Mycobacterium species Acid fast bacilli - cell walls contain unusual glycolipids (e.g.mycolic acids)

Mycobacterium species Acid fast bacilli - cell walls contain unusual glycolipids (e.g.mycolic acids) Intracellular organisms (some are facultative others are obligate)

Diseases caused by Mycobacterium species M. tuberculosis - tuberculosis M. leprae - leprosy

Diseases caused by Mycobacterium species M. avium - lung and skin infections in immunocompromised hosts - lymphadenopathy in children - catheter-related infections

Mycobacterium tuberculosis Closely related to M. bovis (a cattle parasite/pathogen?) M. tuberculosis believed to have evolved from M. bovis after domestication of cattle (8,000-4,000 BC) Archeologists have shown that tuberculosis of the bones seems to have preceded the disease of the lungs

Tuberculosis (TB) Most common cause of death due to bacterial infection worldwide 2 billion infected worldwide / 8-9 million new cases per year Aggressive measures decreased infections in developed countries

Tuberculosis (TB)

TB Once known as consumption Afflicted individuals considered beautiful and erotic Thought that TB sparked genius

TB Spread by aerosols Symptoms include : fever coughing (often with blood) weight loss malaise (loss of energy)  progressive lung damage

Systemic TB Can infect any area of the body including: Bones and joints Internal organs Brain

Progression of TB M. tuberculosis can survive within unactivated macrophages Activated macrophages can kill the bacteria Individual’s immunological response determines the outcome of exposure

Progression of TB T-cells involved in controlling infection Gamma interferon (IFN-  ) activates macrophages Cytotoxic T-cells (T c -cells) kill infected macrophages

Progression of TB Healthy individual exposed to low dose  activated macrophages stop infection Individuals unable to mount a rapid response  bacteria multiply in lung macrophages

Progression of TB Individuals unable to mount a rapid response  bacteria multiply in lung macrophages  phagocytes attracted to site of infection  infection may be walled-off/ forms tubercle Tubercles may calcify and become visible in chest X-rays (Ghon complex)

Ghon complex

Progression of TB Continuous growth of bacteria causes interior of tubercle to liquefy Rupture of tubercle allows bacteria to escape Leads to infection of others (aerosols) or other parts of the body

Progression of TB

Bacteria in tubercles may survive for decades (latency) Suppression of immune system may allow bacteria to break out of lesions and multiply (reactivation) Old age, cancer, immunosuppressive drugs and HIV infection can lead to reactivation

Virulence factors Invasion of and survival within phagocytes Interference with T-cell activation Eliciting inflammatory response

Diagnosis of TB Acid-fast staining of sputum samples

Diagnosis of TB TB skin test - injection of M. tuberculosis proteins (tuberculin) - positive test leads to red area at injection site

Treatment of TB Streptomycin - first antibiotic used against M. tuberculosis - did not always cure patients - slowly dividing cells became resistant

Treatment of TB Rifampin - used to treat TB and prophylactically for bacterial meningitis - resistant mutants arise readily - used in combination with other drugs

M. tuberculosis specific drugs Isoniazid - isonicotinic acid hydrazide or INH - must be converted into the active form by a bacterial enzyme (catalase-peroxidase) - inhibits the formation of mycolic acid - resistance occurs by inactivation of catalase- peroxidase or by mutation of enzyme in mycolic acid synthesis pathway

M. tuberculosis specific drugs Pyrazinamide - bacterial enzyme (PZase) converts it to pyrazinoic acid (active form) - target of the drug is unknown - uptake increases under acidic conditions (vacuoles of phagocytes) - targets bacteria inside phagocytic cells - lowered activity of PZase results in resistance

DOTS - directly observed therapy short course System in which patients were monitored by health care workers to ensure they took their medications Cocktail of different drugs are required to ensure resistant strains do not arise

Development of resistant M. tuberculosis DOTS system dismantled in the 1970s Rise in prison population Rise in the homeless living in crowded shelters

Development of resistant M. tuberculosis Physicians no longer trained to diagnose and treat TB Organisms exist in different compartments and exhibit different metabolic activities  one or more drug may not be effective

Multidrug resistant tuberculosis (MDR-TB) Defined as the presence of M. tuberculosis resistant to at least isoniazid and rifampicin Treatment involves use of “second line” drugs Some of these were first line antituberculosis drugs when they were first introduced (e.g. Streptomycin and p-Aminosalicylic acid (PAS))

Multidrug resistant tuberculosis (MDR-TB) Good diagnostics is critical in controlling MDR-TB DOTS Plus strategy - includes monthly monitoring of patients for presence of resistant strains and changing drug regimen as resistance status changes