Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock.
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.
Ferwerda
Bart
B
Department of Internal Medicine and Nijmegen Institute for Infectious Inflammation and Immunity, Radboud University Nijmegen Medical Center, HB, Nijmegen, The Netherlands.
Alonso
Santos
S
Banahan
Kathy
K
McCall
Matthew B B
MB
Giamarellos-Bourboulis
Evangelos J
EJ
Ramakers
Bart P
BP
Mouktaroudi
Maria
M
Fain
Pamela R
PR
Izagirre
Neskuts
N
Syafruddin
Din
D
Cristea
Tudor
T
Mockenhaupt
Frank P
FP
Troye-Blomberg
Marita
M
Kumpf
Oliver
O
Maiga
Boubacar
B
Dolo
Amagana
A
Doumbo
Ogobara
O
Sundaresan
Santhosh
S
Bedu-Addo
George
G
van Crevel
Reinout
R
Hamann
Lutz
L
Oh
Djin-Ye
DY
Schumann
Ralf R
RR
Joosten
Leo A B
LA
de la Rúa
Concepcion
C
Sauerwein
Robert
R
Drenth
Joost P H
JP
Kullberg
Bart-Jan
BJ
van der Ven
André J A M
AJ
Hill
Adrian V
AV
Pickkers
Peter
P
van der Meer
Jos W M
JW
O'Neill
Luke A J
LA
Netea
Mihai G
MG
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*
D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; D012694:Serine; D007930:Leucine