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Human Genetics of Infectious Diseases: Application to mycobacterial infections

Human Genetics of Infectious Diseases: Application to mycobacterial infections. The genus Mycobacterium. ‘Virulent’ ‘Weakly virulent’ M. tuberculosis complex > 80 species (e.g. M. avium , M. leprae M. marinum, M. fortuitum…)

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Human Genetics of Infectious Diseases: Application to mycobacterial infections

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  1. Human Genetics of Infectious Diseases: Application to mycobacterial infections

  2. The genus Mycobacterium ‘Virulent’ ‘Weakly virulent’ M. tuberculosis complex > 80 species (e.g. M. avium, M. leprae M. marinum, M. fortuitum…) Human transmission Environmental transmission (airborne) (water, soil, air…) M. ulcerans (Buruli ulcer) BCG vaccine Aquatic bug transmission? Injection transmission

  3. Human genetics in infectious diseases ? Epidemiological observations Concept Experimental models Genetic epidemiology Proof of concept Mendelian genetics

  4. Individual variability in response to infection (1) M. tb factors (virulence…) PRIMARY DISEASE (Ext.Pulm., children) ~5% INFECTION (primary/latent) Mycobacterium tuberculosis REACTIVATION DIS. (Pulm., adults) ~5% IMMUNE RESPONSE Environmental factors Exposure factors Host factors (age, immune status GENES, …)

  5. Individual variability in response to infection (2) Ranke, K. 1910. Diagnose und Epidemiologie der Lungentuberculose des Kindes. Archiv für Kinderheilkunde 54:279-306.

  6. Methods of investigation in humans Rare mutation Common polymorphism

  7. MENDELIAN AND COMPLEX INHERITANCE HYPOTHESIS-DRIVEN APPROACH GENOME-WIDE APPROACH DIFFERENTIAL EXPRESSION ASSOCIATION STUDIES LINKAGE STUDIES HUMAN DATA ANIMAL MODELS CANDIDATE GENES VARIANT DETECTION ‘RARE’ MUTATIONS ‘COMMON’ POLYMORPHISMS ASSOCIATION STUDIES (Replications) FUNCTIONAL STUDIES

  8. MENDELIAN SUSCEPTIBILITY TO MYCOBACTERIAL DISEASES (MSMD) • Disseminated infections by environmental mycobacteria (EM), BCG • No known primary or acquired immunodeficiency • Very rare (10-5 – 10-6) but often familial (consanguinity) • Mendelian transmission (7 identified genes so far)

  9. Mycobacteria IL12R1 p35 IL-12 gp91phox IL12R2 p40 NEMO CD40 CD40L IFNR1 IFNR2 STAT1 IFN- Macrophage/Dendritic Cell T Lymphocyte • New specific antimycobacterial immunological pathway • Medical implications (IFN- treatment) From EM to M. tuberculosis

  10. IL12-R1 deficiency and tuberculosis Inherited IL12R1 deficiency : Spanish family No BCG/NTM disease No IL12R1 expression No cellular responses to IL-12 IL12RB1 mutation: 1721+2TG 17 yo 15 yo Pulm TB 8 yo Diss TB

  11. Mendelian TB: Conclusion and questions Mendelian disorders of the IL12-IFN axis are genetic etiologies for severe forms of tuberculosis: - What is the proportion of ‘Mendelian’ tuberculosis? (in children) …

  12. Alcais et al, J Exp Med, 2005

  13. Mendelian TB: Conclusion and questions • Mendelian disorders of the IL12-IFN axis are genetic etiologies • for severe forms of tuberculosis: • - What is the proportion of ‘Mendelian’ tuberculosis? (in children) • May common polymorphisms in these genes also predispose to • tuberculosis?  Complex TB inheritance

  14. Complex predisposition to common mycobacterial diseases Tuberculosis (M. tuberculosis) Leprosy (M. leprae) ~ 400,000 new cases per year ~ 95% of infected subjects do not develop the disease ~ 8 millions new cases per year ~ 90% of infected subjects do not develop the disease • Very large spectrum of clinical manifestations

  15. TUBERCULOSIS INHERITANCE: CANDIDATE GENES HYPOTHESIS-DRIVEN APPROACH GENOME-WIDE APPROACH LINKAGE STUDIES DIFFERENTIAL EXPRESSION ASSOCIATION STUDIES HUMAN DATA ANIMAL MODELS CANDIDATE GENES VARIANT DETECTION ‘RARE’ MUTATIONS ‘COMMON’ POLYMORPHISMS ASSOCIATION STUDIES Population or family-based FUNCTIONAL STUDIES  Examples : NRAMP1, HLA-DR, IL12RB1

  16. PULMONARY TUBERCULOSIS (PTB) AND IL12RB1 • Family-based association study : • 101 families including 157 offspring >15 years with PTB (culture +) TT TT AT AT AT TT • - Sequencing of promoter and coding regions in 40 PTB patients • No rare loss of function mutations • Detection of common polymorphisms >5% • Genotyping in the whole sample • Test for association with PTB

  17. I II III IV V VI VII VIII IX X XI XII XIII XIV XV XVI XVII IL12RB1 M365T(1094T>C) R156H (467G>A) Q214R (641A>G) G378R (1132G>C) 5’ 3’ +34C>T -111A>T -2C>T 387G>C +21C>A 684C>T +46T>C +24C>T +47G>T • Association with the two promoter polymorphisms in strong LD • especially for -2C>T (p=0.004), with T frequency ~ 0.1 • OR for CT or TT vs. CC = 3.8 [1.6-10.2] •  Replication studies • Functional studies T is an uncommon allele at position –2 (consensus site) Remus et al, J Inf Dis, 2004

  18. TUBERCULOSIS INHERITANCE: MAJOR GENES HYPOTHESIS-DRIVEN APPROACH GENOME-WIDE APPROACH LINKAGE STUDIES DIFFERENTIAL EXPRESSION ASSOCIATION STUDIES HUMAN DATA ANIMAL MODELS CANDIDATE REGION VARIANT DETECTION ‘RARE’ MUTATIONS ‘COMMON’ POLYMORPHISMS ASSOCIATION STUDIES Family-based FUNCTIONAL STUDIES

  19. CD AB AC BC AC AD IBD=2 IBD=1 IBD=0 TUBERCULOSIS: Genome-wide screen Affected sib-pair linkage study 96 multiplex families Total of 227 offspring with positive pulmonary TB El Baghdadi et al, J Exp Med, 2006

  20. Linkage to chromosome 8q12-q13 p<0.00002 39 families with affected parent p<0.00007 All 96 families Consistent with dominant inheritance Linkage disequilibrium mapping is ongoing

  21. LEPROSY INHERITANCE HYPOTHESIS-DRIVEN APPROACH GENOME-WIDE APPROACH LINKAGE STUDIES DIFFERENTIAL EXPRESSION ASSOCIATION STUDIES HUMAN DATA ANIMAL MODELS CANDIDATE REGIONS VARIANT DETECTION ‘RARE’ MUTATIONS ‘COMMON’ POLYMORPHISMS ASSOCIATION STUDIES Replication FUNCTIONAL STUDIES

  22. LEPROSY: Genome-wide screen 86 multiplex families Leprosy subtype Mira et al, Nat Genet, 2003

  23. 6p21 • Lod Score = 2.6 (p=2.10 –4) 3 2 Lod MLB LD mapping 1 0 [Mb] 20 25 30 35 40 45 50 ~ 10 Mb HLA Non-HLA III II Two linkage peaks 6q25 • Lod Score = 4.3 (p=5.10 –6) PARK2/PACRG (Mira, Alcaïs, et al. Nature 2004)

  24. Leprosy subtype LD mapping 194 simplex families 2 parents + 1 affected offspring 307 informative SNPs Alcais et al, Nat Genet, 2007

  25.  SNPs density

  26.  Association with a bin of several SNPs in the LTA region

  27. Replication in an independent Vietnamese sample of 104 trios with the same allele at risk LTA+80: OR=2.34 (1.27-4.31), p=0.003 LTA-293: OR=1.95 (1.11-3.31), p=0.03

  28. Replication in an Indian sample of 364 cases and 371 controls  LTA+80 is the most likely candidate

  29. The LTA+80 effect is strongly age-dependent Study in a Brazilian sample of 209 cases and 192 controls  No overall effect of LTA+80 Strong differences in mean age of patients between the three samples: Vietnam : 19 years India : 31 years Brazil : 38 years Strong heterogeneity of association results according to age

  30. The LTA+80 effect is strongly age-dependent 1st Vietnamese sample (194 trios) 2nd Vietnamese sample (104 trios) Indian sample 364 cases/371 controls Brazilian sample 209 cases/192 controls

  31. Summary for leprosy Strong association of LTA+80 A allele with early onset leprosy. In combined sample of Vietnamese trios < 16 years: OR for LTA+80 AA/AC vs CC subjects = 5.6 (2.5-12.5), p<10-6 LTA+80 A decreases LTA protein production (Knight et al, Nat Genet, 2004) LTA KO mice are susceptible to mycobacteria (Roach et al. J Exp Med, 2001) The effect of LTA is totally independent of HLA DRB1 alleles Other genes in the 6p21 region (especially in adults): HLA DR…

  32. Genetic predisposition to mycobacterial infections  continuous spectrum RR 100 10 5 2 1 •  Mendelian mutations with causal role demonstrated • direct clinical and therapeutic implications (disseminated TB of children) • information on immunological pathways ( candidate genes) •  Intermediate major gene effects • - in specific populations, phenotypes, age class … • - implications ~ Mendelian •  Common polymorphisms with moderate effect • - molecular basis difficult to validate (same pathway, interest of GWA) • - may have strong attributable risk at the population level Genetic dissection needs to combine different strategies

  33. Mendelian Major gene Polygenic 50 Genetic spectrum depends on age Origin of genetic cases (%) Age 15 30 45 60 Primary infection - - - - - - - - - - - - - -  Reactivation Extra-pulmonary - - - - - - - - - - - - - - Pulmonary

  34. March of Dimes FRM Laboratory of Human Genetics of Infectious Diseases Mycobacterium Alexandre Alcaïs L. de Beaucoudrey L.Blancas-Galicia Jacinta C. Bustamante Aurélie Cobat Stéphanie Dupuis Jacqueline Feinberg Audrey Grant Lucile Jannière Daniel Nolan Brigitte Ranque Natascha Remus Yoann Rose Bacteria Virus Laure Gineau E. Jouanguy Lazaro Lorenzo S. Plancoulaine V. Sancho-Shimizu Shenying Zhang Horst von Bernuth Maya Chrabieh Pegah Gandil Capucine Picard Anne Puel Laurent Abel Jean-Laurent Casanova

  35. McGill University, Montreal, Canada Andrea Alter Mariana Orlova Erwin Schurr Laboratoire d’Immunologie, Hôpital Militaire de Rabat, Maroc Jamila El Baghdadi Abdellah Benslimane Hospital of Dermato-Venereology, Ho Chi Minh City, Vietnam Nguyen Van Thuc Nguyen Thu Huong Vu Hong Thai All India Institute of Medical Sciences, New Delhi, India Meenakshi Singh Narinder Mehra Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil Milton Moraes Centro de Ciências Biológicas e da Saúde,Curitiba, Brazil Marcelo Mira

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