Sherman: the Spectrum of Ideas about TB Latency. 2/24/16- Advances in the Science. Tuberculosis globally. TB disease progression

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1 The Spectrum of Ideas about TB David R. Sherman, PhD TB CONFERENCE 2016 February 24 Tuberculosis globally 16 million acjve TB infecjons 1.4 million TB deaths 1.8 billion PPD(+) Latent TB 5 billion PPD(- ) TB disease progression 5% Transmission ACTIVE infection 10 M / Yr DEATH 1.4 M / Yr 95% 5% LATENT infection 1.8 B globally CURE 1

2 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. 2

3 Metabolically inactive? Metabolically inactive? Metabolically inactive? Non-replicating. 3

4 Metabolically inactive? Non-replicating. Conditions: hypoxia, starvation, acid ph. Metabolically inactive? Non-replicating. Conditions: hypoxia, starvation, acid ph. TB bacilli (latent) = TB bacilli (active). Metabolically inactive? Non-replicating. Conditions: hypoxia, starvation, acid ph. TB bacilli (latent) = TB bacilli (active). Every dogma has its day Anthony Burgess 4

5 The current known record J Infect Dis ;185: The current demonstrated record Risk of TB disease following infection Progressive? Reactivation Depends on: Age at infection Current age Geography (host factors?) Strain? Avg. time to symptoms = 1.4 yrs Emilia Vynnycky and Paul E. M. Fine 5

6 How important is reactivation TB? How important is reactivation TB? How important is reactivation TB? ~30,000 S. African gold miners. Very high TB rate (~2%). Widespread INH prophylaxis (IPT) for 6+ months. 6

7 How important is reactivation TB? ~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. What s the evidence? 7

8 Conditions associated with latency: Condi&on Hypoxa Low ph Carbon shi7 (lipids) MTB response DosR; Enduring hypoxic response (EHR) Acid response genes KstR; cholesterol uptake and metabolism All these conditions promote bacteriostasis in vitro, and all occur in vivo. Conditions associated with latency: Condi&on Hypoxa Low ph Carbon shi7 (lipids) MTB response DosR; Enduring hypoxic response (EHR) Acid response genes KstR; cholesterol uptake and metabolism All these conditions promote bacteriostasis in vitro, and all occur in vivo. However, they also occur during active disease! Are bacteria non-replicating in latency? TB never stops replicajng in mice (Nat Med. 2009;15:211). 8

9 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). 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. Now what? 9

10 New tools provide new ideas about latency: Animal models. Systems biology (sequencing; transcriptomics; modeling). PET/CT imaging. PET/CT imaging of TB in primates Probe: 18 FDG Seen in acjve and latent TB; also in humans. Lin et al, Nature Medicine, 20, (2014) AcJve and latent TB overlap Primate lesions Lin et al, Nature Medicine, 20, (2014) 10

11 AcJve and latent TB overlap Primate lesions Lin et al, Nature Medicine, 20, (2014) AcJve and latent TB overlap Primate lesions Lin et al, Nature Medicine, 20, (2014) The spectrum of tuberculosis Nat Rev Microbiol. 2009; 7:845 11

12 Latent TB..sub-clinical TB active disease Time (months to years) Phil. Trans. R. Soc. B 369: 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. 12

13 Thank you! 13