Payne- TB Flashcards
Describe pathogenesis of TB
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)
MOA of isoniazid
Isoniazid inhibits mycolic acid synthesis, a key component of the Mycobacterium tuberculosis cell wall. It is activated by the bacterial enzyme KatG, forming an adduct with NAD, which inhibits InhA, a key enzyme in the fatty acid synthase II (FAS-II) system. This prevents mycolic acid elongation, disrupting cell wall integrity and leading to bacterial lysis
Bactericidal in growing cells, bacteriostatic in resting cells
How does isoniazid cause peripheral neuropathy
It metabolites inhibit the enzyme pyridoxine phosphokinase, which is responsible for converting pyridoxine to its active form. Isoniazid may also directly inactivate pyroxidine –> Pyroxidine is a co-factor in neurotransmitter synthesis as well as the upkeep of the myelin sheath.
MOA of pyrazinamide
prodrug converted to pyrazinoic acid by pyrazinamidase
Inhibts FAS-I system preventing synthesis of mycolic acids for mycobacterial cell wall –> cell death
MOA of Ethamutol
Inhibits arabinosyl transferases which are necessary in the synthesis of arabinogalactan for the mycobacterial cell wall –> impaired arabinogalactan synthesis –> increased cell wall permeability –> bacteriostatic
MOA of rifampicin
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.
Briefly describe the pathogenesis of primary TB
On first exposure, Mycobacterium tuberculosis is phagocytosed by alveolar macrophages but evades degradation by inhibiting phagolysosome fusion, allowing intracellular replication and macrophage lysis.
The bacteria spread via lymphatics to nearby lymph nodes, where antigen-presenting cells stimulate CD4+ T cells.
IL-12 from macrophages and dendritic cells drives Th1 differentiation, leading to IFN-γ secretion, which activates macrophages and promotes granuloma formation. Activated macrophages relase inducible nitric oxidase, TNF-a and defensive to augment the response against the bacteria.
Granulomas consist of a central necrotic core with bacteria, surrounded by epithelioid macrophages, Langhans giant cells, T cells, and fibroblasts, serving to contain the infection.
This granuloma is known as a ghon focus and/or ghon complex if ipsilateral hilar lymphadenopathy co-exists.
Outline 4 ways that mycobacterium TB enhances its own survival in the host
- M. tuberculosis inhibits host cell signaling by disrupting TLR pathways and suppressing cytokine release (e.g., IL-12, TNF-α), weakening immune activation.
- It prevents phagolysosome fusion by releasing virulence factors allowing intracellular survival.
- The bacteria exploit macrophage-derived lipids (e.g., cholesterol) as a nutrient source for persistence.
- In low-oxygen environments (e.g., granulomas), M. Tb enters a dormant, non-replicating state, increasing drug tolerance.
Define granuloma and describe its composition
Definition
A granuloma is a focal, organised collection of activated macrophages, giant cells, lymphocytes and fibroblasts surrounding a bacterial core. It is a feature of chronic inflammation and occurs in response to a T cell mediated immune response against a persistent, poorly degradable pathogen.
Composition
- Core containing bacteria
- Epithelioid macrophages (histiocytes) containing the bacteria
- Multinucleated giant cells/ Langhan cells formed by fusion of macrophages.
- Lymphocytes, particularly Th1 cells
- Outer fibroblast layer
What is the difference between Multi drug resistant and Extensive drug resistant TB?
MDR-TB: Resistant to Rifampicin and isoniazid
XDR-TB: Resistant to Rifampicin (and possibly isoniazid) and to at least one fluoroquinolone
(levofloxacin or moxifloxacin) and to at least one other “Group A” drug (bedaquiline
or linezolid)
Briefly outline to MOA of Bedaquiline, Pretomanid, Linezolid, Moxifloxacin
Bedaquiline
-Inhibits bacterial ATP synthase. Bacteria cannot make ATP –> bactericidal
Pretomanid
-Inhibits production of cell wall lipids
Linezolid
-Binds to 50S subunit of ribosome which inhibits bacterial translation/ protein synthesis
Moxifloxacin
-Inhibits DNA gyrase (Topoisomerase II) and Topoisomerase IV, preventing DNA replication.
Name 4 diagnostic tests for TB
- Sputum culture (gold standard)
- Acid fast bacilli sputum smear
- Interferon gamma release assays
- Nucleic acid amplification (PCR) of sputum (used to confirm AFB smear)
- Tissue biopsy (shows caseating granulomatous inflammation)
- Chest x ray (consolidation, cavitations, hilar lymphadenopathy)
Outline 4 extrapulmonary manifestations of TB
- GI
-Ileocecal TB
-Peritoneal TB - GU
-Dysuria, haematuria, Sterile pyuria - Cardiac
-Pericardial TB - Skeletal
-Potts disease - Adrenal insufficiency
Describe the structure of mycobacterium tuberculosis
M.TB is an acid fast bacillus (rod shaped), obligate aerobe.
Cell wall: acyl lipids, mycolic acid, peptidoglycan, arabinogalactan
Plasma cell membrane
