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dc.contributor.authorJahn, Kristin
dc.contributor.authorHandtke, Stefan
dc.contributor.authorPalankar, Raghavendra
dc.contributor.authorWeißmüller, Sabrina
dc.contributor.authorNouailles, Geraldine
dc.contributor.authorKohler, Thomas P
dc.contributor.authorWesche, Jan
dc.contributor.authorRohde, Manfred
dc.contributor.authorHeinz, Corina
dc.contributor.authorAschenbrenner, Axel F
dc.contributor.authorWolff, Martina
dc.contributor.authorSchüttrumpf, Jörg
dc.contributor.authorWitzenrath, Martin
dc.contributor.authorHammerschmidt, Sven
dc.contributor.authorGreinacher, Andreas
dc.identifier.citationBlood Adv. 2020 Dec 22;4(24):6315-6326. doi: 10.1182/bloodadvances.2020002372.en_US
dc.description.abstractCommunity-acquired pneumonia by primary or superinfections with Streptococcus pneumoniae can lead to acute respiratory distress requiring mechanical ventilation. The pore-forming toxin pneumolysin alters the alveolar-capillary barrier and causes extravasation of protein-rich fluid into the interstitial pulmonary tissue, which impairs gas exchange. Platelets usually prevent endothelial leakage in inflamed pulmonary tissue by sealing inflammation-induced endothelial gaps. We not only confirm that S pneumoniae induces CD62P expression in platelets, but we also show that, in the presence of pneumolysin, CD62P expression is not associated with platelet activation. Pneumolysin induces pores in the platelet membrane, which allow anti-CD62P antibodies to stain the intracellular CD62P without platelet activation. Pneumolysin treatment also results in calcium efflux, increase in light transmission by platelet lysis (not aggregation), loss of platelet thrombus formation in the flow chamber, and loss of pore-sealing capacity of platelets in the Boyden chamber. Specific anti-pneumolysin monoclonal and polyclonal antibodies inhibit these effects of pneumolysin on platelets as do polyvalent human immunoglobulins. In a post hoc analysis of the prospective randomized phase 2 CIGMA trial, we show that administration of a polyvalent immunoglobulin preparation was associated with a nominally higher platelet count and nominally improved survival in patients with severe S pneumoniae-related community-acquired pneumonia. Although, due to the low number of patients, no definitive conclusion can be made, our findings provide a rationale for investigation of pharmacologic immunoglobulin preparations to target pneumolysin by polyvalent immunoglobulin preparations in severe community-acquired pneumococcal pneumonia, to counteract the risk of these patients becoming ventilation dependent. This trial was registered at as #NCT01420744.en_US
dc.publisherAmerican Society of Hematologyen_US
dc.rightsAttribution 4.0 International*
dc.titlePneumolysin induces platelet destruction, not platelet activation, which can be prevented by immunoglobulin preparations in vitro.en_US
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalBlood advancesen_US
dc.source.journaltitleBlood advances
dc.source.countryUnited States

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Attribution 4.0 International
Except where otherwise noted, this item's license is described as Attribution 4.0 International