Hepatitis C reference viruses highlight potent antibody responses and diverse viral functional interactions with neutralising antibodies.
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Authors
Bankwitz, DorotheaBahai, Akash
Labuhn, Maurice
Doepke, Mandy
Ginkel, Corinne
Khera, Tanvi
Todt, Daniel
Ströh, Luisa J
Dold, Leona
Klein, Florian
Klawonn, Frank

Krey, Thomas
Behrendt, Patrick
Cornberg, Markus
McHardy, Alice C
Pietschmann, Thomas
Issue Date
2020-12-15
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Show full item recordAbstract
Community-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 www.clinicaltrials.gov as #NCT01420744.Citation
Gut. 2020 Dec 15:gutjnl-2020-321190. doi: 10.1136/gutjnl-2020-321190. Epub ahead of print.Affiliation
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.Publisher
BMJ Publisher. GroupJournal
GutPubMed ID
33323394Type
ArticleLanguage
enEISSN
1468-3288ae974a485f413a2113503eed53cd6c53
10.1136/gutjnl-2020-321190
Scopus Count
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- Creative Commons
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