TY - JOUR
T1 - A mouse model of human TLR4 D299G/T399I SNPs reveals mechanisms of altered LPS and pathogen responses
AU - Richard, Katharina
AU - Piepenbrink, Kurt H.
AU - Shirey, Kari Ann
AU - Gopalakrishnan, Archana
AU - Nallar, Shreeram
AU - Prantner, Daniel J.
AU - Perkins, Darren J.
AU - Lai, Wendy
AU - Vlk, Alexandra
AU - Toshchakov, Vladimir Y.
AU - Feng, Chiguang
AU - Fanaroff, Rachel
AU - Medvedev, Andrei E.
AU - Blanco, Jorge C.G.
AU - Vogel, Stefanie N.
N1 - Publisher Copyright:
© 2020 Richard et al.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - Two cosegregating single-nucleotide polymorphisms (SNPs) in human TLR4, an A896G transition at SNP rs4986790 (D299G) and a C1196T transition at SNP rs4986791 (T399I), have been associated with LPS hyporesponsiveness and differential susceptibility to many infectious or inflammatory diseases. However, many studies failed to confirm these associations, and transfection experiments resulted in conflicting conclusions about the impact of these SNPs on TLR4 signaling. Using advanced protein modeling from crystallographic data of human and murine TLR4, we identified homologous substitutions of these SNPs in murine Tlr4, engineered a knock-in strain expressing the D298G and N397I TLR4 SNPs homozygously, and characterized in vivo and in vitro responses to TLR4 ligands and infections in which TLR4 is implicated. Our data provide new insights into cellular and molecular mechanisms by which these SNPs decrease the TLR4 signaling efficiency and offer an experimental approach to confirm or refute human data possibly confounded by variables unrelated to the direct effects of the SNPs on TLR4 functionality.
AB - Two cosegregating single-nucleotide polymorphisms (SNPs) in human TLR4, an A896G transition at SNP rs4986790 (D299G) and a C1196T transition at SNP rs4986791 (T399I), have been associated with LPS hyporesponsiveness and differential susceptibility to many infectious or inflammatory diseases. However, many studies failed to confirm these associations, and transfection experiments resulted in conflicting conclusions about the impact of these SNPs on TLR4 signaling. Using advanced protein modeling from crystallographic data of human and murine TLR4, we identified homologous substitutions of these SNPs in murine Tlr4, engineered a knock-in strain expressing the D298G and N397I TLR4 SNPs homozygously, and characterized in vivo and in vitro responses to TLR4 ligands and infections in which TLR4 is implicated. Our data provide new insights into cellular and molecular mechanisms by which these SNPs decrease the TLR4 signaling efficiency and offer an experimental approach to confirm or refute human data possibly confounded by variables unrelated to the direct effects of the SNPs on TLR4 functionality.
UR - http://www.scopus.com/inward/record.url?scp=85096814835&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85096814835&partnerID=8YFLogxK
U2 - 10.1084/JEM.20200675
DO - 10.1084/JEM.20200675
M3 - Article
C2 - 33216117
AN - SCOPUS:85096814835
SN - 0022-1007
VL - 218
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 2
ER -