TB Flashcards
What is the leading killer of HIV infected patients?
TB
What lifestyle choice increases risk of TB?
smoking
what treatment is used for TB?
every day fro siz months is isoniazid and rifampicin.
For first two months as well, pyrazinamide and ethambutol.
Issues with drugs for TB?
drug toxicity, along with long term use makes adherence poor.
what are multidrug restistant TB resistant to normally? HOw long does alternative treatment last?
resistant to isoniazid and rifampicin.
20 months and with lower success.
What are extensively resistant drugs resistant to?
resistant to isoniazid and rifampcicin and another drug.
Why does m.TB primarily infect the lungs?
Becuase its an obligate aerobe, lik high O2 tissue concentration.
What other parts of the body does disseminated (extrapulmonary) Tb affect?
the lymph nodes, the CNS, bone and joints.
How slow is the mTB generation time?
18hrs
What are the four layers of the thick wall of mTB made up of?
capsule- proteins/peptides and polysaccharidess.
Mycolic acid layer, bound to underlying arabinogalacta.
Peptidoglycan cell wall which is heavily cross linked.
What benefit does complex lipid cell wall give?
protection against drying- long survival.
resistant to chemicals and lysozyme.
What dye is used for diagnosis?
acid fast stain (carbolfuchsin) stains thick cell wall (mycolic acid)
3 outocmes with after TB bacilli have reached alveolar?
active diease
latent disease (can later become active in 5-10%, or 10% risk of this in HIV patients each year).
Eradication
In what cell does m TB replicate?
In lung macrophages following its phagocytosis.
What happens characteristically to the infected lung macrophages?
They form large multi nuclear cells and granulamas. They become ‘foamy’.
describe what the containment and escape phase of granulomas looks like?
T cells surround th macrophages adifferentiated into epithelioids- containment in latent stage.
Escape the blood vessels are broken down leading to rupture of granuloma and active disease.
4 different memory responses in Tb?
Tcm Tem, Trm and Brm (resident memory cells are in the lungs.
What does AECs stand for and how do they help to fight TB?
- airway epithelial cells in the upper respiratory tract.
- Recognise mTB via PRRs, secrete cytokines and can -present antigen to MAIT cells via MR1?
- Can also control the composition of the airway surface liquid
What does ASL stand for and how does it protect against TB?
airway surface liquid, contains AMPS e.g. cathelldicin, Beta defensins, and cytokines.
What is the a chain of the semi invariant MAIT cell TCR?
Va 7.2
What do MAIT cells recognise?
riboflavin derivative 5-OP-RA presented on MR1.
what effector functinos of MAIT cells could contribute to mTB protection?
cytotoxic effects and cytokine relesas e.g. of IFN-y and IL-17.
MAIT cells are mostly CD8+ or DN, what about CD4+ MAITS in active infection and latent infection?
CD4 MAITS upregulated in active infection.
In latent infection CD8+ MAITS predominate.
Overall in active infection the MAITS in circulation are reduced (going to the tissues?)
Why might MAIT cells not be protective in macaques?
because of slow Mtb regernation , or due to immune evasion by mTB?
What are the roles of type 1 and type 2 epithelial cells?
type 1 line alveoli involved in gas exchange.
type 2 produce AMPs, and realise surfactant prtoeins (SP-A and SP-D?).
What two aspects of phagocytosis could be targeted for bacterial escape?
endosome acidification, and phagosome lysosome fusion.
4 ways macrophages can contribute to mTB control?
1) phagocytosis
2) cytokine production and inflammation.
3) ROS and nitrogen species/toxic metals.
4) via cell death- macroautophagy and apoptosis.
What kind of changes are associated with trained innate memory?
metabolic reprogramming and epigenetic modifications.
Can be induced by the BCG vaccine as well.
Evidence that innate responses alone can be protective?
Some individuals with high exposure to mTB never get disease, but also don’t have the memory responses either.
Why might there be such a delay for arrival of CD4 and CD8 T cell responses to the lungs and site of infection?
Because of slow regeneration? Or situation of infection deep in lungs causes delay?
CD4 T cells important for mTB response, what mechanissm are protective?
directly activate macrophages and via secretion of IFN-y which increases macrophage killing.
CD8 T cells important in later infection, what mechanisms important for mtB responses?
perforin granzyme killing, and Fas-FasL as well as IFN-y ecretion.
Which two cytokines are most important for the mTb response?
IFN-y and TNF-a
Why is anti-TNF-a not recommened for patients with TB?
Because it increases the liklihood of activation of TB.
What other cytokines are imporatnt for mTB response apart from INF-y and TNF-a?
IL-17, Il21, Il22 and IL23.
What can Th17 responses increase, and why might they be dangerous?
INreases neutrophil recruitment, and inflammation.
But increasing too much may contribute in increased lung damage and pathology.
Why might Tregs be activated in mTB and what can this impari?
Tregs presumably activated to control the specific TH1 responses and lung damage.
But may impair Mtb control
unconventional T cells involved in Tb?
ydelta T cells (big IL-17 producers) invariant NKT (CD1 restricted) MAIT cells (MR1 presented 5-OP-RA) HLA-E restricted CD8s
what might be a problem with alveolar macrophages?
they may not be as bactericidal (for lung protection) making them more permissive.
Evidence for and agaisnt B cells in TB?
B cell and ab deficiencies aren’t a risk for TB disease.
However, MVA85A vaccine study showed higher specific IgG titres correlated with reduced TB risk.
What kind of differences exist between ab in active and latently infected people?
functional and glycosylation differences.
6 ways Ab can help with protection against TB
1) enhance phagocytosis
2) enhance phagosome-lysosomal fusion
3) neutralisation
4) enhance inflammasome
5) induce ADCC
6) also complement activation!
what is at the centre and periphery of tubercles? What walls off the granuloma?
centre is necrosis containing bacilli.
Periphery are lymphocytes and plasma cell aggregates.
fibroblasts lay down collagen to wall off granuloma.
different between langhans cells and epithelioid cells?
Langhans are giante multinucleated cells.
epithelioid are macrophages with eosinophilic cytoplasm (foamy?)
How does mTb survive in host?
interferes with phagosome maturation(e.g. maturation and fusion with lysosomes)
- Can still fuse with other vesicles for nutrients.
- escape to the cytosol by creating proes with ESTAT6.
- decoy molecule secretion and interference with IFN-y signalling.
What does mtB inhibition of apoptosis allow?
prolonged survival of infected cells allwoign greater number of bacteria to accumulate.
What are the bacterial benefits of necrosis?
reruitiment of fresh macrophages for growth and expansion.
Is cell wall compostin fixed?
No it changes with active and lantency, eg. mycoclic acids layer thicker in active disease.
What are the two secretion systems for mTB rpoteins?
ESX system accross the inner membrane. Or type VII seccretion system across outer membrane.
What three important proteins does the virulent ESX1 region encode?
ESPG and H, and ESTAT6.
What does ESX-3 encode?
mycobactin for iron binding and growtn.
What is ESX-5 mportant for?
secretion of ppe secretory proteins.
ESX 2+4 not essential for growht or virulence
How do ESXG and H evade immunity in DCs?
by interfering with tranlocation of ESCRT complex mediated mtB antigen fusion with MHC II containing vesicles.
