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Microbiology and Immunology
Microbiology and Immunology 2500A/B
John Mc Cormick

Tuberculosis and Leprosy Mycobacteria M. tuberculosis  Causes tuberculosis in humans  Humans are the only known reservoir  Often called TB for tubercle bacilli M. bovis  Causes tuberculosis in cows, rarely in humans  Humans can be infected by the consumption of unpasteurized milk leading to extrapulmonary tuberculosis M. avium  Can cause tuberculosis-like illness in humans, particularly in AIDS patients M. leprae  Causative agent of Leprosy in humans This lecture focuses on two diseases caused by the same genus, Mycobacteria. Tuberculosis affects one-third of the world’s population at some point in their life. Out of these, one-tenth (of the one-third) will progress to active tuberculosis in their lifetime (actual sickness). TB is contagious (spreads in the air) and if the active form is not treated, it will infect 10-15 people per year. In 2011, there were almost 9 million cases of TB with the highest rates per capita is in Africa, but half of the new cases are in six Asian countries (Bangladesh, India, China, Philippines, Indonesia, Pakistan). There are two types of drug resistant forms of TB:  Multidrug resistant (MDR): The disease is still spreading, and we have drug resistant TB (MDR-TB). MDR-TB doesn’t respond to the first-line antibiotics.  Extensively drug resistant (XDR): Organisms are resistant to the first line AND second-line of drugs you can use for TB (some of the strains are impossible to treat, extremely dangerous). TB is the second leading cause of death by infectious organisms, while the first is HIV  synergism between the two. Global incidence per 100,000 The more developed counties have a lower incidence of TB. The major centers for disease are in Africa and Asia because TB is a disease of poverty (healthcare isn’t as advanced as in developed countries). The pathogen: Mycobacteria tuberculosis M. tuberculosis is an obligate human pathogen that lives in macrophages (intracellular pathogen):  Non-motile  Rod shaped  Obligate aerobe M. tuberculosis can be grown in the lab on specialized media but it takes 4-6 weeks to get small colonies  long growth time is a problem for research. This is also important for drug resistance and treatment, because when you’re treating tuberculosis patients, you need to be on antibiotics for a long time. Actively growing cells are easier to kill, but TB grows extremely slow. Mycobacteria have high concentrations of mycolic acid in the cell envelope. The main hallmark of this organism is the cell envelope, and it is associated with resistance to:  Antibiotics  Killing by acidic and alkaline compounds  Osmotic lysis via complement deposition  Lethal oxidative stress and promotes survival inside macrophage The cell envelope is also impermeable to stains and dyes. The waxy, lipid-rich cell envelope (very hydrophobic) is resistant to common stains (i.e. gram stain). The “Acid fastness” is due to the presence of mycolic acid. The acid-fast stain process: 1. Stained with the basic dye carbolfuchsin with slow heating (to melt the wax, allowing dye to enter) 2. Washed with EtOH and HCl 3. Counterstained with methylene blue (analogous to safranin staining in gram) Acid-fast organisms appear red whereas non-acid fast organisms appear blue. TB is closer to gram-positives from an evolutionary standpoint (no outer membrane) but it won’t stain with the gram stain. Spread and Progression of Tuberculosis Stage 1: Transmission from inhalation of droplets from an infected host, usually by coughing or sneezing. Coughing/sneezing can generate 3000 droplet nuclei; droplet nuclei can contain ~3 bacteria. Small diameter droplets (~5 um) can stay airborne for extended periods of time, and these can be inhaled directly into the lungs. Stage 2: Begins 7-21 days after initial exposure. Alveolar macrophages phagocytize TB cells, and TB can multiply in UNACTIVATED macrophages. Macrophages will lyse and release TB cells to infect more macrophages. A key virulence property of M. tuberculosis is the ability to survive within the host macrophage. Stage 3: Infected macrophages may form granulomas. TB granulomas are tubercles of immune cells that try to destroy invading pathogens (typically formed by macrophages, surrounded by lymphocytes). Immune cells try and destroy the pathogen, but TB sits in the granuloma structures and inside the macrophage it will prevent the fusion of the lysosome with the phagosome to grow within the macrophage. Lymphocytes to get at these macrophages, but the granuloma represents a balance (stalemate) between the pathogen and the host  latent infection (you may be infected by TB, but you’re not showing signs of disease). Macrophages at the center of the granuloma are harder to activate by T-cells. Activated macrophages can kill TB and present antigens to T-cells. TCR activated T- cells can secrete cytokines to activate the macrophages, and a chronic inflammation occurs around these tubercles  macrophages cause necrosis “cheese-like”  caseous necrosis (leading to inflammation of the immune system). Stage 4: Some macrophages remain inactivated and infected. The tubercle grows, the erosion of the granuloma into the airway provides the route of transmission into the airways and the organism has access to other people due to coughing. Deterioration of host immunity can result in a life threatening infection, active tuberculosis (live TB cells  transmissible  active TB). The caseous center can liquefy leading to cavitation (rupturing and spilling). Tuberculosis 75% of active tuberculosis is pulmonary (contagious)  Progressive, irreversible lung destruction can occur, and the bacteria may enter the blood stream  Latent carriers do not transmit the infection  It is though that a single inhaled bacterium can infect 25% of active tuberculosis is extra-pulmonary (non-contagious)  can vary widely depending on where TB has spread  More likely to occur in immunocompromised individuals  Can infect: bone, joints, liver, spleen, GI tract, and brain  Systemic spread, called military tuberculosis is almost always fatal Only ~10% of TB infected people develop disease. Symptoms are non-specific:  A prolonged (>2 weeks) cough with thick and possibl
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