MICR 454L
Emerging and Re-EmergingInfectious Diseases
Lecture 7:M. tuberculosis
Dr. Nancy McQueen & Dr. Edith Porter
Overview M. tuberculosis Morphology
Growth and metabolic characteristics
Virulence factors Diseases Diagnosis
Culture PCR Immune response
Therapy Threats
Mycobacterium tuberculosis
M. tuberculosis
Acid fast rods Lipid-rich cell wall
Mycolic acids Lowenstein Jensen
agar Eggs Potatoes Malachite green
Slow growth Up to 6 weeks
http://www.ann-clinmicrob.com/content/figures/1476-0711-4-18-5.jpg
M. tuberculosis: Virulence Factors Lipid-rich cell wall
Mycolic acids Resistant to host defense Intracellular survival in macrophages
Iron capturing ability Sulfolipids prevent phagsome-lysosome fusion
Requires a T-cell mediated immune response for infection control/eradication
Granuloma formation
The Course of TB Infection and Disease
Airborne Infection
No symptomsNot sick
Cannot spread disease
Chest X Ray and sputum are normal
AIDS increases susceptibility
Reactivation(secondary) TB
Untreated:Severe illness,
Death
SymptomsCan sp[read
infectionPositive skin test
Possible abnormal chest X ray
Positive sputum smear or cultureDissemination
Latent TB TB Disease
10 %90 %
M. tuberculosis: Diseases
General Symptoms Feelings of sickness or weakness Weight loss Fever Night sweats
Lung tuberculosis Coughing Chest pain Hemoptysis
Extrapulmonary Depends on localization
Lung Tuberculosis
Extrapulmonary Tuberculosis
M. tuberculosis: Diagnosis
History Physical exam Mantoux Skin test (tuberculin test with
purified protein derivative) QuantiFERON®-TB Gold Test Chest radiograph Sputum smear Culture
Principle of the Tuberculin Test
QuantiFERON®-TB Gold Test
Measure IFN production by patient peripheral blood leukocytes in response to M. tuberculosis antigens (protein antigens ESAT-6 and CFP-10)
Rapid T cell response only in primed individuals
Interpretation of Tuberculin and QuantiFERON
Positive = previous contact with M. tuberculosis
Positive DOES NOT mean TB disease
M. tuberculosis: Therapy
Isoniazid (INH) Rifampin (RIF) Ethambutol Pyrazinamide
DOTS Direct observational therapy short course
At least 2 in combination (INH + RIF)Prolonged time (at least 6 months)
Anti-Tuberculosis Drug Targets
Mycolic acid INH inhibits mycolic acid synthesis Ethambutol inhibits mycolic acid
incorporation into the cell wall
Fatty acid synthetase I (FASI) Pyrazinamide inhibits fatty acid
synthesis
RNA synthesis Inhibited by rifampin
Resistance of M. tuberculosis
Mutations in codon 306 of the embB gene (ethambutol) are discussed as marker and predictor of resistance development to multiple antibiotics Not all mutated strains are resistant but resistant
strains are mutated. Alterations in RNA polymerase (Rifampicin)
Worldwide Threats byM. tuberculosis
1/3 of world population is infected Each year ~ 9 million new cases 5 – 10 % will develop active tuberculosis (TB) Worldwide ~ 1.5 million deaths from TB
However: In 2006, a total of 13,767 tuberculosis (TB) cases (4.6 per
100,000 population) in the US 3.2% decline from 2005
Co-infection with HIV Multidrug resistant TB Extremely drug-resistant TB
3 cases reported in the US in 2006
Extremely Drug-Resistant M. tuberculosis XDR TB Resistant to almost all drugs used to treat TB,
including the two best first-line drugs: isoniazid and rifampin
Resistant to the best second-line medications: fluoroquinolones (DNA gyrase mutations)
And at least one of three injectable drugs (i.e., amikacin, kanamycin, or capreomycin; mutations in 16sRNA and ribosomal protein genes).
Possibly involvement of drug efflux pumps. 49 cases of XDR TB have been reported between
1993 and 2006 in the US
Reported Cases of XDR in the US
MMWR Weekly, March 23rd, 2007
New Drugs are Needed
Immune modulators IL-2, IFN-gamma, GM-CSF, IL-12
New chemicals targeting essential genes of M. tuberculosis
Take Home Message
One third of the world population is infected with M. tuberculosis but only 10% develop active disease.
The lipid rich cell wall and slow growth contribute to resistance to host defense and difficulties in antibiotic treatment.
The emergence of extremely drug resistant tuberculosis strains poses a great threat to the public.
Additional Resources The Microbial Challenge, by Krasner, ASM Press, Washington DC, 2002. Brock Biology of Microorganisms, by Madigan and Martinko, Pearson Prentice Hall, Upper
Saddle River, NJ, 11th ed, 2006. Immunobiology, by Janeway,, Travers, Walport, and Shlomchik, Garland Science, 6 th ed, 2005. Malak Kotb Genetics of Susceptibility to Infectious Diseases Volume 70, Number 10, 2004 / ASM
News Y 457-463 htttp://www.cdc.gov/ulcer/keytocure.htm#whatis http://dermatlas.med.jhmi.edu/derm/resultNoCache.cfm Zager and McNerney (2008) Multidrug-resistant tuberculosis. BMC Infectious Disease. 8: 10. Safi H, Sayers B, Hazbón MH, Alland D. (2008) Antimicrob Agents Chemother. Mar 31
[Epub ahead of print] Transfer of embB306 mutations into clinical Mycobacterium tuberculosis alters susceptibility to ethambutol, isoniazid and rifampin.
Zimhony O et al. (2000) Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis. Nat Med. Sep;6(9):1043-7.
http://images.google.com/imgres?imgurl=http://www.biozentrum.uni-wuerzburg.de/fileadmin/REPORT/BIOTE/pic/biote016_img_0.jpg&imgrefurl=http://www.biozentrum.uni-wuerzburg.de/fileadmin/REPORT/BIOTE/biote016.htm&h=734&w=488&sz=82&hl=en&start=4&tbnid=_R4zGz7SCgf70M:&tbnh=141&tbnw=94&prev=/images%3Fq%3Dmycobacterium%2Btuberculosis%2Bcell%2Bwall%26gbv%3D2%26hl%3Den (accessed 4 15 08)
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