evasion of the host immune response by mycobacterium tuberculosis
TRANSCRIPT
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Evasion of the Host Immune Response by Mycobacterium
tuberculosisRichard Bautista
Middle Tennessee State University
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Overview• Background• Evasion Mechanisms• Cell Wall• Granuloma• Apoptosis/Necrosis• Mesenchymal Stem Cells (MSC)• Asparagine
• Conclusion
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Background• Aerobic
• Microaerophilic• Non-spore forming• “Considered” Gram positive• Around ~70,000 years• ~1/3 of world’s population is infected• Opportunistic• Leading killer of people with HIV• 2014: 9.6 million fell ill with TB; 1.5 million died
• 480,000 developed MDR-TB, including XDR-TB• Mortality rates declining
• 2013: 86% of patients successfully treated
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Background• Transmission by respiratory droplets• Infection• Engulfed by alveolar macrophages• Intracellular replication• Dissemination
• Immune Response• Cell-mediated immune response, 2-8 weeks after infection• Immune cells form granulomas, disease spread stopped
• Most M. tb. cells killed
• Latency
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Cell Wall• Complex structure• Mycolic acid• Mycothiol• Lipoarabinomannan (LAM)• High lipid content• Protection
• Impermeable• Antibiotics• Oxidative stress• Acid/alkaline environments• Lysozyme
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Granuloma• Thought to stop spread of M. tb.• Benefit to pathogen?• MΦ motility high at start• Early granulomas recruit MΦ
• More hosts for pathogen
• Recruitment dependent on RD1 locus• Also important for ESAT-6/ESX-1
(virulence factor)
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Apoptosis/Necrosis• Apoptosis or necrosis?• Apoptosis: Cell-to-cell spread
• Affected by ESAT-6/ESX-1• Plays role in early-phase infection
• Necrosis: Release to extracellular environment• M. tb. Blocks plasma membrane repair• Plays role in late-phase infection
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Mesenchymal Stem Cells (MSC)• MSC from host adipocytes• M. tb. recruit MSC to infection site• MSC produce NO
• NO suppresses T-cell responses• NO has mycobactericidal properties
• MSC surround granulomas• Gets between T-cells and pathogens they
target• Keeps M. tb. from spreading outside
granuloma
• Equilibrium leads to latent infection
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Asparagine• Macrophage > Phagosome > Phagolysosome
• Increasing acidity• Limited nutrient availability
• Asparagine imported into M. tb. via AnsP2• Asparagine hydrolyzed by asparaginase AnsA
to aspartate and ammonia• N assimilated into glutamine and glutamate
• H+ imported via v-ATPase + ammonia = ammonium ion• Buffers pH• Protects from acid stress
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Conclusion• Multiple methods used by Mycobacterium tuberculosis to evade host
immune response and persist in latent infection• Potential targets for novel therapeutics
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Questions?
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Acknowledgements• Dr. Jeffrey Leblond, Department of Biology, Middle Tennessee State
University• Department of Biology and the Professional Science Program, Middle
Tennessee State University
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