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73 Cards in this Set
- Front
- Back
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Latent TB and reactivation
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of everyone exposed, 75% won't get infected
Of 25% infected, 90% will contain the TB (latent TB) Of that 90%, 5-10% will get reactivation of disease |
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What are the symptoms of active TB?
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Coughing
Fever weight loss Coughing blood Lung damage Ability to transmit bacteria |
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What happens in latent infection?
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Containment of the pathogen
Absence of clinical symptoms Non-infectious Most cases, prevent active TB |
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Where do most of active cases of TB come from?
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Reactivation of latent infection
-> if only 5% of population reactivates: 10^8 new cases, since ~2 billion ppl infected with TB |
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When does reactivation of TB occur?
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When immune system is suppressed
->Therapeutic interventions, malnourishment, old-age -> HIV infection: greatest risk factor for progression of latent infection to active disease |
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When can reactivation occur?
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Years or decades after initial infection
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How is latent TB detected?
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1)PPD skin test
2) Chest X-Ray 3) QuantiFERON |
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How does the PPD skin test work?
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Tuberculin's test, mantoux tes
Relies on specific T-cell DTH response to purified TB ptns, indicating prior/current infection with TB (CMI response) => Can get false + due to BCG vaccines and exposure to env't M. avium/scrofulaceum/vaccae |
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What does the X-ray do?
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Required to rule out active TB disease
-Latent disease often visualized as small, calcified granulomatous lesions |
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What does the QuantiFERON assay do?
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IFN-y release assay
In-vitro assay that detects IFN-y released by T-cells specific for purified M. tb Ag CFP-10 and ESAT-6 Like PPD test, it relies on T-cell memory that shows prior infection and exposure to TB Ag ->Incubate blood wiht ESAT-6 and CFP-10, then detect IFN-y with ELISA -> BCG and most env't strains don't have the genes coding for these 2 Ag |
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How is latent TB treated?
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INH (daily 6-9 months)
-Very effective (90%) -but only active vs replicating bacteria, since it inhibits mycolic acid synthesis RIF (rifampicin) -active vs replicating and stationary bact -inhibits RNA-pol B-subunit |
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What does this tell us?
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"Latent" TB must be viable and undergoing some lvl of metabolic activity
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What are new TB drugs being dev'p to treat?
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LATENT TB
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Why?
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Can be given to 2-3 billion ppl (as opposed to only vs active TB which would only work vs 10 million ppl)
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Where does the latent TB infection take place in the bacterial life cycle?
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In the granuloma
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What controls dev'p of granulomas?
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Coordinated release of chemokines and cytokines produced by infected macs and local tissue cells, and PMNs
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What are granulomas composed of?
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Concentric layers of macs (infected and uninfected), lymphocytes and fibroblasts
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What usually arrests bacterial multiplication and halts progress of infection?
Problem? |
Vigourous CMI response
Problem: Without anitbiotic treatment, complete elimination of the pathogen very difficult (.: continued latent infection) |
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What does the granuloma do?
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Prevents dissemination of the pathogen throughout the host (infection is contained)
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Overtime, what happens to the center core of the granuloma?
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Becomes necrotic (acellular due to cell death)
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What does the granuloma structure do?
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1) Protects host from unlimited bact replication/spreading
2) Also, after the host thinks it has pathogen under control, any remaining bact cells are protected from constant fresh, attack by the IS ->Host-pathogen balance exists |
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What kind of lesions are there in primary infection/.
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Solid and hard, decreased size and calcity
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What is Caseation?
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Necrotic center becomes liquified and develops a characteristic white, cheesy appearance
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What happens when there is necrosis and the grarnuloma is in an airway?
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A lot of the liquefied material drains out aand leaves behind a cavity (cavitary TB)
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What happens when the bacteria has access to fctnal airway?
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Rapid bacterial replication
Transmission/spread of pathogen to unifected individuals (+highest numbers of bacteria are found in cavitary lesions) |
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How are TB lesions physiologically diverse structures?
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Calcified and fibrotic lesions to caseous necrotic lesions to open/closed cavitary lesions
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Do latent TB lesions have a lot of bacteria?
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No, very few detectable bacili
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Where have bacteria been identified in the lesions?
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Acellular, necrotic region and in the peripheral zone of granulomas (mostly ass't with macs in these regions)
Granulomas very heterogenous structures and .: the bacteria in them are exposed to a wide range of env't conditions |
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What are the factors that induce bacterial dormancy or persitance within latent TB infections?
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1-Deficiency in a specific nutrient (iron, glucose)
2- Acidic pH in necrotic lestion (pH=6.5) Both unlikely cuz TB can grow in simople medium and 6.5 = optimal pH for it 3- Inhibitory cmpds such as NO or AMPs 4- O2 availability |
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What role does O2 play in TB?
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Many TB lesions exist in a state of depleted O2 and O2 is essential to M. TB replication
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What does Pimonidazole HCL do?
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When activated, binds to tissues (only under hypoxic conditions)
Look at Figures |
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Can TB live for extended periods without O2?
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Yes
Can survive without O2 in years Still retains its virulence |
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What is the Major Trigger for inducing bacterial dormancy leading to dev'p of latent TB?
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Reduced [O2] in granulomas
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What is the Wayne in vitro model?
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Model of non-replicative persistance
Used to study dormancy in the lab |
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What happens to M. tb if there is gradual depletion of O2?
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Inhibition of bacterial replication
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What happens if there is rapid depletion of O2?
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Cell death
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What happens if O2 is added back to the medium?
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Bacterial start to grow rapidly again
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What happens to the cells in absence of detectable growth?
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Cells remain viable
Maintain low level of respiration/metabolic activity (This is why they can start growing again if O2 is added back) |
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What happens to antibiotic response during hypoxia conditions?
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The cells become less sensitive to isoniazid (similar to the bacteria on latent TB lesions)
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Which metabolic pathways are increased when M. tb is in its dormancy stage?
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1) e- transport and respiration under anaerobic conditions (nitrate reductase, cytochrome bd oxidase; when O2 not available as a terminal acceptor)
2) Dideoxynucleotide synthesis under anaerobic conditions (DNA synthesis continues at low levels) 3) Antioxidant defense mechanisms (peroxidase, etc) 4) Iron storage: bacterioferritin |
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Which metabolic pathways are DECREASED when M. tb is in its dormancy stage?
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Pathway's ass't with biosynthesis (ptn, lipid, aa)
Cell division Aerobic metabolism (since lack of O2) |
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Where are e- transported during respiration? (aerobic or anaerobic)
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O2 or NO3-
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What happens during e- transport in respiration?
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H+ are pumped outside of the cell
ATP synthase generates ATP inside the cell using the E stored in the proton gradient |
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How is the ATP level in dormant, non growing M. tb?
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ATP level is stable, but low
(decreased from regular levels) |
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What does this tell us?
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Even dormant M. tb undergo respiration (have fctnal ETC) and maintain a fctnal H+ gradient across the cell mb
=> Still viable and metabolically active |
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What do Diarylquinolones (R207910) do?
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Specifically inhibit F0F1-ATP synthase of mycobacterium species
->currently in phase IIb trials |
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What is more efficient: R207910 or INH?
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R207910 is:
10^5 times more efficient at killing dormant bacilli 10^3 times more efficient at killing aerobic bacilli |
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What E source does M. tb use?
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Fatty acids
-> high lipid catabolism in M.tb infecting host macrophages |
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How are host lipids and FA broken down?
What does it yield? |
Beta oxidation
->yields acetyl CoA -> goes into TCA cycle and is completely oxidized to CO2 (make ATP and NADH too) |
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What pathway is needed to survive using only FA as an E source?
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Glyoxylate path (modified TCA cycle needed to get biosynthetic precursors)
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What is the essential enzyme of the glyoxylate cycle?
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Isocitrate lyase (ICL)
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What does ICL do?
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Catalyzes isocitrate --> succinate + glyoxylate
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What happens in the glyoxylate cycle?
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1) No C lost as CO2
2) C's are now available to synthesize central biosynthetic precursor metabolites (via OAA) |
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How many ICL genes does M. tb have?
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2 (ICL-1 and 2)
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What does this tell us?
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Glyoxylated cycle is very important
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What is the glyoxylate cycle important for?
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-Growth/persistance in the mouse model of TB infection
-Host lipids/FA are critical for M. tb survival |
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What happens to M. tb bacteria that are ICL deficient?
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No bacterial growth and baceria are quickly cleared
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Where is ICL highly expressed?
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M. tb in human lung samples isolated from TB patients
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Why is this a good drug candidate?
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Glyoxylate cycle absent from humans
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What part if host does TB use as an important source of nutrients?
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Cholesterol
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Which operon encodes the major cholesterol import system?
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mce4 operon
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What does the mce4 operon allow?
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M. tb to catablize host for Carbon and Energy
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What is mce4 required for?
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Long term infection/persistence
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Is mce4 required for initial infection?
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No (but is required for persistence)
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What "state" are the bacteria in?
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Viable, metabolically active
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What "triggers
M. tb latency? |
Hypoxia/reduced O2
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What do bacteria "feed on" in the host?
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C and E sources
-> Host lipids and FA |
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How can we exploit this info to develop new anti-TB drugs?
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R207910
Glyoxylate path drugs |
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What accounts for the majority of active TB and transmission?
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Reactivation of latent TB infections
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What is the host immunological response to TB?
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Granulomas
(macs, fibroblasts, T-cells) |
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Describe granuloma structure.
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Diverse
Exhibit areas of hypoxia (low [O2]) |
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What does hypoxia trigger in M. tb?
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Persitence/dormancy
->Dormant bacteria are non-replicating, but still metabolically active and undergoing respiration (ex: ATP synthase) |
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What does M. tb use to utilize host lipids and FA as C and E sources?
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ICL and mce4
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