Genetic Factors Governing Susceptibilities to Severe Infections GSK-Chair of Infectious Diseases Pr Jean-Paul MIRA
Sommes- -nous tous égaux devant nous tous égaux devant Sommes les infections graves? les infections graves? Université catholique de Louvain Université catholique de Louvain Ecole de médecine Ecole de médecine 18 Février 2005 Février 2005 18 Pr. Jean- -Paul Mira Paul Mira Pr. Jean Réanimation Médicale et Département de Biologie Cellulaire Réanimation Médicale et Département de Biologie Cellulaire Hôpital Cochin & Institut Cochin, Paris Hôpital Cochin & Institut Cochin, Paris
SEPSIS • Major Cause of Mortality – 1 st cause of death in ICU • 1,5 million of severe sepsis/year (Europe) – 9% of ICU admissions – Estimated cost : 17 milliards $/year (USA) – Increased incidence over the years
Septic Shock Epidemiology Septic Shock Epidemiology Annane D. Am J Respir Crit Care Med 2003;168:165–172
« If it were not for the great variability among individuals medicine might as well be a science and not an art » Sir William Osler, 1892 1953 1953 2001- -2003 2003 2001 « Today we are learning the language in which God created life. Today we are learning the language in which God created life. « It will revolutionize the diagnosis, prevention and treatment of most, most, It will revolutionize the diagnosis, prevention and treatment of if not all human diseases. » » if not all human diseases. William J. Clinton, June 26, 2000
From Watson Watson and and Crick Crick to Human Genome to Human Genome From 1953 Watson and Crick: double helical structure of DNA 1960s Role of RNA and Genetic Code 1970s Recombinant DNA technology 1977 Sanger and Gilbert: DNA sequencing 1983 Mapping of disorders by linkage (Huntington disease) 1986 Polymerase Chain Reaction 1990 Human Genome Project 1995 Haemophilus influenzae genome 2003 Mice and Human genome sequence Human SNP Map
Molecular Genetic Research Molecular Genetic Research Heriditary disorder Linkage studies Mutation or polymorphism Genetics Milewitcz DM. Circulation 2000; 102: IV-103
TOUS LES ÊTRES HUMAINS TOUS LES ÊTRES HUMAINS PARTAGENT LES MÊMES GÈNES PARTAGENT LES MÊMES GÈNES MAIS… MAIS…
Small differences in genotype make big differences to phenotype
Evidences for a for a genetic genetic component to sepsis component to sepsis Evidences Animal Studies - Susceptibility/resistance to certain infection in mice - Susceptibility/resistance phenotypes of knock-out mice
Mice Susceptibility Susceptibility to Infection to Infection with with Group A Group A Streptococci Streptococci Mice 10 3 cfu Strepto Subcutaneous d2 Goldman O. J Infect Dis 2003;187:854-61.
Monocyte or Dendritic cell LPS Gram- Bacteria Flagellin Double-stranded ? RNA Lipoproteins CpG DNA Gram+ Bacteria Fungi TLR4 TLR3 TLR5 TLRx TLR9 TLR2 +/- TLR1/6 NF- κ B Signalisation Immunomodulatory genes Adaptative Response Tissue Injury Bacteria Lysis Septic Apoptosis Cellular Immunity Shock
TLR2- -KO Mice KO Mice and Response and Response to Gram Positive to Gram Positive Bacteria Bacteria TLR2 Intraveneous infusion of Staphylococcus aureus Takeuchi et al., J. Immunol. 1999; 165:5392
Evidences for a for a genetic genetic component to sepsis component to sepsis Evidences Animal Studies - Susceptibility/resistance to certain infection in mice - Susceptibility/resistance phenotypes of knockout mice Human Studies - Clinical Evidences - Ethnic Differences - Twin Studies - Adoptee Studies
Twin Studies Twin Studies • Tuberculosis Kallmann FJ, Am rev Tuber 1943. Comstock GW, Am Rev Respir Dis 1978. • Leprosis Fine PE, Int J leprosy 1981 • Helicobacter pylori Malaty HM, Ann Intern Med 1994. • Malaria Jepson AP, J Infect Dis 1995. • AIDS Chang J, J Virol 1996.
Genetic and and environmental environmental influences influences Genetic on premature death premature death in in adult adoptees adult adoptees on Cause of Death Relative risk for the adoptee (Parent Dead before the age of 50) to die from the same cause All causes 1.71 Biologic 0.71 Adoptive Infection Biologic 5.8 Adoptive 0.73 Vascular 4.5 Biologic 3.1 Adoptive Sørensen TI, et al. NEJM 1988; 318:727-32.
Host Genetics of Infectious Diseases Mendelian Genetics Genetics of Complex Diseases P H Genes Gene E N O Environmental Influences T Y P Pathogen Pathogen E S
Genetics of Phagocyte Immune Defects Rolling Deficiciency Type II: Sialyl Lewis X (AR) Number Selectin Deficiency ( AR) Leukocyte Adhesion Deficiency Cyclic neutropenia (AD) Congenital agranulocytosis Type I: CD18 (AR); (Kostmann syndrome) Bacterial lysis Deficiency Phagocytosis Deficiency Chronic Granulomatous Disease (AR, X) Complement deficiencies Myeloperoxidase deficiency Mutations of MBL Neutrophil granule defects Recurrent Bacterial Infections Holland SM and Gallin JI, Annu Rev Med 1998
Single Gene Defects and Severe Immunodeficiency Disorders System involved Typical clinical syndrome Genetic Defect B cell tyrosine kinase B lymphocyte Defective antibody production CD40 ligand T lymphocyte Defective humoral and cellular immunity IL-2 receptor Cytochrome b Neutrophil Defective phagocytosis β 2 integrin Interferon γ receptor Macrophage Susceptibility to mycobacterial infection Complement Recurrent Neisseria infections Terminal complement components
Single Gene Defects and Severe Tuberculosis Gene Defects and Severe Tuberculosis Single • Parental consanguinity • Affected siblings • Familial forms of disseminated infections with weakly pathogenic mycobacteria Search for recessive genetic disorders
Bacteria Early Defense Late Defense Parasite Yeast NO MAC T MAC Th1 H 2 O 2 IFN- γ IL-12 MAC IL-12 HLA-DR NO NK MAC H 2 O 2 IFN- γ (Biron et Gazzinelli. Curr. Op. Immuno. 1995;7:485-496)
Mendelian susceptibility to mycobacterial infection in man Mycobacterium IFN- γ R1 IFN- γ R2 IFN- γ R1 IFN- γ R2 IFN- γ IL-12 R β 1 IL-12 p35 IL-12 R β 2 IL-12 p40 Macrophage / dendritic cell NK cell / T cell Altare F et al. Curr Op Immunol 1998
Early Defense Late Defense Mycobacteria NO MAC T MAC Th1 H 2 O 2 IFN- γ IL-12 MAC IL-12 HLA-DR NO NK MAC H 2 O 2 IFN- γ
Host Genetics Genetics of of Infectious Diseases Infectious Diseases Host Genetics of Complex Diseases P H Genes E N O Environmental Influences T Y P Pathogen E S
Polymorphismes Génétiques Polymorphismes Génétiques
Polymorphismes génétiques fonctionnels Polymorphismes génétiques fonctionnels Promoteur Exon1 Intron1 Exon2 Changement Quantitatif Changement Qualitatif Détection des pathogènes (CD14; MBL) Détection des pathogènes(Toll; FcR;…) Inflammation (TNF; IL-1;…) Inflammation (TNFR;iNOS;…) Coagulation (PAI-1; VII;…) Coagulation (Leyden;…) Thérapeutique (CYP) Thérapeutique … …
Background vs. Functional SNPs ! S M O T A G E I P R Before E N DNA T M A Sequencing S IMPORTANT MESSAGE ! DNA Sequence IMPERTANT MESSAGE ! Variation 1 IMPORTANT MASSAGE ! Variation 2
Genetic Polymorphisms and Severe Sepsis Gene Susceptibility and/or Outcome Mannose Binding Lectin Meningococcemia, Pneumococcemia Severe sepsis Toll-Like Receptor 4/2 Gram negative/positive Septic Shock Toll-Like Receptor 5 Legionnaire’s Disease CD14 Septic Shock FC γ RII Receptor Meningococcemia; Pneumococcemia TNF locus Meningococcemia Septic Shock; Cerebral Malaria IL-18 Severe Sepsis IL-10 Severe Sepsis, Meningococcemia IL-6 Severe sepsis IL-1 locus Severe Sepsis IL-4 Viral Pneumonia Caspase 12 Severe Sepsis PAI-1 Meningococcemia; Severe sepsis FactorV Leiden Meningococcemia; Severe sepsis
Pathogen Detection
TLR2 and and Streptococcus pneumoniae Streptococcus pneumoniae meningitis meningitis TLR2 WT TLR2 -/- Echchannaoui H et al. JID 2002;186:798
Anthrax Listeria Brucella Yersinia Virus Campylobacter Streptomycces E. coli S. pneumoniae Legionella S. enterococcus Fungi
Mannose- -Binding Lectin Binding Lectin Mannose Gram+ Yeast Gram- Mycobact. • Collectin Collectin • • Structural Structural homology with homology with C1q C1q • • Associated Associated to 2 serine to 2 serine proteases proteases • • Variability Variability: : • - Point mutations codons 52, 54, 57 Point mutations codons 52, 54, 57 - - Polymorphisms Polymorphisms in in the the promoter promoter -
Mannose- -binding Lectin Polymorphisms binding Lectin Polymorphisms Mannose & The Risk The Risk of Infections of Infections & • Repeated bacterial and fungal infections Sumiya et al., Lancet 1991 Summerfeld et al., Lancet 1995 Garred et al., Lancet 1995 Summerfeld et al., BMJ 1997 • Infections after chemotherapy Neth et al., Lancet 2001 Peterslund et al., Lancet 2001 • Increased severity of lung disease and low survival in cystic fibrosis Garred et al., J. Clin. Invest. 1999 • Meningococcal disease Hibberd et al., Lancet 1999
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