The role of Toll-like receptor-4 in pertussis vaccine-induced immunity

<p>Abstract</p> <p>Background</p> <p>The gram-negative bacterium <it>Bordetella pertussis </it>is an important causative agent of pertussis, an infectious disease of the respiratory tract. After introduction of whole-cell vaccines (wP) in the 1950's, pertussis incidence has decreased significantly. Because wP were found to be reactogenic, in most developed countries they have been replaced by acellular vaccines (aP). We have previously shown a role for Toll-like receptor 4 (Tlr4) in pertussis-infected mice and the pertussis toxin (Ptx)-IgG response in wP-vaccinated children, raising the issue of the relative importance of Tlr4 in wP vaccination of mice. Here we analyze the effects of wP and aP vaccination and <it>B. pertussis </it>challenge, in <it>Tlr4</it>-deficient C3H/HeJ and wild-type C3H/HeOuJ mice. aP consists of Ptx, filamentous hemagglutinin (FHA), and pertactin (Prn).</p> <p>Results</p> <p>We show an important role of Tlr4 in wP and (to a lesser extent) aP vaccination, induction of Th1 and Th17 cells by wP but not aP vaccination, and induction of Th17 cells by infection, confirming data by Higgins et al. (<it>J Immunol </it>2006, <b>177:</b>7980–9). Furthermore, in <it>Tlr4</it>-deficient mice, compared to wild-type controls (i) after vaccination only, Ptx-IgG (that was induced by aP but not wP vaccination), FHA-IgG, and Prn-IgG levels were similar, (ii) after infection (only), lung IL-1α and IL-1β expression were lower, (iii) after wP vaccination and challenge, Prn-IgG level and lung IL-5 expression were higher, while lung IL-1β, TNF-α, IFN-γ, IL-17, and IL-23 expression were lower, and lung pathology was absent, and (iv) after aP vaccination and challenge, Prn-IgG level and lung IL-5 expression were higher, while Ptx-IgG level was lower.</p> <p>Conclusion</p> <p>Tlr4 does not influence the humoral response to vaccination (without challenge), plays an important role in natural immunity, wP and aP efficacy, and induction of Th1 and Th17 responses, is critical for lung pathology and enhances pro-inflammatory cytokine production after wP vaccination and challenge, and diminishes Th2 responses after both wP and aP vaccination and challenge. wP vaccination does not induce Ptx-IgG. A role for LPS in the efficacy of wP underlines the usefulness of LPS analogs to improve bacterial subunit vaccines such as aP.</p

Association of Interacting Genes in the Toll-Like Receptor Signaling Pathway and the Antibody Response to Pertussis Vaccination

BACKGROUND: Activation of the Toll-like receptor (TLR) signaling pathway through TLR4 may be important in the induction of protective immunity against Bordetella pertussis with TLR4-mediated activation of dendritic and B cells, induction of cytokine expression, and reversal of tolerance as crucial steps. We examined whether single nucleotide polymorphisms (SNPs) in genes of the TLR4 pathway and their interaction are associated with the response to whole-cell vaccine (WCV) pertussis vaccination in 490 one-year-old children. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed associations of 75 haplotype-tagging SNPs in genes in the TLR4 signaling pathway with pertussis toxin (PT)-IgG titers. We found significant associations between the PT-IgG titer and SNPs in CD14, TLR4, TOLLIP, TIRAP, IRAK3, IRAK4, TICAM1, and TNFRSF4 in one or more of the analyses. The strongest evidence for association was found for two SNPs (rs5744034 and rs5743894) in TOLLIP that were almost completely in linkage disequilibrium, provided statistically significant associations in all tests with the lowest p-values, and displayed a dominant mode of inheritance. However, none of these single gene associations would withstand correction for multiple testing. In addition, Multifactor Dimensionality Reduction Analysis, an approach that does not need correction for multiple testing, showed significant and strong two and three locus interactions between SNPs in TOLLIP (rs4963060), TLR4 (rs6478317) and IRAK1 (rs1059703). CONCLUSIONS/SIGNIFICANCE: We have identified significant interactions between genes in the TLR pathway in the induction of vaccine-induced immunity. These interactions underline that these genes are functionally related and together form a true biological relationship in a protein-protein interaction network. Practically all our findings may be explained by genetic variation in directly or indirectly interacting proteins at the extra- and intracytoplasmic sites of the cell membrane of antigen-presenting cells, B cells, or both. Fine tuning of interacting proteins in the TLR pathway appears important for the induction of an optimal vaccine response

Comparative gene expression profiling in two congenic mouse strains following <it>Bordetella pertussis </it>infection

<p>Abstract</p> <p>Background</p> <p>Susceptibility to <it>Bordetella pertussis </it>infection varies widely. These differences can partly be explained by genetic host factors. HcB-28 mice are more resistant to <it>B. pertussis </it>infection than C3H mice, which could partially be ascribed to the <it>B</it>. <it>pertussis susceptibility locus-1 </it>(<it>Bps1</it>) on chromosome 12. The presence of C57BL/10 genome on this locus instead of C3H genome resulted in a decreased number of bacteria in the lung. To further elucidate the role of host genetic factors, in particular in the <it>Bps1 </it>locus, in <it>B. pertussis </it>infection, and to identify candidate genes within in this region, we compared expression profiles in the lungs of the C3H and HcB-28 mouse strains following <it>B. pertussis </it>inoculation. Twelve and a half percent of the genomes of these mice are from a different genetic background.</p> <p>Results</p> <p>Upon <it>B. pertussis </it>inoculation 2,353 genes were differentially expressed in the lungs of both mouse strains. Two hundred and six genes were differentially expressed between the two mouse strains, but, remarkably, none of these were up- or down-regulated upon <it>B. pertussis </it>infection. Of these 206 genes, 17 were located in the <it>Bps1 </it>region. Eight of these genes, which showed a strong difference in gene expression between the two mouse strains, map to the immunoglobulin heavy chain complex (<it>Igh</it>).</p> <p>Conclusion</p> <p>Gene expression changes upon <it>B. pertussis </it>infection are highly identical between the two mouse strains despite the differences in the course of <it>B. pertussis </it>infection. Because the genes that were differentially regulated between the mouse strains only showed differences in expression before infection, it appears likely that such intrinsic differences in gene regulation are involved in determining differences in susceptibility to <it>B. pertussis </it>infection. Alternatively, such genetic differences in susceptibility may be explained by genes that are not differentially regulated between these two mouse strains. Genes in the <it>Igh </it>complex, among which <it>Igh-1a/b</it>, are likely candidates to explain differences in susceptibility to <it>B. pertussis</it>. Thus, by microarray analysis we significantly reduced the number of candidate susceptibility genes within the <it>Bps1 </it>locus. Further work should establish the role of the <it>Igh </it>complex in <it>B. pertussis </it>infection.</p

Toll-like receptor 4 polymorphism associated with the response to whole-cell pertussis vaccination in children from the KOALA study

We examined the association between haplotype tagging single-nucleotide polymorphisms in TLR4 and the pertussis toxin-specific immunoglobulin G response after whole-cell pertussis (wP) vaccination in 515 1-year-old children from the KOALA study. A lower titer was associated with the minor allele of rs2770150, supporting a role for Toll-like receptor 4 in the antibody response to wP vaccination

Influence of <i>TOLLIP</i> and <i>TRL4</i> and their interaction on log PT-IgG titers.

<p>Influence of <i>TOLLIP</i> (rs4963060) and <i>TLR4</i> (rs6478317) interaction on log PT-IgG titers following pertussis vaccination in a dominant model of inheritance. The presence of one or two minor alleles of one of these SNPs, but not the presence of one or two minor alleles of both SNPs, was associated with a lower PT-IgG titer. 0, 1, and 2 represent the number of minor alleles. * Significantly different from the group homozygous for the wild-type alleles (<i>p</i> = 0.04). <i>P</i> interaction term = 0.01. Vertical bars indicate standard errors.</p

Results of gene-gene interactions analyzed by MDR.

a<p>Average testing balanced accuracy is the accuracy of classification of cases and controls in the testing dataset (one-tenth of the data) calculated as (Sensitivity+Specificity)/2.</p>b<p>Average cross validation consistency is the number of times the model was selected as the best model after 10-fold cross-validation runs.</p>c<p>Significance of accuracy (empirical <i>p</i>-value based on 1000 permutations).</p

Influence of single-nucleotide polymorphisms (SNPs) on vaccine-induced PT-immunoglobulin G titers.

<p>Influence of single-nucleotide polymorphisms (SNPs) on vaccine-induced PT-immunoglobulin G titers.</p