13.3 Pathology of Mycobacterial tuberculosis infections Flashcards
Explain the possibility of transmission of TB?
Depending on:
- Infectiousness of person with TB (dose)
- Environment in which exposure occurred
- Length of exposure
- Virulence (strength) of tubercle bacilli
What is the best way to stop transmission?
1) Isolate infectious people 2) Providing effective treatment to infectious people as soon as possible
What are the risk factors of TB?
1) Socioeconomic status 2) Crowding 3) Immune suppression 4) Health Care Workers 5) Overall health/immune system status 6) Alcoholism 7) Smoking 8) Diabetes 9) TB within the last 2 years (recent infection) 10) HIV Co-infection 11) Strain Virulence ? 12) Genetic Predisposition ?
What are the outcomes after exposure to TB?
What are the infection sites of TB?
-
Pulmonary containment (85%)
- Infection from lungs and spreads to other areas of the body
-
Extrapulmonary TB (e.g. liver, intestines)
- Usually non-contagious and more frequent in immunosuppressed individuals
How to diagnose active TB?
- Often based on symptomatic presentation
- Persistent cough, fever, night sweats, weight loss, chest pain
-
SLOW mycobacterial culture
- Colonies dry, raised, irregular, white –> yellow
- AFB smear (sputum microscopy) - acid-fast bacillus testing
- Radiography (chest x-ray) - calcification (e.g. calcified granulomas)
- Molecular approaches (Gene expert-TB)
What is a TST?
TST - Tuberculin Skin Test
- PPD (TB antigens) planted under skin
- Monitor for cell mediated immune response
What are the problems with TST?
- Cross reactivity with BCG vaccine
- Cannot distinguish between active and latent
- LOW sensitivity and specificity
- NO good in HIV
- Reader variability
What is IGRA?
IGRA - Interferon Gamma Release Assay
- Measures IFN-gamma production in whole blood in response to stimulation with Mtb antigens
What are the positives and negatives of IFRA?
POSITIVES
- These antigens are not present in BCG strains and thus, do not cross react with most environmental strains
- Is very quick and specific
NEGATIVES
- Doesn’t distinguish between active and latent
- Not appropriate for HIV patients
What drawbacks are there in treating TB?
- Treating kids
- HIV patients are harder to treat
- NO new drugs in 50 years
- Long chemotherapeutic treatments (months) –> INCREASED risk of toxicity and resistance
Explain the vaccines in TB
- BCG (bacillus calmette Guerin)
- Is attenuated
- BCG = non protective
- SOME efficacy in severity of disease
- Efficacy varies depending on population and environment (endemicity)
Explain anti-tubercle drugs
- Combination therapy
- Long treatment periods
- Complex disease may require monitoring
Explain the emergence of resistance
Explain MDR-TB
- Is isoniazid and rifampicin resistant
- Is treated with second line drugs
Explain XDR-TB
- Is resistant to second and third line drugs
- NO standardized treatment available
Explain the types of TB
- •Mycobacterium tuberculosis
- Mycobacterium bovis (BCG)
- Mycbacterium africanum
- All from the family mycobacterium (are all very similar)
- Can affect humans and animals
- Are all obligate pathogens
What are the general characteristics of mycobacterium?
- Slightly curved bacili, aerobic, non-motile
- THICK lipid rich cell wall
- Can remain dormant, non-spore forming
- Slowly multiplies (18-24hour generation time)
- Acid fast - resists stain decolorisation with acid/lcohol
Explain the Mycobacterial cell wall
- Lipids = lipopolysacccharides
- Mycolic acids = responsible for 50% dry weight of cell wall and responsible for acid fastness & are immunostimulatory
- Plasma membrane associated proteins = form PPD (protein purified derrivative) –> stimulates T cell response and antibody response
- Cord factor - in virulent strains, inhibits migration of leukocytes, causes chronic granulomas
Explain the pathogenesis of TB
- Mostly due to host immune response to infection
- Some strains are more pathogenic than others
- It is able to evade both the innate and adaptive immune system responses
- 3 stages in the course of the disease:
- INVASION, pre-cellular immune response
- PERSISTENCE, post-cellular response
- REACTIVATION, secondddry acute infection
Explain stage 1 of TB
- INVASION
- Is a facultative intracellular pathogen –> replicates in macrophages (most important to spread)
- Is ingested by alveolar macrophages
- Utilises phagocytic cellular receptors e.g. C-type leptin receptors, NLRs, Scavenger receptors, complement recptors, TLRs
What receptors allow mTB to survive and die?
- mTB survive = FcyR receptor –> pro-inflammatory response, respiratory burst
- Mtb die = inhibit macrophage activation
Explain the role of the innate immune system in Mtb
- First step in host defense is Mtb recognition by innate cells
- The innate cells initiate the host battle thanks to Pattern Recognition Receptors (PRR)- Toll-like receptors (TLR’s), C-type lectin receptors (CLR’s), nod-like Receptors (NLR’s)
Explain the balance of triggers in mtb
- Anti-inflammatory/suppressive reponse = Man-LAM/mannosee receptor and DCC-SIGN binding
- Inflammatory/protctive response = TLR binding by Mtb
Explain the role of the cellular immune system
- Th1 mediated response is critical.
- Production of IFN-g by primarily CD4+ T cells leads to macrophage activation of resting/arrested cells leading to death of Mtb infected cells
- IFN-g also recruits new macrophages
- Tcells, Th17, NK, Treg,and CD8 subsets also contribute
- The cellular immune system (CD4) is critical for Mtb immunity is that HIV positive patients have increased risk of TB reactivation as they lose CD4 T cells
Explain macrophage activation by the cellular response and how Mtb tries to resist this
- Following engagement of the cellular immune response, Interferon (IFN)-γ can overcome the early endosome–like arrest of M. tuberculosis, promoting delivery of bacteria to autolysosomes, where growth is curtailed
- Mtb fights back yet again: Resists oxidative stress, Subverts the cell death pathways: Necrosis vs apoptosis
Explain stage 2 of Mtb
INHIBITION OF PHAGOLYSOSOMAL MATURATION
- Impaired fusion of phagosome with lysosome
- Inhibition of phagosome acidification
- Inefficient recruitment of proton-ATPase pump
results in a lack of acidification of the phagosome
-
Modified maturation of phagosome
- Over expression of Rab5 on the phagosomes harboring bacilli causes maturation arrest at early endosomal stage
Explain the process of granuloma formation in Mtb
- Is host induced to prevent the spread of bacteria
- It is an organised aggregate of immune cells that surround a foci of infected tissue
- It is formed when infection of macrophage has occured, infecting macrophages alone is SUFFICIENT for initiation of granuloma forming MULTINUCLEATED GIANT CELLS (MGC’s)
- MGC’s –>associated with virulent mycobacteria
- Promotion of MGC’s formation thanks to glycolipids e.g. PIMS, TDM (trehalose)
- This macrophage produces strong pro-inflammatory response (TNF-a key)
- These recruit MORE immune cells
*
- These recruit MORE immune cells
- This macrophage produces strong pro-inflammatory response (TNF-a key)
What are the types of granulomas and explain them
What are the factors associated with bacterial latency?
- Mtb is able to persist as an intracellular pathogen due to ability to alter phagosomal maturation and MtB in this can form can persist for decades
- Centre of the granuloma is hypoxic
- Little nutrient availability , low oxygenation, low pH
- This environment induces a shift in bacterial metabolism in response
- There are latency associated genes (LATs)
- Dormancy (Dormancy is a period in an organism’s life cycle when growth, development, and (in animals) physical activity are temporarily stopped.)
- Dormancy allows bacteria to survive yet escape the activated immune system
Explain stage 3 of Mtb
MTB REACTIVATION
- Occurs in 5-10% of patients with LTBI
- Reasons unknown (think that resuscitation proomoting factors (RPF’s) produced by Mtb have been key to bacterial revival)
- Likely due to a disruption in the balance of the host immune response
- Caused by immune suppression of some sort
- HIV is the most potent risk factor for Mtb reactivation from latency
- Bacteria begin to replicate again and lead to activation of the immune response that leads to most pathology
- Induce TNF-a production
- Tissue destruction allows for bacterial dissemination and transmission
Explain the mechanism of action of fluoroquinolone, rifamycin, streptomycin, macrolides, isoniazid and ethionamide, ethambutol, pyrazinamide
