Tuberculosis: When two genomes go to war

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TuberculosisWhen two genomes go to war

• Marcel A. Behr
• McGill University
• marcel.behr_at_mcgill.ca
• www.molepi.mcgill.ca

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Overview

• Introduction
• Basic pathogenesis of TB
• Global TB epidemiology
• Molecular epidemiologic methods and lessons from
  molepi study
• Genetic approaches
• Lessons from host genetics
• Concluding thoughts on TB and other diseases

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Human tuberculosis Natural History
Infection
Initial containment 95
Early Progression - 5 Fast TB
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Tuberculosis Transmission and Natural History
Self-Cure 90
Infection
Initial containment 95
Early Progression - 5 Fast TB
Late Progression - 5 Reactivation TB
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Clinical Manifestations of TB

• General
• fever, weight loss, weakness, consumption
• result from inflammatory response
• Organ specific
• pneumonia cough, sputum /- blood
• scrofula swollen lymph nodes
• genitourinary sterile pyuria
• bone back pain, fracture, hump-back
• meningitis headache, obtundation
• miliary TB no obvious source

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Overview of TB pathogenesis
90 no sequellae
WHY?
Primary infection (tuberculin positive)
5 primary TB (within 2 years)
GET IN
5 reactivation (later in life)
GET OUT
STAY IN
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TB pathogenesis two genomes do battle
M. tuberculosis
H. sapiens
Virulent vs. attenuated
Susceptible vs. resistant
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90
TB infection (2 billion people)
Active TB 2-3 million deaths / year tie for
first with HIV/AIDS
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TB pathogenesis three genomes do battle
M. tuberculosis
H. sapiens
Virulent vs. attenuated
Susceptible vs. resistant
40
60
TB infection (2 billion people)
Active TB (2-3 million deaths / year)
HIV
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TB and AIDS Epidemiology

• Infection rates often high to both
• Most notably sub-Saharan Africa, South-East Asia
• M. tuberculosis accelerates progression of HIV to
  AIDS
• TB cause of death in about 25 AIDS
• HIV infection is single strongest risk factor for
  progression of TB infection to TB disease
• Evil synergy where resources most limited

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Tuberculosis Global epidemiology
Infected 2 billion
Cases 20 million New cases 8 million per
year Deaths 2 million per year
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Role of interventions
INH
BCG

• Sanitorium
• Antibiotics

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DNA fingerprinting of M. tuberculosisIS6110-based
RFLP

• 1. Chromosomal DNA
• restriction site
• IS6110 site
• 2. DNA digested using PvuII
• 3. Fragments separated by gel electrophoresis
• 4. Agarose blotted onto nitrocellulose and
  hybridization performed with labelled IS6110

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RFLP patterns

• If random, gt 250 patterns
• Not random, therefore need to empirically
  determine there is sufficient background
  diversity
• Diversity a function of
• Bacteria under study
• Genetic clock of marker
• Local epidemiology

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Planes of molepi study
Individual Clinician
Defined outbreak Disease Control
Population Epidemiologist
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Treatment failureRelapse vs. reinfection?

• Relapse a therapeutic failure
• Change treatment approach
• End point in clinical trials
• Reinfection a TB control failure
• Do source investigation
• Implications for immunity
• Can you be dually infected?
• Does infection provide protection against
  superinfection?

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Treatment failures with MDR-TB
Relapses have original strain
Reinfections - house strain
Small et al., NEJM, 1993
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Systematic studies of reinfection

• Highly variable results
• Depend on local epi
• Capetown 75 failures are reinfections
• Van Rie, NEJM, 1999
• Canary Island 44
• Caminero, Am J Resp CCM, 2001
• Netherlands, SF extremely rare
• Dual infection 1 case in 6 years, SF
• Yeh et al, IJTLD, 1999

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Molepi within suspected outbreak

• Often markers used to confirm outbreak
• Defined setting provides validation
• May only provide concordant data
• No value added
• May provide confirmation with extra information

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AIDS-related TB outbreak Epi curve

• Hospice, 1990, S.F.
• 14 cases of TB in 10 months suspected outbreak
• Unusual time course