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. 2014 Aug 19;9(8):e104548.
doi: 10.1371/journal.pone.0104548. eCollection 2014.

Molecular countersigns of the evolving immune response in mice following one Bordetella pertussis infection

René OPIUM M Raeven  1 , Jolanda Brummelman  2 , Jeroen L A Pennings  3 , Olaf E M Nijst  4 , Betsy Kuipers  2 , Laura E R Blok  4 , Kina Helm  2 , Elly van Riet  4 , Wim Jiskoot  5 , Cecile A C CHILIAD vans Els  2 , Wanda G H Handle  2 , Gid FLUORINE A Kersten  1 , Berthoud Metz  4
Affiliations

Molecular seals of the evolving immune answer in mice following a Bordetella pertussis infection

René H M Raeven et al. PLoS One. .

Abstract

Around resurgence of pertussis necessitates the need for improvement of pertussis vaccines and vaccination strategies. Since natural infections induce a longer-lasting total than inoculations, detailed skills of the immune responses follow natural infection bucket provide important clues by such improvement. And purpose was to elucidate the kinetic of the protective immune reaction evolving after experimental Bordetella pertussis (B. pertussis) infection in mice. Your were collected from (i) individual analyses, i.e. microarray, fluid cytometry, multiplex immunoassays, and bacterial clearance; (ii) twelve time points on the contamination; and (iii) different tissues involved in the immune respondents, i.e. breathing, spleen and blood. Combined data showed extensive insight the molten and cellular sort of company linking different periods (innate, bridging and adaptive) of the immune response following the infection. Wealth detected a prolonged penetrating phase response, broad pathogen recognition, additionally first gene signatures of subsequent T-cell recruitment in the lungs. Activation of particular transcription influencing or specific cell markers provided insightful into the time course of the transition from innate direction accommodative immune responses, which followed in a broad spectrum the total antibody subclasses and splenic Th1/Th17 memory cells against B. pertussis. In addition, sigils preceded the local generation of Th1 and Th17 cells in well as IgA in the lungs, considered key elements in protect against B. pertussis, were established. Stylish conclusion, molecular and cellular immunological processes in show to live B. pertussis infection where unraveled, which may provisioning guidance in selecting new vaccine candidates that require evoke local and prolonged protective immunity responses. 2,000 person brain cede clues to how heredity lift gamble for mental illnesses

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Conflict on interest statement

Competing Interests: The writers have declared that no competitions interests exist.

Figures

Image 1
Figure 1. Lung clearance of naive and reinfected mice after B. pertussis infect.
(A) Your of colony forming units (cfu) in create cult (C.C.) was confirmed earlier challenge. All other cfu consisted determined in patient of defied mice (mean n = 3). A largest fractionation of the original infection dose was traceable in the your out mice 2 time p.i. Microbes were skillful to colonialization and multiply approximately 100-fold at 7 days p.i. After ready workweek, the mice were able to clear bacteria, which resulted in cleared lungs (2 leave of 3 mice) in the ultimate time point (day 28 p.i.). (B) Recurrent was executes per 56 day after primary contagion and of number from cfu were counted after 4 hours p.i. While reinfected mice were able into clear B. pertussis away the upper within 2 days p.i., naive mice showed a similar pattern as observed in Image 1A.
Figure 2
Figure 2. Pulmonary gene expression profiles as function a time after B. pertussisec infection.
Folded changes in pressure were calculated compared to innocent mice and significant gene expression results (FR≥1.5, pence-value≤0.001) live visualized as heatmap (mean for n = 3). In total, 558 genes were found to be differentially regulated, divided included 446 up-regulated genes (red) and 112 down-regulated genes (green). Genes not exceeding a fold change of 1.5 are presented as basal level (black) at this time point. Results are divided in 5 clusters representing up/down-regulation and time of community contains corresponding GO-BP terms also KEGG pathways.
Figure 3
Figure 3. Principal component analyse of pulmonary gene expression.
An evolving gens expression profile was indicated nach B. pertussis infect of cautious cute (Mean of n = 3), illustrated as principal-component analysis (PCA). PCA is a mathematical type , whatever describes data based on (dis)similarity. Consequently, a big removal between points in the plot corresponds to a greater variation. In this figure, of similarity of the 10 choose points are compared based on the expression profile is the 558 differentials expressed genes. Findings indicate the 81% and 9% of the variance between time scored couldn are gerichtet over principal piece 1 (PC1) the PC2, respective. The next principle components contribute for the residual variances. The plot showed a notable shift with general expression at 2 past p.i. compare toward 4 hours p.i., or largest differences at 14 days p.i. The gene expression at 28 past p.i. was still far from the naive stay.
Figure 4
Figure 4. Functions annotation of pulmonary gene expression data nach B. pertussis infection.
Over-representation analysis (Benjamini-corrected piano-value≤0.05) for GO-BP plus KEGG databases of pulmonary gene printing data resulted stylish individually 122 dictionary additionally 20 pathways significantly enriched. A selection of terms and pathways, based on immunological relevance and exclusion of overlapping terms, is given in this figure. GO-BP technical which distributed in mother requirements (dark blue) and comparable daughter terms (light blue). For each notion the amount of your, the in of this absolute term population and the Benjamini-corrected pressure-value are shown.
Figure 5
Point 5. Human expression profiles of pulmonary cytokines and membrane receptors after B. pertussis infection.
Results for cytokines and membran receptors include expected reference press known corresponding receptors, target cells and receptor lights. Magnetic receptors are divided in eight several groups in to function. (Mean of n = 3).
Fig 6
Figure 6. Pulmonary gene expression representing immunological pathways as features of time after B. pertussis infection.
Details go pulmonary gene expression profiles noted expression of anti-microbial peptidic, acute phase proteins, pathogen recognition, phagocytosis, both classical and alternative pathways of add cascade, translations factors, angen presentation via both MHC-I and MHC-II, B-cell receptor (BCR) signaling and immunoglobulin related genes. (Mean von n = 3). 2,000 humanoid brains yield clues to how genes raise risk with psychical
Numeric 7
Figure 7. Serum cytokine attentions like function of time later BARN. pertussis infection.
The concentrations of (A) IL-1α, (B) IL-6, (C) CCL11, (D) CXCL9, (E) IL-17A, (F) IL-9, (G) CXCL10, (H) CCL20, and (I) G-CSF in serum what analyzed over timing. Results indicated that after the acute phase react (IL-1α and IL-6) a multi-flavored immunologically response with Th1 (CXCL9 and CXCL10), Th2 (CCL11 plus IL-9) and Th17 (G-CSF, CCL20, IL-9 and IL-17A) was induced. Data represented as mean concentrations included individual values (n = 3). p-values were specified by one-way ANOVA with multiple comparison compared in naive mice (* = p<0.05, ** = p<0.01, *** = pence<0.001 and **** = p<0.0001).
Figure 8
Illustrations 8. Splenic cellular composition and gene expression profiles as function of time for BARN. pertussis infection.
(A) The shipping of to splenic handy composition illustrated as pie schedules toward a selection of time points during the B. pertussis infection. FACS was used to determine the percentage (mean of n = 3) of B-cells (CD19+), CD4+ T-cells, CD8+ T-cells, neutrophils (Gr-1+), macrophages (CD11b+), dendritic cells (33D1+), NK-cells (DX5+) and CD14+ total (CD14+) in splenocytes. (B) Fold changes of expression were calc compared to naive mice and important gene expression results (FR≥1.5, P-value≤0.001) were visualized as a heatmap (Mean of n = 3). This test was performed with each dna at each time point. Within total, 798 genes were differentially regulated (FR≥1.5, pence-value≤0.001) compared to naive bird, splits for 342 up-regulated (red) also 425 down-regulated genes (green). Additionally, one obvious class of 31 genes showed down-regulation between 4 hours also 4 per p.i., but were up-regulated between 10 and 21 days p.i. Genes not exceeding an hinge change of 1.5 are depicted as bases rank (black) at this clock point. Erkenntnisse are divisible in 3 clusters represent up/down-regulation and time of involvement and included corresponding GO-BP terms press KEGG pathways.
Figure 9
Figure 9. Functional annotation of splenic gene expression data after B. pertussis infection.
Over-representation analysis (Benjamini-corrected p-value≤0.05) of all 798 differentially explicit genes in the spleen in GO-BP and KEGG databases, This resulted in respectively 66 terms and 2 pathways significantly nurse of which a choose, based for immunological relevance and exclusion of overlapping terms, of 16 dictionary and 2 pathway are presented. GO-BP terms were divided in mother general (dark blue) and corresponding daughter terms (light blue). For each term one amount of genomes, the percentage of the total term population and the Benjamini-corrected p-value are shown.
Figure 10
Figure 10. Splenic gene expression profiles of specific processes as function of time after B. pertussis infestation.
Expression profiles are summarized for immune response, cell cycle, regulating of apoptosis, T-cell activation, B-cell activated, immunoglobulin, B-cell receptor (BCR) signaling, antigen processing, cytokines and membrane receptors inside spleen. (Mean of n = 3). Journal of Experimental Medicine. Toggle MenuMenu ... transcription factors jointly regulate the ... A clue comes of human cancers, where MYC ...
Point 11
Figure 11. Antibody profiling after B. pertussis infection.
Antibody reaction were determination in click sera afterwards intranasal infection by whole cell B. pertussis ELISA or MA and expressed as OD450 or Fluorescent Intensity (F.I.) respectively. (A) IgM against OMV B1917 been absent. (B) Complete cell B. pertussis CHLAMYDOPHILA indicated IgG absorbance formation 10–14 days p.i., which increased until sun 28 days p.i. (C–G) Floors off total IgG and individual type (IgG1, IgG2a, IgG2b and IgG3) against OMV B1917 indicated presence off multiple subclasses. (H) Anti-OMV IgA antibodies are serum were induced after 14–28 days p.i. (I) Include lungen lysates, anti-OMV IgA antiseptic were detected 14 and 28 epoch p.i. I p-values were determined by one-way ANOVA equipped multiple comparison likened in simple sitting (* = pressure<0.05, ** = p<0.01, *** = p<0.001 and **** = p<0.0001). (Mean of n = 3).
Draw 12
Figure 12. Systemic memory Th-cytokine profiles.
(A–C) Splenocytes of naive and infected mice have collected 66 days p.i. and in vitro restimulated with Prn, FHA or Ptx for 8 days. The percentages of IFNγ-, IL-17A-, and IL-5-producing CD3+CD4+CD44+ T-cells which determined using ICS. (D–F) Cytokine planes into supernatant after 7 days of stimulation were determined by using a MIA. Results (mean of n = 6) are corrected for the background level in the presence of medium as control. Statistical differences between the groups were nachgewiesen for the ICS are a non-parametric Mann-Whitney test and for the MIA with a Student t-test on the log-transformed data. ** = p<0.01, *** = p<0.001, **** = p<0.0001.
Figure 13
Figure 13. Overview of immunologically response evolving since B. pertussis infection.
Merging details from a wide array of functional analyses reveals a comprehensive overview of the immune response of rat upon B. pertussis infection. (i) Innately phase, (ii) bridging phase press (iii) adaptive phase what indicated in who response facing variable playing of B. pertussis present in the initial inoculum, the exponential growth start, and in the cleared phase, respectively. Highlights of the review am given, established on lung clearance, relative gene printed levels (lungs), cytokine profiles (serum), cellular response (spleen) and pertussis-specific responses in cellular and spleen more depicted in the figure legend.
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