Proposed modulation of the fibrinolytic system by schistosomes.

<p>The fibrinolytic system inhibits blood coagulation through degradation of the formed fibrin clot by plasmin. Plasminogen is cleaved to plasmin by plasma kallikrein, but mainly by t-PA and urokinase, which are inhibited by PAI-1 and PAI-2. Furthermore, plasmin activity is inhibited by TAFI. Schistosomes may stimulate fibrinolysis by the presence of enolase, GAPDH, and annexin, which bind plasminogen and facilitate its conversion to plasmin by t-PA. Green arrows indicate stimulation. Inhibition is indicated by the red lines. Schistosome proteins are denoted in the shaded box. Abbreviations: tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1) and 2 (PAI-2), thrombin-activatable fibrinolysis inhibitor (TAFI), glyceraldehyde-3-phosphate dehydrogenase (GAPDH).</p

Proposed interference with the haemostatic system and vascular tone by schistosome molecules.

<p>Proposed interference with the haemostatic system and vascular tone by schistosome molecules.</p

Proposed modulation of secondary haemostasis and vascular tone by schistosomes.

<p>Secondary haemostasis can be activated through two different pathways: either by the presence of TF or by contact of coagulation factors with collagen, pathogens, or other negatively charged surfaces. This triggers a cascade of cleavage reactions, ultimately leading to the cleavage of fibrinogen to fibrin and the formation of a stable fibrin clot. This process is regulated by antithrombin, TFPI, and protein C. Schistosomes potentially interfere with secondary haemostasis at several steps in the cascade. Schistosome whole worm homogenate blocks the conversion of XII to XIIa and inhibits the actions of XIIa. The proteolytic activity of thrombin is inhibited by the schistosome antigen Sm22.6. Furthermore, schistosome heparin-like glycosaminoglycans may enhance the activity of antithrombin and, possibly, TFPI, and the schistosome serpin SHW 4-2 might mimic human antithrombin. The vascular tone can be influenced by schistosomes through the production of both vasodilating and vasoconstricting eicosanoids and the presence of sK1 and SmSP1 that could potentially convert HMWK into the vasodilator bradykinin. The green arrows indicate stimulation. Inhibition is indicated by the red lines. The shaded boxes indicate schistosome proteins. Abbreviations: activated coagulation factor XII (XIIa), coagulation factor XII (XII), High-molecular-weight kininogen (HMWK), tissue factor (TF), tissue factor pathway inhibitor (TFPI).</p

DataYETI10

The data are percentages of Tetramer+ YFV-specific CD8+ T cells prospectively in primary vaccinated individuals as well as in primo vs. boosted individuals, and the antibodies for all volunteers in IU/mL

Correlation between YF-Antibody titers in 99 individuals that received a single vaccination and time since vaccination.

<p>The y-axis shows the time since vaccination and the x-axis shows the YF-serum antibody titer. The correlation between serum titer and time since vaccination was calculated with Spearman’s Rank Correlation coefficient. As a reference, the red line depicts the YF antibody serum level threshold of protection (0.5 IU/mL).</p

Frequency of YF-tetramer positive CD8⁺ T-cells in 6 singly vaccinated individuals (one individual (# 10) had 2 tetramer compatible HLA types, therefore seven lines are depicted).

<p>A. Dot plots of a representative donor B. Frequency of YF-tetramer⁺CD8⁺ T-cells expressed as percentage of YF-tetramer positive CD8⁺ T-cells directed against the NS2b, NS4b and NS5 epitopes in HLA-B35, HLA-A02 and HLA-B07 positive individuals at days 0, 3, 5, 12, 28 and 180 after vaccination.</p

Percentages of YF-tetramer positive CD8⁺ T-cells over time in 13 healthy individuals that received a single vaccination of whom 11 were HLA A02, 2 HLA B27, 1 HLA B35 and 1 HLA B07 (2 donors had 2 HLA types compatible with tetramer reactivity).

<p>Seven donors, 3 HLA A02, 2 HLA B07 and 2 HLA B35 had received a booster vaccination. On the x-axis the number of years since last vaccination until PBMC collection is shown. On the y-axis the percentage of YF-tetramer⁺ cells gated on total CD8⁺ T cells is shown. Black, closed symbols depict single vaccinated individuals; red, open symbols depict boosted individuals. In 4 donors tetramer⁺ CD8⁺ T cells could not be detected directly ex-vivo but only after in vitro expansion by culturing for 9 days in the presence of IL-2 and a YF-peptide pool. Analysis of the correlation between YF-tetramer⁺ CD8+ T cells of singly vaccinated HLA-A2⁺ donors and time since vaccination showed a significant negative correlation (r = -0.76, p = 0.0086, Spearman’s Rank Correlation Coefficient).</p

Longitudinal analysis of T-bet eomes expression in singly vaccinated individuals.

<p>A Dot plots of a representative donor. Total CD8⁺ T-cells are depicted in grey and YF-tetramer positive CD8⁺ T-cells in black. B-C T-bet:Eomes ratios on days 12, 28 and 180 in CD8⁺ tetramer⁺ cells. D Correlation between Granzyme K and Eomes expression and Granzyme B and Tbet expression on days 12, 28 and 180 after vaccination. E. T-bet:Eomes ratios of YF-tetramer positive at T = 180 in different subsets. Comparisons were performed with a paired Wilcoxon Rank sum test. ns = not significant.</p

Longitudinal analysis of the phenotype of YF-tetramer positive CD8⁺ T-cells on days 12, 28 and 180 in singly vaccinated individuals.

<p>A Dot plots of a representative donor. Cells are gated on total CD8⁺ T-cells (in grey) and YF-tetramer positive cells (in black). B-D Summary of percentages of tetramer positive cells expressing CD45RA, CD27, granzyme K, granzyme B and Ki67 in 6 donors (1 donor had 2 matching HLA types). Comparisons were performed with a paired Wilcoxon Rank sum test. ns = not significant.</p

Place of exposure and place of diagnosis (arrows) of GeoSentinel Zika patients from Africa (green dot), Asia (red dots), and the Pacific (blue dots)—Circular arrows indicate cases in international travelers who contracted Zika while abroad and were diagnosed in the country of exposure while traveling.

<p>Linear arrows indicate cases in international travelers who contracted Zika while abroad and had their diagnosis confirmed on returning to their home country.—Base map is available free of charge from <a href="http://www.histgeo.ac-aix-marseille.fr/ancien_site/carto/" target="_blank">http://www.histgeo.ac-aix-marseille.fr/ancien_site/carto/</a>.</p