Genetic Factors Governing Susceptibilities to Severe Infections GSK-Chair of Infectious Diseases Pr Jean-Paul MIRA
GENETIC PREDISPOSITION GENETIC PREDISPOSITION TO SEVERE SEPSIS TO SEVERE SEPSIS Université catholique de Louvain Cliniques universitaires Saint-Luc 17 février 2005 Pr. Jean-Paul MIRA Medical ICU & ICU & Dept Dept. of . of Cell Biology Cell Biology Medical Cochin University University Hospital Hospital & Cochin & Cochin Institute Institute, Paris, F , Paris, F Cochin
Recurrent Purpura Fulminans Recurrent Purpura Fulminans 2002/01: 15 yo girl admitted in ICU - Temperature 40°C; HR 125; BP 74/45; RR 38 - Meningitis with purpura fulminans - MOF (Shock, ARDS, ARF, DIC, Lactic acidosis) - Meningococcus type N in the skin biopsy - Survival with multiple finger amputations and skin grafting - 6 month hospitalization 2003/02: - Temperature 39°C; HR 125; BP 83/48; RR: 33 - Meningitis with purpura fulminans - Lumbar punction � meningococcus type Y - Shock and DIC - Survival (Xigris) with new skin grafting - 3 month hospitalization Bohé J. et al.
« 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
Watson JD, Crick FHC. Nature 1953;171:737
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
WE ALL, AS HUMANS, SHARE THE SAME BASIC GENES BUT…
Small differences in genotype make big differences to phenotype
Genetic Polymorphisms Genetic Polymorphisms � Human SNP Map
Genetic Polymorphisms Genetic Polymorphisms
Molecular Genetic Research Molecular Genetic Research Heriditary disorder Linkage studies Mutation or polymorphism Genetics Milewitcz DM. Circulation 2000; 102: IV-103
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 LPS Dendritic cell 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
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.
Genetic Polymorphisms and Severe Sepsis Susceptibility and/or Outcome Gene 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
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 -
Shi L, J Exp Med 2004; 199:1379 MBL-Deficient Mice and Staphylococcus Infection
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
Low serum MBL MBL Low serum Normal serum serum MBL MBL Normal
MBL Polymorphisms Polymorphisms, SIRS, , SIRS, and Sepsis and Sepsis MBL 272 ICU Pts with SIRS 75 Pts Without Sepsis 197 Pts With Severe Sepsis 100 100 80 80 % Patients % Patients 60 60 40 40 20 20 55 20 A/A A/O O/O A/A A/O O/O A: Wild Type O: Structural polymorphism associated with low MBL levels Garred P. J Infect Dis 2003;188:1394
MBL Polymorphisms Polymorphisms, SIRS, , SIRS, and Sepsis and Sepsis MBL 50 40 % Mortality 30 20 10 A/A A/O O/O : Predicted Mortality Garred P. J Infect Dis 2003;188:1394
MBL genotype and risk of invasive pneumococcal disease P < 0.05 % Variants homozygotes 12 10 8 6 4 2 Contrôles Patients Odds ratio 3.48 (1.51 – 8.01); p=0,003 n=1032 n=337 Roy et al. Lancet 2002; 359: 1569-1573
Shi L, J Exp Med 2004; 199:1379 MBL-Deficient Mice and Staphylococcus Infection
Monocyte or LPS Dendritic cell 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
TLR4 mutation and and LPS LPS responsiveness responsiveness TLR4 mutation 40 IL-1 α (pg/ml) 20 WT/Asp299Gly WT/WT & Thr399Ile Arbour NC, et al. Nature NC, et al. Nature Genetics Genetics 2000 2000 Arbour
TLR4 Polymorphisms and Septic Shock Polymorphisms and Septic Shock TLR4 Gram negative Gram negative Control Control Septic shock Septic shock 30 patients mutated patients 25 20 % TLR4 mutated 15 10 % TLR4 5 Lorenz , Arch. Intern. Med. 2002 162:1028
TLR4 Variants and Predisposition and Predisposition to Gram to Gram Negative Sepsis Negative Sepsis TLR4 Variants With TLR4 TLR4 Without TLR4 TLR4 With Without infection negative infection Mutation Mutation Mutation Mutation 100 P = 0.004 80 % Gram negative 60 40 % Gram 20 Agnese DM, JID 2002; 186:1522
Cytokine Polymorphisms
Cytokine Polymorphisms and Meningococcemia Gene Polymorphism Csqs Pts Su Severity Outcome Ref ↑ ACE ↑ 14% Death ACE DD (deletion) 110 Harding D. [OR]= 2.8 2002 ↑ TNF α TNF - 308 (TNF2) 98 [OR] =2.5 Nadel S. [CI]: 1.1-5.7 1996 ↑ IL-6 -174 (G � C) [OR]= 3.06 IL-6 85 [OR] = 2.64 Balding J. [CI]: 1.1- 6.2 2001 � IL-1 β IL-1B -511 (1+) 1106 [OR] = 0.61 Read RC. ↓ IL -1 β ILRN +2018 (2+) [CI] 0.38-0.98 2003
TNF locus TNF locus LT- β TNF- α LT- α TNF1 Nco.I -308 -376 TNF2 TNFB1 TNFB2
Association of TNF2 with with TNF TNF levels levels in in Septic Shock Septic Shock Association of TNF2 TNF1 TNF2 Appoloni O. Am J Med 2001; 110:486
TNF2 polymorphism and septic shock susceptibility polymorphism and septic shock susceptibility TNF2 p= 0.002 80 % Patients 60 40 20 TNF1 TNF2 TNF1 TNF2 Control Septic shock JAMA. 1999, 282:561-8
TNF2 polymorphism and septic shock outcome polymorphism and septic shock outcome TNF2 TNF1 TNF2 39.2% 42.6% 71.4% JAMA 1999;282:561-8
α and severe - α TNFB2 in LT LT- and severe sepsis sepsis outcome outcome TNFB2 in Mortality (%) 100 P=0.007 80 60 40 20 13 37 30 0 TNFB1/TNFB1 TNFB1/TNFB2 TNFB2/TNFB2 Stüber. J Inflamm 1996;46:42-50
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