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Sherman: the Spectrum of Ideas about TB Latency 2/24/16Advances in the Science 1 David R. Sherman, PhD TB CONFERENCE 2016 February 24 The Spectrum of Ideas about TB Latency 1.4 million TB deaths 5 billion PPD() 1.8 billion PPD(+) 16 million acJve TB infecJons 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%
Transcript of 2pm 1 1DSherman - American Lung Association Spectrum of Ideas... ·...
Sherman: the Spectrum of Ideas about TB Latency
2/24/16-‐Advances in the Science
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David R. Sherman, PhD TB CONFERENCE 2016
February 24
The Spectrum of Ideas about TB Latency
1.4 million TB deaths
5 billion PPD(-‐)
1.8 billion PPD(+)
16 million acJve
TB infecJons
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%
Sherman: the Spectrum of Ideas about TB Latency
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TB latency: Clinically defined: evidence of TB infection with no evidence of disease. ~1.8 billion people. Host immune status matters:
~10% lifetime chance of reactivation. HIV+ = 10% reactivation per year.
Assumptions about TB latency • Reactivation is a major driver of the TB pandemic.
Assumptions about TB latency • Reactivation is a major driver of the TB pandemic. • During latency, the bacteria are dormant:
Sherman: the Spectrum of Ideas about TB Latency
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Assumptions about TB latency • Reactivation is a major driver of the TB pandemic. • During latency, the bacteria are dormant:
Metabolically inactive?
Assumptions about TB latency • Reactivation is a major driver of the TB pandemic. • During latency, the bacteria are dormant:
Metabolically inactive?
Assumptions about TB latency • Reactivation is a major driver of the TB pandemic.
• During latency, the bacteria are dormant: Metabolically inactive? Non-replicating.
Sherman: the Spectrum of Ideas about TB Latency
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Assumptions about TB latency • Reactivation is a major driver of the TB pandemic.
• During latency, the bacteria are dormant: Metabolically inactive? Non-replicating. Conditions: hypoxia, starvation, acid pH.
Assumptions about TB latency • Reactivation is a major driver of the TB pandemic.
• During latency, the bacteria are dormant: Metabolically inactive? Non-replicating. Conditions: hypoxia, starvation, acid pH.
• TB bacilli (latent) = TB bacilli (active).
Assumptions about TB latency • Reactivation is a major driver of the TB pandemic.
• During latency, the bacteria are dormant: Metabolically inactive? Non-replicating. Conditions: hypoxia, starvation, acid pH.
• TB bacilli (latent) = TB bacilli (active).
Every dogma has its day – Anthony Burgess
Sherman: the Spectrum of Ideas about TB Latency
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The current known record………
“Reactivation is a major driver of the TB pandemic.”
J Infect Dis. 2002 1;185:401-4.
The current demonstrated record………
“Reactivation is a major driver of the TB pandemic.”
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.”
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.
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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….”
“During latency, the bacteria are dormant.”
What’s the evidence?
“During latency, the bacteria are dormant.”
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“During latency, the bacteria are dormant.”
Conditions associated with latency: Condi&on MTB response Hypoxa DosR; Enduring hypoxic response
(EHR) Low pH Acid response genes Carbon shi7 (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: Condi&on MTB response Hypoxa DosR; Enduring hypoxic response
(EHR) Low pH Acid response genes Carbon shi7 (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 replicaJng 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 replicaJng in mice (Nat Med. 2009;15:211).
• In primates, TB acquires as many mutaJons in latency as in acJve disease (Nat Genet. 2011;43:482).
“During latency, the bacteria are dormant.”
Are bacteria non-replicating in latency?
• TB never stops replicaJng in mice (Nat Med. 2009;15:211).
• In primates, TB acquires as many mutaJons in latency as in acJve disease (Nat Genet. 2011;43:482).
• INH prophylaxis in humans.
“During latency, the bacteria are dormant.”
Now what?
Sherman: the Spectrum of Ideas about TB Latency
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New tools provide new ideas about latency:
Animal models. 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 acJve and latent TB; also in humans.
Probe: 18FDG
AcJve and latent TB overlap
Lin et al, Nature Medicine, 20, 75–79 (2014)
Primate lesions
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AcJve and latent TB overlap
Lin et al, Nature Medicine, 20, 75–79 (2014)
Primate lesions
AcJve and latent TB overlap
Lin et al, Nature Medicine, 20, 75–79 (2014)
Primate lesions
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.
ImplicaJons of the TB spectrum model
Not everyone is equally at risk for acJve disease.
Sub-‐clinical disease should leave a different molecular signature.
TB bacilli (latent) is similar to TB bacilli (acJve). Similar treatments may work!
Conclusions
Ligle evidence supports older ideas of TB dormancy. Recent evidence suggests a TB disease spectrum. New hope for tackling latency!
ID those most at risk of acJve disease. latency treatments should also shorten therapy.
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Thank you!
