title: A Common Genetic Variant in TLR1 Enhances Human Neutrophil Priming and Impacts Length of Intensive Care Stay in Pediatric Sepsis.
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.
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, IA 52242; Iowa Inflammation Program, University of Iowa, Iowa City, IA 52242;
authors.forename: Laura C
authors.initials: LC
authors.lastname: Whitmore
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Hook
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, IA 52242; Iowa Inflammation Program, University of Iowa, Iowa City, IA 52242;
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Philiph
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, IA 52242; Iowa Inflammation Program, University of Iowa, Iowa City, IA 52242;
authors.forename: Brieanna M
authors.initials: BM
authors.lastname: Hilkin
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, IA 52242;
authors.forename: Xinyu
authors.initials: X
authors.lastname: Bing
authors.affiliation: Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
authors.forename: Chul
authors.initials: C
authors.lastname: Ahn
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Hector R
authors.initials: HR
authors.lastname: Wong
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, IA 52242;
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Ferguson
authors.affiliation: 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.
authors.forename: Jessica G
authors.initials: JG
authors.lastname: Moreland
mesh_terms: D002648:Child; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D007362:Intensive Care Units; D007902:Length of Stay; D018375:Neutrophil Activation / Q000235:genetics*; D009504:Neutrophils / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis; D051194:Toll-Like Receptor 1 / Q000235:genetics* / Q000276:immunology
chemical_list: D051194:Toll-Like Receptor 1