Brief reportAssociations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine: Preliminary results☆
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.
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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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2019, VacunasCitation Excerpt :Dhiman et al.,27 with 190 randomly selected subjects from a 346 heathy children cohort, previously recruited by the Mayo Vaccine Research Group, analyzed the genetic association of 96 SNPs in 17 candidate genes that included TLRs genes and genes involved in TLR-intracellular signaling. In this study, the authors reported significant associations between two TLR4 coding SNPs (rs4986790 and rs4986791) and measles specific IL4 secretion (p = 0.02 and p = 0.009 respectively) measured in cultured peripheral blood leukocytes.27 A second study of the same group,28 in a larger cohort of 764 subjects, analyzed 385 SNPs in 26 candidate genes involved in vaccine response.
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This work was partially presented at the 44th Meeting of Infectious Diseases Society of America, Toronto, Ontario, Canada, October 12–15, 2006, Abstract#1085.