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

References• 10 facts about tuberculosis. [Internet]. World Health Organization. 2016 Mar [cited 2016 Apr 22]. Available from

http://www.who.int/features/factfiles/tuberculosis/en/• Aguiló N, Marinova D, Martín C, Pardo J. ESX-1 induced apoptosis during mycobacterial infection: to be or not to be, that is the question.

Front Cell Infect Microbiol. 13 Dec 2013;3(88):1-7.• Ahmad S. Pathogenesis, immunology, and diagnosis of latent Mycobacterium tuberculosis infection. Clin Dev Immunol. 2011;2011:814943.• Babalola MO. The strengths, weaknesses, opportunities and threats (SWOT) analysis of Mycobacterium tuberculosis: a systematic review. J

Tuberc Res. 2015;3:184-205.• Behar SM, Divangahi M, Remold HG. Evasion of innate immunity by Mycobacterium tuberculosis: is death an exit strategy? Nat Rev

Microbiol. 2010 Sep;8(9):668–674.• Bold TD, Ernst JD. Who benefits from granulomas, mycobacteria or host? Cell. 9 Jan 2009;136(1):17-19.• Cambier CJ, Falkow S, Ramakrishnan L. Host evasion and exploitation schemes of Mycobacterium tuberculosis. Cell. 18 Dec

2014;159(7):1497-1509.• Gouzy A, Larrouy-Maumus G, Bottai D, Levillain F, Dumas A, Wallach JB, Caire-Brandli I, de Chastellier C, Wu T, Poincloux R, et al.

Mycobacterium tuberculosis exploits asparagine to assimilate nitrogen and resist acid stress during infection. PLoS Pathog. Feb 2014;10(2):e1003928.

• Raghuvanshia S, Sharmaa P, Singhb S, Kaerc LV, Dasa G. Mycobacterium tuberculosis evades host immunity by recruiting mesenchymal stem cells. Proc Natl Acad Sci. 14 Dec 2010;107(50):21653–21658.

• Tille PM. Mycobacteria. In: Bailey & Scott’s diagnostic microbiology. St. Louis (MO): Elsevier; 2014. p. 484-512.• Weiss G, Schaible UE. Macrophage defense mechanisms against intracellular bacteria. Immunol Rev. 2015;264:182-203.