Tuberculosis

Question 1

What organ is primarily affected?

Answer 1

Lungs

Question 2

What makes M. Tuberculosis so difficult to cure?

Answer 2

1. Complex cell envelope
2. Intracellular survival strategies
3. Non-replicating persistence

Question 3

Describe M. Tuberculosis.

Answer 3

Strict aerobe, Slow growing, Acid fast, Gram+, Waxy cell envelope.

Question 4

Describe the cell envelope virulence factors of M. Tuberculosis.

Answer 4

1. Mycolic acid: Protects from environmental stress.
2. Trehalose Dimycolate (Cord Factor): Major immunogenic TB lipid. Elicits granuloma formation; Inhibits PMN migration.
3. Lipoarabinomannan: Inhibits cell mediated immunitiy; Inhibits T-cell proliferation and induction of IFN-y genes. Protects from ROS.

Question 5

How does M. tuberculosis get inside of a macrophage?

Answer 5

1. Mannose and CD 14 receptors detect LAM.
2. Scavenger receptors detect TDM.
3. Fc receptors detect IgG opsonized M. Tuberculosis

Question 6

How does M. tuberculosis survive in the macrophage?

Answer 6

Lipid cell envelope allows bacterium to withstand ROS; Arrests phagosome maturation to avoid bactericidal lysosome.

Question 7

Explain Non-replicating persistence.

Answer 7

TB granuloma is hypoxic; Mtb arrests growth and remodels its physiology for long-term survival. DosRT two component regulator coordinates hypoxia dependent initiation of NRP.

Question 8

How does a Mtb granuloma form?

Answer 8

A macrophage releases TNF-a to recruit CD4, CD8 and B cells which forms granuloma to limit spread of disease. Lymphocytes downregulate granuloma formation and INF-y. Impaired CD4 causes breakdown of granuloma and onset of disease.

Question 9

How does cell mediated immunity kill Mtb?

Answer 9

1. CD4 Th1 produce INF-y and IL-12 to activate macrophages.
2. CD8s kill resting infected macrophages.
3. B-cells produce antibodies for Mtb antigens

Question 10

Explain the delayed hypersensitivity response of Mtb.

Answer 10

Bacterial proteins are presented to CD4 Th1 cells. Th1 release chemokines and cytokines that increase vessel permeability. Leads to more tissue destruction.

Question 11

What are the drawbacks of Mtb (BCG) vaccine?

Answer 11

1. Poorly effective in adults
2. Can’t clear infection
3. Positive TB skin test interferes with TB surveillance.

Question 12

Understand TB skin tests

Answer 12

pg 257 & 258

Question 13

How is Mtb diagnosed?

Answer 13

Weight loss, fatigue, hemoptysis and chest pain; Chest X-ray and culture

Question 14

How are latent Mtb infections treated?

Answer 14

Antibiotics; Isoniazid and rifapentine

Question 15

What are the mechanism of action for isoniazid, rifampin, ethambutol, pyrazinamide?

Answer 15

Isoniazid: Targets Mycolic acid synthesis; enoyl-acyl carrier protein
Rifampin: Targets RNA synthesis; RpoB, RNA polymerase.
Ethambutol: Targets Arabinogalactan synthesis; arabinosyl transferase.
Pyrazinamide: Targets translation; RpsA