what is persistence? - lung - sherman... · assumptions about tb persistence • reactivation is a...
TRANSCRIPT
David R. Sherman, PhD The Union
21st Conference North American Region
February 25, 2017
What is persistence?
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.
What is persistence?
Congressman John Lewis
What is persistence?
Congressman John Lewis, civil rights hero.
1.4 million TB deaths
5 billion PPD(-)
1.8 billion PPD(+)
16 million active
TB infections
Tuberculosis globally
Latent TB
TB disease progression
Transmission ACTIVE infection
10 M / Yr
5%
95%
LATENT infection
1.8 B globally
DEATH
1.4 M / Yr
CURE
5%
TB persistence:
The ability of MTB to survive
in vivo despite immunity
or chemotherapy.
TB persistence:
The ability of MTB to survive
in vivo despite immunity
or chemotherapy.
TB latency: infection in the
absence of disease.
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
Assumptions about TB persistence
• Reactivation is a major driver of the TB pandemic.
Assumptions about TB persistence
• Reactivation is a major driver of the TB pandemic.
• TB bacilli (latent) = TB bacilli (active).
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:
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?
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
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.
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.”
How important is reactivation TB?
“Reactivation is a major driver of the TB pandemic.”
How important is reactivation TB?
“Reactivation is a major driver of the TB pandemic.”
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.
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….”
“During latency, the bacteria are dormant.”
What’s the evidence?
“During latency, the bacteria are dormant.”
“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.
“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!
“During latency, the bacteria are dormant.”
Are bacteria non-replicating in latency?
• TB never stops replicating in mice (Nat Med. 2009;15:211).
“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).
“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.
“During latency, the bacteria are dormant.”
Now what?
New tools provide new ideas about persistence:
Systems biology: sequencing transcriptomics modeling PET/CT imaging.
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
Active and latent TB overlap
Lin et al, Nature Medicine, 20, 75–79 (2014)
Primate lesions
Active and latent TB overlap
Lin et al, Nature Medicine, 20, 75–79 (2014)
Primate lesions
Active and latent TB overlap
Lin et al, Nature Medicine, 20, 75–79 (2014)
Primate lesions
The spectrum of TB disease
Persistence and TB chemotherapy
Std Rx: 4 drugs, 6 months, ~95% cure rate. But………
Persistence and TB chemotherapy
Std Rx: 4 drugs, 6 months, ~95% cure rate. But………
Am Rev Respir Dis 130: 23-28., 1984
Relapse
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
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
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!
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
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
Dhar and McKinney, Current Opinion in Microbiology Volume 10, Issue 1, 2007, 30–38
The problem with averages
Quantifying replication & cell death in response to antibiotic insult
Rifampin Isoniazid Untreated
Analysis at single-cell resolution
Can we deal with MTB heterogeneity?
Prediction: BDQ hyper-sensitivity
Systems biology: genetics gene expression metabolism modeling
Can we deal with MTB heterogeneity?
Prediction: BDQ hyper-sensitivity
Systems biology: genetics gene expression metabolism modeling Select drug synergies…..
Prediction validated!
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.
Thank you!
REMEMBER
Thank you!
The spectrum of tuberculosis
Nat Rev Microbiol. 2009; 7:845
Time (months to years)
Latent TB…..sub-clinical TB……active disease
Phil. Trans. R. Soc. B 369: 20130437.
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!