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p53-responsive TLR8 SNP enhances human innate immune response to respiratory syncytial virus
Daniel Menendez, … , Steven R. Kleeberger, Michael A. Resnick
Daniel Menendez, … , Steven R. Kleeberger, Michael A. Resnick
Published August 20, 2019
Citation Information: J Clin Invest. 2019;129(11):4875-4884. https://doi.org/10.1172/JCI128626.
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Research Article Genetics Infectious disease Article has an altmetric score of 4

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

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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 1

TLR8 gene responsiveness to p53 activation by chemotherapeutic drugs is SNP rs3761624 dependent.

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TLR8 gene responsiveness to p53 activation by chemotherapeutic drugs is ...
(A) Graphical location of TLR8 p53-SNP rs3761624 (A/G*) relative to the TSS of the gene and to the p53 Response Element (p53RE). Blinded TLR8 gene (B) and protein (C) expression and (D) p53 occupancy profiles in human lymphocytes after 24 hours of treatment with p53 activators nutlin (10 μM), DXR (1 μM), and IR (4 Gy). Each dot represents a different donor. A total of 27 donors were evaluated for gene and protein expression, and 17 for occupancy. Presented in (E) nutlin, (F) DXR, and (G) IR are the decoded 24-hour results for TLR8 mRNA (n = 25) and protein (n = 25) expression profiles and p53 occupancy (n = 16) grouped by rs3761624 A/G genotypes. The horizontal bars represent the mean values. *P < 0.05; **P < 0.01; ***P < 0.0001 (2-tailed unpaired Student’s t test).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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