p53-responsive TLR8 SNP enhances human innate immune response to respiratory syncytial virus
Daniel Menendez, Joyce Snipe, Jacqui Marzec, Cynthia L. Innes, Fernando P. Polack, Mauricio T. Caballero, Shepherd H. Schurman, Steven R. Kleeberger, Michael A. Resnick
Daniel Menendez, Joyce Snipe, Jacqui Marzec, Cynthia L. Innes, Fernando P. Polack, Mauricio T. Caballero, Shepherd H. Schurman, Steven R. Kleeberger, Michael A. Resnick
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Research Article Genetics Infectious disease

p53-responsive TLR8 SNP enhances human innate immune response to respiratory syncytial virus

Abstract

The Toll-like receptor 8 (TLR8) has an important role in innate immune responses to RNA viral infections, including respiratory syncytial virus (RSV). We previously reported that TLR8 expression was increased directly by the tumor suppressor and transcription factor p53 via a single nucleotide polymorphism (SNP) (rs3761624) in the TLR8 promoter, thereby placing TLR8 in the p53/immune axis. Because this SNP is in linkage disequilibrium with other SNPs associated with several infectious diseases, we addressed the combined influence of p53 and the SNP on downstream inflammatory signaling in response to a TLR8 cognate ssRNA ligand. Using human primary lymphocytes, p53 induction by chemotherapeutic agents such as ionizing radiation caused SNP-dependent synergistic increases in IL-6 following incubation with an ssRNA ligand, as well as TLR8 RNA and protein expression along with p53 binding at the TLR-p53 SNP site. Because TLR8 is X-linked, the increases were generally reduced in heterozygous females. We found a corresponding association of the p53-responsive allele with RSV disease severity in infants hospitalized with RSV infection. We conclude that p53 can strongly influence TLR8-mediated immune responses and that knowledge of the p53-responsive SNP can inform diagnosis and prognosis of RSV disease and other diseases that might have a TLR8 component, including cancer.

Authors

Daniel Menendez, Joyce Snipe, Jacqui Marzec, Cynthia L. Innes, Fernando P. Polack, Mauricio T. Caballero, Shepherd H. Schurman, Steven R. Kleeberger, Michael A. Resnick

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Figure 2

Activation of p53 by chemotherapeutic drugs amplifies the TLR8-mediated immune response in human lymphocytes in a SNP rs3761624–dependent manner.

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Activation of p53 by chemotherapeutic drugs amplifies the TLR8-mediated ...
(A) IL-6 secretion measured by ELISA in blinded samples from PHA-stimulated lymphocytes pretreated with DMSO, nutlin, DXR, or IR for 24 hours then washed twice with PBS and challenged with water, TLR8 PAMP ssRNA40 (5 μg/mL) or its decoy ssRNA41 (5 μg/mL) for 3 hours. Each dot represents a different donor (n = 27). Presented are IL-6 secretion profiles (n = 25) grouped by A/G rs3761624 genotypes after (B) nutlin, (C) DXR, and (D) IR treatments for 24 hours. #P < 0.001 for drug-treated samples when compared with NT or DMSO treatments after ssRNA40 challenge for each genotype (2-tailed unpaired Student’s t test). *P < 0.01; **P < 0.001; ***P < 0.0001 when compared with drug- and ssRNA40-treated group expressing the A (male) or AA (female) rs3761624 SNP allele (s) (Wilcoxon signed-rank test).