroy mitochondria, cause chronic granulomatosis, suppress WBC wandering Pathogenesis primary infection 1) lung infection secondary infection 2) Out lung infection Clinical syndromes a. fatigue, weakness, weight loss and fever b. pulmonary involvement: chronic cough,spit blood c. meningitis or urinary tract involvement d. bloodstream dissemination: miliary tuberculosis with lesions in many organs and a high mortality rate. Epidemiology high epidemic area : babies and children low epidemic area : elderly people Mortality g High g Moderate g None or low Primary Tuberculosis • The organisms are transmitted among human via aerosol. • TB bacilli lodge in the alveoli or lung alveolar ducts and most of bacilli are phagocytosed by alveolar macrophages. • Macrophages migrate to the hylar lymph node and generate T cell-mediated immune response. (can be monitored by tuberculin test) Tuberculin Skin Test • Tuberculin is a mixture known as purified protein derivatives (PPD) from TB bacilli. • It is a test for delayed type hypersensitivity. Positive reaction, reddening and thickening (> 5mm) at the site of injection after 2-3 days, indicates cellular immunity to tubercle bacilli. • Macrophages containing TB bacilli clump together and begin to form tubercles. (granulomatous response) • With time, the centers of the tubercles become necrotic and form cheesy acellular masses of caseous materials. (caseous lesion) 粟粒性肺结核 图注:肺组织内可 见多个灶性粉染无 结构结节——结核 性肉芽肿。中央组 织彻底坏死,可见 核缩、核碎现象。 周围有组织细胞增 生形成上皮样细胞 和郎罕巨细胞,淋 巴细胞散在浸润。 Symptoms: Activation of macrophages -> cytokine secretion, IL-1: fever, TNF: lipid metabolism, weight loss, tissue necrosis. Oxygen radicals: tissue damages Tissue necrosis -> inflammation -> mucous secretion, destruction of blood vessels -> frequent cough and bloody sputum 肾结核 结核的坏死破坏到肾盂组织,形成与输尿管道相 同的腔洞,坏死组织随尿排出体外形成空洞。 图注:1.结核巨细胞(郎罕细胞),胞体巨大,外 形不规则。胞浆灰蓝略带紫色,边缘部有少许空泡 且不整,并围以淋巴细胞形成栏栅状。浆中含有上 皮样肾形核约60个,个别核为圆形,排列紊乱。核 染色质细致,有者隐约有核仁/。其余增色为淋巴细 胞。 结核性肉芽肿是由于结核杆菌感染引起的具有诊断意义 的病变。中央为干酪样坏死,周围为增生的上皮样细胞, 其内散在Langhans巨细胞,外围聚集的淋巴细胞。 于上皮样细胞 及组织细胞, 淋巴细胞间, 可见郎罕氏巨 细胞及残留骨 组织。 股骨远侧干骺端骨质 破坏与硬化,其中有 散在死骨。病变穿过 骺板累及关节,关节 囊肿胀。 PULMONARY TUBERCULOSIS TUBERCULOSIS Large caseating tubercle HUMAN LUNG Miliary tubercles HUMAN LUNG MYCOBACTERIUM TUBERCULOSIS Can infect (disseminate) and cause disease in many different body locations such as: 1. Meninges 2. Brain 3. Bone 4. Kidney 5. Essentially any organ (lung primary target) Steps in the development of tuberculosis Inhalation of bacteria Bacteria reach lungs, enter macrophages Dead phagocytes, necrosis M. tuberculosis Bacteria reproduce in macrophages Lesion begins to form (caseous necrosis) Activated macrophages Bacteria cease to grow; lesion calcifies Lesion liquefies Immune suppression Spread to blood organs Reactivation Death Phagocytes, T cells, and B cells trying to kill bacteria Bacteria coughed up in sputum Immunity High rate of infection, but low morbidity. Nonspecific immune AIDS, immunosuppressive agents, endocrine disease, etc. Immunity-cellular Immunity First time: TB invade→proliferate on the spot →invade local lymph node Macrophage engulf TB →TH cell →IL-1 → TH proliferate →bloodstream Then TH meet TB again →MCF →macrophages congregate to focus →MAF →macrophages become more active →MIF →macrophages stay at the focus Then if it is successful granulomatosis forms,prevent TB diffusing;If it is not successful,macrophage can not kill TB, patients deteriorate. Immunity Cellular immunity 3-6 weeks, T cell VS macrophage 1. CD4+TH : INF-γ→macrophage→epithelioid cell granulomatosis 2. CD8 +TS : granule dependent, dissolve infected macrophage,kill TB 3. CD4- CD8 –t(γδ-T):Fas dependent, dissolve infected macrophage,but not kill TB, cause caseous focus in the center of granulomatosis; Acidity and lack of oxygen also make TB die. Immunity IV hypersensitivity Koch phenomenon; wax D+tuberculin protein; wax D →macrophage→epithelioid cell→tubercles→protect TB being phagocytized Immunity Humoral immunity A lot of Ab comes out, but meaningless TB active patient: immune complex more TB stable patient: immune complex less Diagnosis The steps to diagnose TB infection and disease include: • A medical evaluation that includes history and risk assessment • The tuberculin skin test • A chest x-ray • A bacteriological examination Diagnosis 1. Specimen: sputum, pus, CSF, urine, etc. 2. Microscopic examination: Ziehl-Neelsen stain 3. Concentration: 4%NaOH-3%HCL; 6% H2SO4 4. Culture: solid culture (2-4 weeks 37℃) ; liquid culture (1-2 weeks) 5. Animal inoculation: guinea pig 6. quick Diagnosis: PCR Skin test PPD-C BCG-PPD >5mm + >15mm + + PPD-C>BCG-PPD infected Mantoux method When the Mantoux skin test is performed, a needle is injected into the upper skin layer of the patient's arm. The arm is examined 48 to 72 hours after the tuberculin injection in order to evaluate the reaction on the patient's skin. Any swelling that can be felt around the site of the injection, also known as induration, is measured. The diagnosis of TB infection depends on the size of the measured induration and the patient's individual risk factors. Prevention BCG vaccination for new infants Freeze-drying vaccine rRNA vaccine eg:south India Chingleput’s failure of BCG Find and cure patients Treatment for Tuberculosis • Chemotherapy treated with a combination of multiple drugs for a long period of time: rifampin, isoniazid (INH), pyrazinamide, ethambutol, and streptomycin. Emergent Problems of Tuberculosis • Emergence of multi-drug resistant M. tuberculosis strains. Mycobacterium avium and AIDS Mycobacteria and AIDS • M. avium is much less virulent than M. tuberculosis – does not infect healthy people – infects AIDS patients • M. avium infects – when CD4 count greatly decreased • M. tuberculosis infection – infects healthy people – infects AIDS patients * earlier stage of disease * more systemic Clinical features with AIDS • systemic disease (versus pulmonary) – greater in AIDS • lesions often lepromatous Antibiotic therapy • selected primarily for M. tuberculosis • if M. avium involved other antibiotics included Mycobacterium avium-intracelluare complex • • • • • • causes tb like disease in birds, opportunistic pathogen in humans. Very prominent cause of disease in aids patients has been decreased following haart. Not easily transmitted. (Runyon group III). Difficult to treat ( drug of choice is rifabutin) Mycobacterium ulceranns • does not grow above 33oc • causes burui ulcer, emerging infectious disease • infection limited to fatty tissue beneath dermis Mycobacterium marinum • extrapulmonary ulcerative lesions • growth of organism restricted to 34oc • disease called “swimming pool granuloma” • does not respond well to therapy • Runyon group I Mycobacterium kansasii • pulmonary and disseminated disease similar to • tuberculosis (organisms do not produce niacin) • does not respond well to antimicrobials, • (no response to anti-tuberculosis therapy) • opportunistic pathogen • Runyon group I (photochromogen) Mycobacterium scrofulaceum • • • causes scrofula (cervical lymphadentis) drug resistant Runyon group II (scotochromogen) Mycobacterium fortuitum complex • causes chronic abscesses • (often wound associated) • can be confused with M. tuberculosis • often drug resistant • rapidly growing (Runyon group IV) Mycobacterium leprae HANSEN’S DISEASE (Leprosy) caused by M. leprae • Hansen’s disease is a chronic, slowly progressive • granulomatous disease involving ectodermally derived • tissue such as the skin and peripheral nerves. The disease is usually limited to the cooler parts of the body such as the skin, nose and upper respiratory tract. It rarely affects internal organs such as the brain, liver, spleen, kidneys, and bones. • It has a specific predilection for peripheral 4 forms of Leprosy • • • • Lepromatous Tuberculoid Borderline indeterminate ulcers, resorption of bone worsened from careless use of hands (nerve damage)