title: Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock.
abstract: Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. This phenotype has been related to an increased resistance to infection. However, an overshoot in the release of proinflammatory cytokines by TIRAP 180L homozygous individuals suggests a scenario of balanced evolution. We have also investigated the worldwide distribution of the Ser180Leu polymorphism in 14 populations around the globe to correlate the genetic makeup of TIRAP with the local infectious pressures. Based on the immunological, clinical, and genetic data, we propose that this mutation might have been selected in West Eurasia during the early settlement of this region after the out-of-Africa migration of modern Homo sapiens. This combination of functional and genetic data provides unique insights to our understanding of the pathogenesis of sepsis.
authors.affiliation: Department of Internal Medicine and Nijmegen Institute for Infectious Inflammation and Immunity, Radboud University Nijmegen Medical Center, HB, Nijmegen, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: Ferwerda
authors.forename: Santos
authors.initials: S
authors.lastname: Alonso
authors.forename: Kathy
authors.initials: K
authors.lastname: Banahan
authors.forename: Matthew B B
authors.initials: MB
authors.lastname: McCall
authors.forename: Evangelos J
authors.initials: EJ
authors.lastname: Giamarellos-Bourboulis
authors.forename: Bart P
authors.initials: BP
authors.lastname: Ramakers
authors.forename: Maria
authors.initials: M
authors.lastname: Mouktaroudi
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Fain
authors.forename: Neskuts
authors.initials: N
authors.lastname: Izagirre
authors.forename: Din
authors.initials: D
authors.lastname: Syafruddin
authors.forename: Tudor
authors.initials: T
authors.lastname: Cristea
authors.forename: Frank P
authors.initials: FP
authors.lastname: Mockenhaupt
authors.forename: Marita
authors.initials: M
authors.lastname: Troye-Blomberg
authors.forename: Oliver
authors.initials: O
authors.lastname: Kumpf
authors.forename: Boubacar
authors.initials: B
authors.lastname: Maiga
authors.forename: Amagana
authors.initials: A
authors.lastname: Dolo
authors.forename: Ogobara
authors.initials: O
authors.lastname: Doumbo
authors.forename: Santhosh
authors.initials: S
authors.lastname: Sundaresan
authors.forename: George
authors.initials: G
authors.lastname: Bedu-Addo
authors.forename: Reinout
authors.initials: R
authors.lastname: van Crevel
authors.forename: Lutz
authors.initials: L
authors.lastname: Hamann
authors.forename: Djin-Ye
authors.initials: DY
authors.lastname: Oh
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Schumann
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Concepcion
authors.initials: C
authors.lastname: de la Rúa
authors.forename: Robert
authors.initials: R
authors.lastname: Sauerwein
authors.forename: Joost P H
authors.initials: JP
authors.lastname: Drenth
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.forename: André J A M
authors.initials: AJ
authors.lastname: van der Ven
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Hill
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000483:Alleles; D019446:Endotoxemia / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007930:Leucine / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D011110:Polymorphism, Genetic; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology*; D012641:Selection, Genetic; D012694:Serine / Q000235:genetics; D012772:Shock, Septic / Q000235:genetics* / Q000276:immunology*
chemical_list: D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; D012694:Serine; D007930:Leucine