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1、Bacillus, Corynebacterium, Nocardia, Mycobacterium, Clostridium, anaerobic, non-spore-forming Gram-positive Bacteria, anaerobic Gran-negative BacteriaChen Niu, PhDChen Niu, PhDSchool of Basic Medical SciencesSchool of Basic Medical Sciences, Fudan University, Fudan UniversityMycobacteriaaerobic, rod
2、 shape, do not form sopresthe genome has high g+c content, unique cell wall; gram stain indeterminant, acid-fastmore than 200 species, many are saprohytes, some are pathogens.Disease caused by mycobacteria usually are chronic, with granuloma formation. Relatively slow growth (two groups)A.Rapid Grow
3、ers (Visible colonies in 5 days)MycobacteriaM. tuberculosisM. tuberculosis complex (MTBC)complex (MTBC)结核分枝杆菌复合群4M. tuberculosisM. tuberculosisM. Bovis M. Bovis ( (牛型结核杆菌牛型结核杆菌) )M. AfricanumM. Africanum（非洲结核杆菌）（非洲结核杆菌）M. CanettiM. Canetti（卡氏结核杆菌）（卡氏结核杆菌） M. microti M. microti （田鼠结核杆菌）（田鼠结核杆菌）Mycoba
4、cterium tuberculosis (结核分枝杆菌结核分枝杆菌)5Nesperhan, priest of Amun, “Gibbous”History of TB：Mummy,Xulao (虚痨)7Chinese Celebrities with TBLu, XunLi, ShutongLin, DaiyuLin, Huiyin8Mozart1756-1791Chopin1810-1849Shelley1792-1822Keats 1795-1821Artists and poets 9 Discovery of M. tuberculosisGlobal TB Epidemicsu1
5、7th-18th century 1/5 of adult death were caused by TB u 1850-1950 1 billion people killed by TB u Currently, about 9 million new TB cases, and 1.4 million deathu China has the second highest TB burden, with 1.3 million new TB cases and more than 100K deathWHO reportWHO reportMycobacteria-Junqis Lect
6、ure for MD students111213CellwallstructuresofMTb High Lipids content, mycolic acidsFix Smear by heat, Cover with Carbolfuchsin for 5 minutes, Wash, Decolorize with 95%Ethanol/3% HCl, Wash, Counter stain with Loeffler metlene blue, WashZiehl Neelsen Staining(Acid-fast stain)TransmissionMainly through
7、 respiratory tractVideo watchingClinicalsyndromes17Extra-pulmonary TBPathogenesis primary infection1) lung infection secondary infection 2) Out lung infection PathogenesisInfection and immunity, the type IV hypersenstivityVirulence factors No spore, no flagella, no exo- or endo-toxin, no invasive en
8、zymelCapsule:polysaccharide, etclLipid/Lipo arabinomannanlHeat-shock protein/Tuberculin protein: antigenicity, old tuberculin; associate with wax D can cause hypersensitivity and form tubercleLipidLipid: closely related to virulencea. Phospholipid monocytes proliferate,cause tuberclesb. Wax D adjuve
9、nt(not only to TB), delayed-type hypersensitivityc. Sulfatide硫酸脑苷脂硫酸脑苷脂 suppress phagosome combine with lysosomed. Cord factor (trehalose-6,6-dimycolate) destroy mitochondria, cause chronic granulomatosis, suppress WBC wanderingImmunity-cellularImmunityFirst time: TB invadeproliferate on the spot in
10、vade local lymph nodeMacrophage engulf TB TH cellIL-1 TH proliferate bloodstreamThen TH meet TB againMCF macrophages congregate to focusMAF macrophages become more activeMIF macrophages stay at the focusGranuloma, double edge sword -prevent TB diffusing; in early granuloma, mycobacterium can recruit
11、 permissive macrophages for disseminationImmunity IVhypersensitivity-Kochphenomenon;waxD+tuberculinprotein;waxDmacrophageepithelioidcelltuberclesprotectTBbeingphagocytizedDiagnosisThestepstodiagnoseTBinfectionanddiseaseinclude:AmedicalevaluationthatincludeshistoryandriskassessmentThetuberculinskinte
12、stAchestx-rayAbacteriologicalexaminationTuberculin Skin TestTuberculin 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 cellu
13、lar immunity to tubercle bacilli. 5mm + 15mm + +Diagnosis1. Specimen: sputum, pus, CSF, urine, etc. 2. Microscopic examination: Ziehl-Neelsen stain3. Concentration: 4%NaOH-3%HCL; 6% H2SO44. Culture: solid culture (2-4 weeks 37) ; liquid culture (1-2 weeks)5. Animal inoculation: guinea pig6. quick Di
14、agnosis: PCR Acid-fast stain of smearsAcid-fast stain of smearsCultivation of MtbSemisynthetic agar media： 7H10 and 7H11 Inspissated egg media Broth media 7H9 18-24 hours doubling time; 3-6 weeks Selective agents: Malachite green, antibiotics 30n1920 French Scientists Calmette & Guerin discovered BC
15、G (Bacillus Calmette-Gurin ) M. bovis M. bovis 13 years, 13 years, 230 generation 230 generation attenuated strain attenuated strain （BCGBCG）n1945 worldwide used, it is still the most popular vaccine nGood protection to infants and childrem, less protection to adultsTB Vaccine In 1943 In 1943 Strept
16、omycin(Streptomycin(链霉素链霉素) ) was first isolated was first isolated on October 19, by Albert Schatz, a graduate on October 19, by Albert Schatz, a graduate student, in the laboratory of Selman Abraham student, in the laboratory of Selman Abraham Waksman at Rutgers University, and was the first Waksm
17、an at Rutgers University, and was the first antibiotic remedy for tuberculosisantibiotic remedy for tuberculosis in 1951, in 1951, Isoniazid (Isoniazid (异烟肼异烟肼) ) was found to be was found to be effective against tuberculosis by inhibiting its effective against tuberculosis by inhibiting its mycolic
18、 acid (wax coat) mycolic acid (wax coat) RifampicinRifampicin（利福平）（利福平）was produced in 1959was produced in 1959，and was and was introduced in 1967as a major addition to the introduced in 1967as a major addition to the cocktail-drug treatment of tuberculosis cocktail-drug treatment of tuberculosis 31
19、Discovery of anti-TB drugsDiscovery of anti-TB drugs32First line anti-TB drugsFirst line anti-TB drugsv异烟肼（isoniazid，INH，H）v利福平（rifampicin，RFP，R）v吡嗪酰胺（pyrazinamide，PZA，Z）v乙胺丁醇（ethambutol，EMB，E）Drug resistant MtbvMultidrug-resistantMultidrug-resistant，MDR-TB: isMDR-TB: is resistantat least to isoniaz
20、id and rifampicinvExtensively drug-resistantExtensively drug-resistant， XDR: XDR: MDR-TB, plus resistance to any member of the quinolone family and at least one of the following second-line anti-TB injectable drugs: kanamycin, capreomycin, or amikacin.34Andrews honeymoon (May, 2007)35XDR-TBMycobacte
21、ria-Junqis Lecture for MD students3637TB EpidemicDOTSHIV EpidemicHIV-TB co-infectionHansens Disease (Leprosy) caused by M. leprae (麻风分枝杆菌麻风分枝杆菌) )Hansensdiseaseisachronic,slowlyprogressivegranulomatousdiseaseinvolvingectodermallyderivedtissuesuchastheskinandperipheralnervesaspecificpredilectionforpe
22、ripheralnervesMorethan10millioncases,mainlyinAsia2 major forms of Leprosy: Tuberculoid （结核样的结核样的） Lepromatous (瘤型）瘤型） The same Lepromatous patient in 2 yearslScrapingsfromskinornasalmucosalSmearpreparationandZ-Nstain:foamycellsacid-fast41Diagnosis42Treatment,PreventionandControl Sulfones such as dap
23、sone are first-line therapy, RMP or clofazimine generally is included in the initial regimens Several years of therapy may be necessary to adequately treat leprosy In US, the current prevention strategy includes a thorough examination of household contacts and close relatives References and Citation Jawetz,Melnick,&AdelbergsMedicalMicrobiology,25th,26th(McGraw-HillEducation)http:/en.wikipedia.org,http:/http:/
