A mouse model of human TLR4 D299G/T399I SNPs reveals mechanisms of altered LPS and pathogen responses-Reference-Cited by-同舟云学术

A mouse model of human TLR4 D299G/T399I SNPs reveals mechanisms of altered LPS and pathogen responses

Published:2020-11-20 Issue:2 Volume:218 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Richard Katharina¹^ORCID,Piepenbrink Kurt H.²^ORCID,Shirey Kari Ann¹^ORCID,Gopalakrishnan Archana¹^ORCID,Nallar Shreeram¹^ORCID,Prantner Daniel J.¹^ORCID,Perkins Darren J.¹^ORCID,Lai Wendy¹^ORCID,Vlk Alexandra¹^ORCID,Toshchakov Vladimir Y.¹^ORCID,Feng Chiguang³^ORCID,Fanaroff Rachel⁴^ORCID,Medvedev Andrei E.⁵,Blanco Jorge C.G.⁶^ORCID,Vogel Stefanie N.¹^ORCID

Affiliation:

1. Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD

2. Department of Food Science and Technology, Department of Biochemistry, University of Nebraska, Lincoln, NE

3. Center for Vaccine Development, University of Maryland, School of Medicine, Baltimore, MD

4. Department of Anatomical Pathology, University of Maryland Medical Center, Baltimore, MD

5. Department of Immunology, University of Connecticut Health Center, Farmington, CT

6. Sigmovir Biosystems, Inc., Rockville, MD

Abstract

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.

Funder

National Institutes of Health

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

Link

http://rupress.org/jem/article-pdf/doi/10.1084/jem.20200675/1405765/jem_20200675.pdf

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