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 Because wP were found to be reactogenic, in most developed countries they have been replaced by acellular vaccines (aP).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

Lung response to Bordetella pertussis infection in mice identified by gene-expression profiling

Host genetics determines the course of Bordetella pertussis infection in mice. Previously, we found four loci, Tlr4 and three novel loci, designated Bps 1–3, that are involved in the control of B. pertussis infection. The purpose of the present study was to identify candidate genes that could explain genetic differences in the course of B. pertussis infection, assuming that such genes are differentially regulated upon infection. We, therefore, studied the course of mRNA expression in the lungs after B. pertussis infection. Of the 22,000 genes investigated, 1,841 were significantly differentially expressed with 1,182 genes upregulated and 659 genes downregulated. Upregulated genes were involved in immune-related processes, such as the acute-phase response, antigen presentation, cytokine production, inflammation, and apoptosis, while downregulated genes were mainly involved in nonimmune processes, such as development and muscle contraction. Pathway analysis revealed the involvement of granulocyte function, toll-like receptor signaling pathway, and apoptosis. Nine of the differentially expressed genes were located in Bps-1, 13 were located in Bps-2, and 62 were located in Bps-3. We conclude that B. pertussis infection induces a wide and complex response, which appears to be partly specific for B. pertussis and partly nonspecific. We envisage that these data will be helpful in identifying polymorphic genes that affect the susceptibility and course of B. pertussis infection in humans

The role of Toll-like receptor-4 in pertussis vaccine-induced immunity-0

Injected with 1/5 human dose (HD) wP, aP, or adjuvant (C), twice before intranasal infection. Three and seven days after challenge lungs were excised, and the number of viable was determined in right lung lobes. Each symbol represents the number of bacteria in the lung of an individual mouse; horizontal lines represent the group average. Non-boxed -values: compared to the indicated treatment group (same strain and day after infection). Boxed -values: compared to the wild-type strain (same treatment and day after infection). ANOVA followed by Bonferroni post-hoc test. A single representative experiment of 2 is shown.<p><b>Copyright information:</b></p><p>Taken from "The role of Toll-like receptor-4 in pertussis vaccine-induced immunity"</p><p>http://www.biomedcentral.com/1471-2172/9/21</p><p>BMC Immunology 2008;9():21-21.</p><p>Published online 22 May 2008</p><p>PMCID:PMC2409298.</p><p></p

The role of Toll-like receptor-4 in pertussis vaccine-induced immunity-1

Uvant (C), twice before intranasal infection. Two hours before challenge, and three and seven days after challenge blood was taken. Test and positive control sera were tested for Ptx-, FHA-, and Prn-specific IgG. Each symbol represents the serum level of an individual mouse; horizontal lines represent the group average. (#) increased compared to the adjuvant control (same strain and time point; < 0.001), (+) increased compared to wP-vaccinated mice (same strain and time point; < 0.001). Non-boxed -values: compared to the indicated group (same strain and time point), boxed -values: compared to the wild-type strain (same treatment and time point), and stippled-boxed P-values: compared to the pre-challenge level (same strain and treatment). ANOVA followed by Bonferroni post-hoc test. A single representative experiment of 2 is shown.<p><b>Copyright information:</b></p><p>Taken from "The role of Toll-like receptor-4 in pertussis vaccine-induced immunity"</p><p>http://www.biomedcentral.com/1471-2172/9/21</p><p>BMC Immunology 2008;9():21-21.</p><p>Published online 22 May 2008</p><p>PMCID:PMC2409298.</p><p></p

The role of Toll-like receptor-4 in pertussis vaccine-induced immunity-5

Injected with 1/5 human dose (HD) wP, aP, or adjuvant (C), twice before intranasal infection. Three and seven days after challenge lungs were excised, and the number of viable was determined in right lung lobes. Each symbol represents the number of bacteria in the lung of an individual mouse; horizontal lines represent the group average. Non-boxed -values: compared to the indicated treatment group (same strain and day after infection). Boxed -values: compared to the wild-type strain (same treatment and day after infection). ANOVA followed by Bonferroni post-hoc test. A single representative experiment of 2 is shown.<p><b>Copyright information:</b></p><p>Taken from "The role of Toll-like receptor-4 in pertussis vaccine-induced immunity"</p><p>http://www.biomedcentral.com/1471-2172/9/21</p><p>BMC Immunology 2008;9():21-21.</p><p>Published online 22 May 2008</p><p>PMCID:PMC2409298.</p><p></p

The role of Toll-like receptor-4 in pertussis vaccine-induced immunity-2

Uvant (C), twice before intranasal infection. Two hours before challenge, and three and seven days after challenge mice were weighed. Data are indicated as mean ± SEM (N = 6). Non-boxed -values: compared to the adjuvant control (same strain and day after challenge). Boxed -value: compared to the wild-type strain (same treatment and day after challenge). ANOVA followed by Bonferroni post-hoc test. A single representative experiment of 2 is shown.<p><b>Copyright information:</b></p><p>Taken from "The role of Toll-like receptor-4 in pertussis vaccine-induced immunity"</p><p>http://www.biomedcentral.com/1471-2172/9/21</p><p>BMC Immunology 2008;9():21-21.</p><p>Published online 22 May 2008</p><p>PMCID:PMC2409298.</p><p></p

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