A Common Genetic Variant in TLR1 Enhances Human Neutrophil Priming and Impacts Length of Intensive Care Stay in Pediatric Sepsis

Laura C Whitmore; Jessica S Hook; Amanda R Philiph; Brieanna M Hilkin; Xinyu Bing; Chul Ahn; Hector R Wong; Polly J Ferguson; Jessica G Moreland

doi:10.4049/jimmunol.1500856

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A Common Genetic Variant in TLR1 Enhances Human Neutrophil Priming and Impacts Length of Intensive Care Stay in Pediatric Sepsis

Journal article

Peer reviewed

A Common Genetic Variant in TLR1 Enhances Human Neutrophil Priming and Impacts Length of Intensive Care Stay in Pediatric Sepsis

Laura C Whitmore, Jessica S Hook, Amanda R Philiph, Brieanna M Hilkin, Xinyu Bing, Chul Ahn, Hector R Wong, Polly J Ferguson and Jessica G Moreland

The Journal of immunology (1950), Vol.196(3), pp.1376-1386

02/01/2016

DOI: 10.4049/jimmunol.1500856

PMCID: PMC4724530

PMID: 26729809

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Abstract

Polymorphonuclear leukocytes (PMN) achieve an intermediate or primed state of activation following stimulation with certain agonists. Primed PMN have enhanced responsiveness to subsequent stimuli, which can be beneficial in eliminating microbes but may cause host tissue damage in certain disease contexts, including sepsis. As PMN priming by TLR4 agonists is well described, we hypothesized that ligation of TLR2/1 or TLR2/6 would prime PMN. Surprisingly, PMN from only a subset of donors were primed in response to the TLR2/1 agonist, Pam3CSK4, although PMN from all donors were primed by the TLR2/6 agonist, FSL-1. Priming responses included generation of intracellular and extracellular reactive oxygen species, MAPK phosphorylation, integrin activation, secondary granule exocytosis, and cytokine secretion. Genotyping studies revealed that PMN responsiveness to Pam3CSK4 was enhanced by a common single-nucleotide polymorphism (SNP) in TLR1 (rs5743618). Notably, PMN from donors with the SNP had higher surface levels of TLR1 and were demonstrated to have enhanced association of TLR1 with the endoplasmic reticulum chaperone gp96. We analyzed TLR1 genotypes in a pediatric sepsis database and found that patients with sepsis or septic shock who had a positive blood culture and were homozygous for the SNP associated with neutrophil priming had prolonged pediatric intensive care unit length of stay. We conclude that this TLR1 SNP leads to excessive PMN priming in response to cell stimulation. Based on our finding that septic children with this SNP had longer pediatric intensive care unit stays, we speculate that this SNP results in hyperinflammation in diseases such as sepsis.

Flow Cytometry

Length of Stay

Neutrophil Activation - genetics

Intensive Care Units

Enzyme-Linked Immunosorbent Assay

Humans

Neutrophils - immunology

Child, Preschool

Genotype

Immunoblotting

Reverse Transcriptase Polymerase Chain Reaction

Toll-Like Receptor 1 - genetics

Sepsis

Polymorphism, Single Nucleotide

Toll-Like Receptor 1 - immunology

Child

Details

Title: Subtitle: A Common Genetic Variant in TLR1 Enhances Human Neutrophil Priming and Impacts Length of Intensive Care Stay in Pediatric Sepsis
Creators: Laura C Whitmore - Department of Pediatrics, University of Iowa, Iowa City, IA 52242; Iowa Inflammation Program, University of Iowa, Iowa City, IA 52242
Jessica S Hook - Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390
Amanda R Philiph - Department of Pediatrics, University of Iowa, Iowa City, IA 52242; Iowa Inflammation Program, University of Iowa, Iowa City, IA 52242
Brieanna M Hilkin - Department of Pediatrics, University of Iowa, Iowa City, IA 52242; Iowa Inflammation Program, University of Iowa, Iowa City, IA 52242
Xinyu Bing - Department of Pediatrics, University of Iowa, Iowa City, IA 52242
Chul Ahn - Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, TX 75390; and
Hector R Wong - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
Polly J Ferguson - Department of Pediatrics, University of Iowa, Iowa City, IA 52242
Jessica G Moreland - Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390; jessica.moreland@utsouthwestern.edu
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.196(3), pp.1376-1386
DOI: 10.4049/jimmunol.1500856
PMID: 26729809
PMCID: PMC4724530
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: United States
Grant note: R01 AR059703 / NIAMS NIH HHS 1R01AR059703-01A1 / NIAMS NIH HHS 1R21 AI109127-01 / NIAID NIH HHS R21 AI109127 / NIAID NIH HHS
Language: English
Date published: 02/01/2016
Academic Unit: Critical Care; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Rheumatology, Allergy, and Immunology; Internal Medicine
Record Identifier: 9984065840102771

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