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State Medical and Pharmaceutical University Chisinau, Moldova Lecture for students
Immunology to tuberculosis
Timo Ulrichs
Vice president and head of the section of tuberculosis, Koch-Metchnikov-Forum, Berlin
Overview Mycobacteria
There are >70 species of mycobacteria
Of these, two are major pathogens: 1.Mycobacterium tuberculosis (Koch, 1882) 2.Mycobacterium leprae (Hansen, 1874)
The remaining mycobacteria are environmental organismscollectively known as MOTTS (Mycobacteria Other Than Tuberculosis) MOTT organisms are responsible for opportunistic infections, especially in people with AIDS
Classification
Mycobacteria belong to the
Cell Wall
Tuberculosis
Threat to mankind already in ancient Egypt:
Famous victims of TB
Anton Checkov Branwell Bront Emily Bront Frdric Chopin John Keats D.H. Lawrence Vivien Leigh George Orwell Paganini Edgar Allan Poe Jean J. Rousseau Sir Walter Scott P.B.Shelly R.L. Stevenson Simonetta Vespucci
Tuberculosis
Tuberculosis
Global numbers of tuberculosis (WHO, 2011) 1.6 million deaths per year 9.4 million new infections per year Every third of the human World population is infected. 5 to 10 % of the infected will develop TB during their life.
Tuberculosis
Global numbers of tuberculosis (WHO, 2011) If TB cannot be brought under control within the next 30 years: 1000 million new infections 200 million new disease cases 35 million deaths
Tuberculosis
Global numbers of tuberculosis (WHO, Geneva)
Slender, straight or slightly curved bacillus, non-motile, nonencapsulated and does not form spores Acid fast bacillus (AFB) Aerobic Slow growing- divides every 18-24 hr. Resistant to drying and chemical disinfectants Sensitive to heat (Pasteurization) and UV light
The M.tb genome has been sequenced First major pathogen to be sequenced 4,411,522 bp 3 924 open reading frames GC content of 65.6% +/- 70% of the genes can be identified at this stage, the remainder are unique and encode proteins with unknown functions 59 % of genes are transcribed in the same direction as chromosomal replication
Anti-TB chemotherapy
1944: Waksman and colleagues discovered Streptomycin: a revolution in the treatment of TB disease
monotherapy, resistance, failure 1950s: Isoniazid, Pyrazinamide: combination therapy the complete eradication of TB disease is in sight 1993: WHO declares of TB as a global health emergency multi-drug-resistance (MDR) increasing
> 10% MDR-TB in Baltic states, Eastern Europe, several provinces in Russia, China
1/106 mutation rate: triple treatment has 10-18 risk of resistance, if strain is susceptible for all agents; 10-6 risk of resistance, if strain is already resistant to two drugs >108 organisms/lesion during active TB
Development of resistance
No eradication possible!
Conventional TB drugs
Drug cellular process targeted molecular target
Isonizid, INH
Pyrazinamide, PZA cell wall fatty acid biosynthesis Ethambutol, ETB cell wall arabinogalactan synthesis Cycloserine cell wall peptidoglycan synthesis Rifampin, RMP Streptomycin, SM Fluoroquinolones RNA synthesis polypeptide synthesis DNA synthesis
Conventional TB drugs
target processes of mycobacterial cell growth and division are bacteriostatic, not bacteriocidal have been selected for effectiveness against M.tb. cultures in vitro, not in vivo often have to be activated in vivo (what is not done by dormant M.tb.) are inactive within the phagosome in most cases
by means of:
information on M.tb. genome and proteome better understanding of mycobacterial strategies for persistence modern high throughput screening: proteomics, transcriptomics for identifying novel targets, test in animal models using chronic vs. acute vs. dormant infection
Tuberculosis
Global numbers of tuberculosis (WHO, Geneva)
Tuberculosis
Directly observed therapy, DOTS
Uncivilized peoples not only rub over their arrow with one kind of poison, but with two or three totally different kinds of poison.
Paul Ehrlich, 1913
If you want to efficiently fight your enemy, first get to know every detail of him!