Payne- TB

Question 1

Describe pathogenesis of TB

Answer 1

Entry & Early Intracellular Survival:

*Mycobacterium tuberculosis enters the lungs, where it is phagocytosed by alveolar macrophages.
*The bacterium interacts with macrophage receptors such as the mannose receptor and complement receptors (CR3, CR4) to facilitate uptake.
*Once inside the macrophage, M. tuberculosis prevents phagolysosome fusion, allowing it to persist and replicate within the phagosome.
*Infected macrophages eventually lyse, releasing bacteria to infect other macrophages and spread to nearby lymph nodes.

T-Cell Activation in Lymph Nodes:

*M. tuberculosis antigens are presented to naïve CD4+ T cells by antigen-presenting cells (macrophages and dendritic cells) in the draining lymph nodes.
*IL-12 released by macrophages induces Th1 differentiation of CD4+ T cells.

Macrophage Activation & Granuloma Formation:

*Th1 cells release IFN-γ, which activates macrophages to kill intracellular bacteria.
*Activated macrophages release TNF-α, inducible nitric oxide synthase (iNOS), and defensins to enhance bacterial killing.
*Persistent infection leads to differentiation of macrophages into epithelioid histiocytes, which cluster to form granulomas in an attempt to contain the infection.
*In primary TB, this typically occurs in the mid-to-lower lobes of the lung, forming a Ghon focus. If nearby lymph nodes are involved, this is termed a Ghon complex.
*Over time, granulomas may undergo fibrosis and calcification, leading to containment of the infection.

Failure of Containment & Progression to Active TB:

*If the immune system fails to fully eradicate the bacteria, M. tuberculosis can persist in a dormant state within granulomas.
*In immunocompromised individuals (e.g., HIV, malnutrition, aging, TNF-α inhibitors), latent TB can reactivate as secondary TB, which typically affects the apical (upper) lobes due to higher oxygen tension favoring mycobacterial growth.
*If uncontrolled, bacteria can spread hematogenously, leading to miliary TB or extrapulmonary TB (e.g., in the CNS, bones, or kidneys)

Question 2

MOA of isoniazid

Answer 2

Prodrug enters mycobacterium and is converted to its active metabolite by KAT-G enzyme

Drug then binds to NADH forming a drug-NAD adduct which then inhibits InhA; a key enzyme in the fatty-acid synthase II (FAS-II) system

This prevents elongation/ synthesis of mycolic acid precursors leading to cell death

Bactericidal in growing cells, bacteriostatic in resting cells

Question 3

How does isoniazid cause peripheral neuropathy

Answer 3

It metabolites inhibit the enzyme pyridoxine phosphokinase, which is responsible for converting pyridoxine to its active form –> Pyroxidine is a co-factor in neurotransmitter synthesis as well as the upkeep of the myelin sheath.

Question 4

MOA of pyrazinamide

Answer 4

prodrug converted to pyrazinoic acid by pyrazinamidase

Inhibts FAS-I system preventing synthesis of mycolic acids for mycobacterial cell wall –> cell death

Question 5

MOA of Ethamutol

Answer 5

Inhibits arabinosyl transferases which are necessary in the synthesis of arabinoglycan for the mycobacterial cell wall –> impaired arabinoglycan synthesis –> increased cell wall permeability –> bacteriostatic

Question 6

MOA of rifampicin

Answer 6

Rifampicin inhibits the transcription of DNA to RNA by inhibiting DNA-dependant RNA polymerase –> By blocking the production of RNA, the bacteria cannot make essential proteins –> cell death.

Can kill both intracellular (in macrophages) and extracellular mycobacteria.