What is persistence? - lung - Sherman... · Assumptions about TB persistence • Reactivation is a...
Transcript of What is persistence? - lung - Sherman... · Assumptions about TB persistence • Reactivation is a...
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David R. Sherman, PhD The Union
21st Conference North American Region
February 25, 2017
What is persistence?
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What is persistence?
• firm or obstinate continuance in a course of action in spite of difficulty or opposition.
• the continued or prolonged existence of something.
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What is persistence?
Congressman John Lewis
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What is persistence?
Congressman John Lewis, civil rights hero.
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1.4 million TB deaths
5 billion PPD(-)
1.8 billion PPD(+)
16 million active
TB infections
Tuberculosis globally
Latent TB
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TB disease progression
Transmission ACTIVE infection
10 M / Yr
5%
95%
LATENT infection
1.8 B globally
DEATH
1.4 M / Yr
CURE
5%
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TB persistence:
The ability of MTB to survive
in vivo despite immunity
or chemotherapy.
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TB persistence:
The ability of MTB to survive
in vivo despite immunity
or chemotherapy.
TB latency: infection in the
absence of disease.
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TB persistence:
The ability of MTB to survive
in vivo despite immunity or
chemotherapy.
TB latency: infection in the
absence of disease.
1.4 million TB deaths
5 billion PPD(-)
1.8 billion PPD(+)
16 million active
TB infections
Latent TB
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Assumptions about TB persistence
• Reactivation is a major driver of the TB pandemic.
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Assumptions about TB persistence
• Reactivation is a major driver of the TB pandemic.
• TB bacilli (latent) = TB bacilli (active).
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Assumptions about TB persistence
• Reactivation is a major driver of the TB pandemic.
• TB bacilli (latent) = TB bacilli (active).
• During latency, the bacteria are dormant:
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Assumptions about TB persistence
• Reactivation is a major driver of the TB pandemic.
• TB bacilli (latent) = TB bacilli (active).
• During latency, the bacteria are dormant:
Metabolically inactive?
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Assumptions about TB persistence
• Reactivation is a major driver of the TB pandemic.
• TB bacilli (latent) = TB bacilli (active).
• During latency, the bacteria are dormant:
Metabolically inactive?
Non-replicating
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Assumptions about TB persistence
• Reactivation is a major driver of the TB pandemic.
• TB bacilli (latent) = TB bacilli (active).
• During latency, the bacteria are dormant:
Metabolically inactive?
Non-replicating
Conditions: hypoxia, starvation, acid pH.
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Risk of TB disease following infection
Emilia Vynnycky and
Paul E. M. Fine
Depends on:
Age at infection
Current age
Geography (host factors?)
Strain?
Progressive
?
Reactivation
Avg. time to symptoms = 1.4 yrs
“Reactivation is a major driver of the TB pandemic.”
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How important is reactivation TB?
“Reactivation is a major driver of the TB pandemic.”
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How important is reactivation TB?
“Reactivation is a major driver of the TB pandemic.”
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How important is reactivation TB?
“Reactivation is a major driver of the TB pandemic.”
~30,000 S. African gold miners.
Very high TB rate (~2%).
Widespread INH prophylaxis (IPT) for 6+ months.
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How important is reactivation TB?
“Reactivation is a major driver of the TB pandemic.”
~30,000 S. African gold miners.
Very high TB rate (~2%).
Widespread INH prophylaxis (IPT) for 6+ months.
Conclusions “Mass screening and treatment for latent tuberculosis had no significant effect on tuberculosis control….”
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“During latency, the bacteria are dormant.”
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What’s the evidence?
“During latency, the bacteria are dormant.”
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“During latency, the bacteria are dormant.”
Conditions associated with latency:
Condition MTB response
Hypoxa DosR; Enduring hypoxic response
(EHR)
Low pH Acid response genes
Carbon shift (lipids) KstR; cholesterol uptake and
metabolism
All these conditions promote bacteriostasis in vitro,
and all occur in vivo.
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“During latency, the bacteria are dormant.”
Conditions associated with latency:
Condition MTB response
Hypoxia DosR; Enduring hypoxic response
(EHR)
Low pH Acid response genes
Carbon shift (lipids) KstR; cholesterol uptake and
metabolism
All these conditions promote bacteriostasis in vitro,
and all occur in vivo.
However, they also occur during active disease!
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“During latency, the bacteria are dormant.”
Are bacteria non-replicating in latency?
• TB never stops replicating in mice (Nat Med. 2009;15:211).
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“During latency, the bacteria are dormant.”
Are bacteria non-replicating in latency?
• TB never stops replicating in mice (Nat Med. 2009;15:211).
• In primates, TB acquires as many mutations in latency as in active disease (Nat Genet. 2011;43:482).
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“During latency, the bacteria are dormant.”
Are bacteria non-replicating in latency?
• TB never stops replicating in mice (Nat Med. 2009;15:211).
• In primates, TB acquires as many mutations in latency as in active disease (Nat Genet. 2011;43:482).
• INH prophylaxis in humans.
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“During latency, the bacteria are dormant.”
Now what?
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New tools provide new ideas about persistence:
Systems biology: sequencing transcriptomics modeling PET/CT imaging.
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PET/CT imaging of TB in primates
Lin et al, Nature Medicine, 20, 75–79 (2014)
Seen in active and latent TB; also in humans.
Probe: 18FDG
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Active and latent TB overlap
Lin et al, Nature Medicine, 20, 75–79 (2014)
Primate lesions
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Active and latent TB overlap
Lin et al, Nature Medicine, 20, 75–79 (2014)
Primate lesions
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Active and latent TB overlap
Lin et al, Nature Medicine, 20, 75–79 (2014)
Primate lesions
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The spectrum of TB disease
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Persistence and TB chemotherapy
Std Rx: 4 drugs, 6 months, ~95% cure rate. But………
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Persistence and TB chemotherapy
Std Rx: 4 drugs, 6 months, ~95% cure rate. But………
Am Rev Respir Dis 130: 23-28., 1984
Relapse
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Persistence and TB chemotherapy
Std Rx: 4 drugs, 6 months, ~95% cure rate. But………
70% were cured in 2 months!
Am Rev Respir Dis 130: 23-28., 1984
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Dhar and McKinney, Current Opinion in Microbiology Volume 10, Issue 1, 2007, 30–38
Bi-phasic kill kinetics in vivo.
INH treatment of TB-infected mice
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Dhar and McKinney, Current Opinion in Microbiology Volume 10, Issue 1, 2007, 30–38
Bi-phasic kill kinetics in vivo.
INH treatment of TB-infected mice Drug tolerance: the ability to survive in the face of otherwise inhibitory or lethal drug concentrations. Bacilli remain drug-sensitive!
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Condition-specific MTB drug tolerance Slow/no-growth: environment (hypoxia, acid, starvation, immunity) toxin/anti-toxin modules biofilms Growing cells: efflux pumps differential enzyme activation detoxification
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Condition-specific MTB drug tolerance Slow/no-growth: environment (hypoxia, acid, starvation, immunity) toxin/anti-toxin modules biofilms Growing cells: efflux pumps differential enzyme activation detoxification Heterogeneity…….stochastic…….bet-hedging
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Dhar and McKinney, Current Opinion in Microbiology Volume 10, Issue 1, 2007, 30–38
The problem with averages
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Quantifying replication & cell death in response to antibiotic insult
Rifampin Isoniazid Untreated
Analysis at single-cell resolution
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Can we deal with MTB heterogeneity?
Prediction: BDQ hyper-sensitivity
Systems biology: genetics gene expression metabolism modeling
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Can we deal with MTB heterogeneity?
Prediction: BDQ hyper-sensitivity
Systems biology: genetics gene expression metabolism modeling Select drug synergies…..
Prediction validated!
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Conclusions
Little evidence supports older ideas of TB dormancy. Recent evidence suggests a TB disease spectrum. Heterogeneity underlies TB persistence New hope for tackling TB!
ID those most at risk of active disease.
latency treatments should also shorten therapy. drug synergies.
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Thank you!
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REMEMBER
Thank you!
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The spectrum of tuberculosis
Nat Rev Microbiol. 2009; 7:845
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Time (months to years)
Latent TB…..sub-clinical TB……active disease
Phil. Trans. R. Soc. B 369: 20130437.
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Implications of the TB spectrum model
Not everyone is equally at risk for active disease.
Sub-clinical disease should leave a different molecular signature.
TB bacilli (latent) is similar to TB bacilli (active). Similar treatments may work!