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Evasion of the Host Immune Response by Mycobacterium
tuberculosisRichard Bautista
Middle Tennessee State University
Overview• Background• Evasion Mechanisms• Cell Wall• Granuloma• Apoptosis/Necrosis• Mesenchymal Stem Cells (MSC)• Asparagine
• Conclusion
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
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
Cell Wall• Complex structure• Mycolic acid• Mycothiol• Lipoarabinomannan (LAM)• High lipid content• Protection
• Impermeable• Antibiotics• Oxidative stress• Acid/alkaline environments• Lysozyme
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)
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
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
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
Conclusion• Multiple methods used by Mycobacterium tuberculosis to evade host
immune response and persist in latent infection• Potential targets for novel therapeutics
Questions?
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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