Elsevier

Vaccine

Volume 26, Issue 14, 25 March 2008, Pages 1731-1736
Vaccine

Brief report
Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine: Preliminary results

https://doi.org/10.1016/j.vaccine.2008.01.017Get rights and content

Summary

Toll-like receptors (TLRs) represent the critical “bridge” between innate and adaptive immunity to viral pathogens. We hypothesized that single nucleotide polymorphisms (SNPs) that potentially influence the expression/function of TLRs and their associated intracellular signaling molecules contribute to variations in humoral and cellular immunity to measles vaccine. We genotyped 190 randomly selected subjects (12–18 years old), previously vaccinated with two doses of measles, for known SNPs in TLR 2, 3, 4, 5, 6, 7, 8 and 9, and their associated intracellular signaling genes. Specific SNPs in the TLR 2, 3, 4, 5, 6, MyD88 and MD2 genes were associated with measles-specific humoral and cellular immunity. Heterozygous variants for rs3775291 (Phe412Leu) and rs5743305 (−926 bp in promoter region) of the TLR3 gene were associated with low antibody and lymphoproliferative responses (p  0.02) to measles vaccination. Heterozygous variants for rs4986790 (Gly299Asp) and rs4986791 (Ile399Thr) in the TLR4 gene demonstrated higher levels of (p  0.02) IL-4 secretion. Heterozygous variants for SNPs in TLR5 (rs5744174) and TLR6 (rs5743818) were associated with higher levels of (p  0.02) IFN-γ secretion. In addition, SNPs in MyD88 and MD2, intracellular molecules that associate with TLRs, also demonstrated associations with variations in antibody and IL-10 production (p  0.03). Thus, we identified specific SNP associations between TLRs and their associated signaling molecules that have a known role in viral immunity and variations in both humoral and cellular immunity following measles vaccination. These data contribute to understanding the immunogenetic mechanisms underlying variations in the immune response to measles vaccine.

Introduction

Toll-like receptors (TLRs) have emerged as important sensors for viral recognition that act as “bridging molecules” between innate and adaptive immunity [1], [2], [3], [4]. TLRs are able to discriminate between different viruses and bacteria by pathogen-associated molecular patterns (PAMPs) and thereby direct a pathogen specific immune response [2], [5]. Upon stimulation, TLRs trigger a cascade of adaptor and intracellular signaling molecules that lead to induction of innate and adaptive immunity [3], [6].

In recent years, it has been suggested that signaling through TLRs may play a role in measles virus pathogenicity and immunogenicity. Wild-type, but not vaccine strains of measles virus, can activate TLR2 expressing human T cells, which leads to subsequent secretion of proinflammatory cytokines, such as IL-6, and up-regulated surface expression of signaling lymphocyte activation molecule (SLAM) [7]. Wild-type measles virus is also known to suppress TLR4 mediated IL-12 induction in dendritic cells [8]. In contrast, the attenuated strains of measles virus are known to induce the expression of TLR3 via an interferon-dependent mechanism triggered as a part of the host response [9]. Measles virus recognition and specificity by TLRs can be influenced by genetic variations in the interaction domains between virus and host receptors. For example, a single amino acid mutation of asparagine at position 481 to tyrosine in the measles virus hemagglutinin (H) protein abolishes the ability of wild-type measles virus to activate via TLR2 [7]. We hypothesize that genetic variations in the TLRs and their associated signaling molecules, that play an important role in measles virus recognition, could result in variable immune responses to measles vaccination.

Section snippets

Study cohort and immune characterization

Our study subjects (n = 190) were randomly sampled from a previously well-characterized study cohort [10], [11]. Measles virus-specific IgG levels were measured in sera using commercially available Enzygnost anti-masern-virus/IgG enzyme immunoassay (Dade Behring Marburg, Germany) following the manufacturer's instructions [12]. IFN-γ, IL-2, IL-4, IL-10 and IL-12p40 secretion in response to measles virus stimulation was determined in PBMC cultures by ELISA as previously described [13], [14].

Demographic and immunological variables of study cohort

The study cohort was primarily Caucasian (94.2%) with a median age of 15 years and had near even gender representation (males = 54%). Median ages at first and second MMR were 15.6 months and 12 years, respectively. The median (inter-quartile range, IQR) measles-specific IgG response was 1430 (646, 2482) IU/L and for proliferation response as measured in stimulation indices (SI) was 3.5 (2.0, 6.1). The median (IQR) for secreted levels of signature Th1 cytokines (IL-12p40 and IFN-γ) was 7.3 (2.7,

Discussion

The genetic mechanisms underlying measles virus modulation of host immunity in response to vaccination are poorly defined and are under active research. In the present study, we identified significant associations between SNPs in TLRs 3, 4, 5 and 6 and the downstream intracellular signaling molecules, MyD88 and MD2, with variations in both antibody and cellular responses following measles vaccination. The associations between TLR3 and measles vaccine immunity are particularly intriguing as TLR3

Acknowledgements

We thank the parents and children who participated in this study. We acknowledge the efforts of the research fellows, nurses and students from the Mayo Vaccine Research Group. We thank Yanhong Wu, Ph.D. and Julie Cunningham, Ph.D. for assistance with genotyping in the Mayo Advanced Genomic Technology Center. We thank Cheri Hart for editorial assistance.

This work was supported by NIH grants AI 33144, AI 48793 and was made possible by Grant Number 1 UL1 RR024150-01 from the National Center for

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