Streptococcus pneumoniae worsens cerebral ischemia via interleukin 1 and platelet glycoprotein Ibα

Adam Denes, Jesus Pradillo, Caroline Drake, Andrew Sharp, Peter Warn, Katie N. Murray, Bazaz Rohit, David H. Dockrell, Janet Chamberlain, Helen Casbolt, Sheila Francis, Bernadett Martinecz, Bernhard Nieswandt, Nancy J. Rothwell, Stuart M. Allan

Research output: Contribution to journalArticlepeer-review


Objective Bacterial infection contributes to diverse noninfectious diseases and worsens outcome after stroke. Streptococcus pneumoniae, the most common infection in patients at risk of stroke, is a major cause of prolonged hospitalization and death of stroke patients, but how infection impacts clinical outcome is not known. Methods We induced sustained pulmonary infection by a human S. pneumoniae isolate in naive and comorbid rodents to investigate the effect of infection on vascular and inflammatory responses prior to and after cerebral ischemia. Results S. pneumoniae infection triggered atherogenesis, led to systemic induction of interleukin (IL) 1, and profoundly exacerbated (50-90%) ischemic brain injury in rats and mice, a response that was more severe in combination with old age and atherosclerosis. Systemic blockade of IL-1 with IL-1 receptor antagonist (IL-1Ra) fully reversed infection-induced exacerbation of brain injury and functional impairment caused by cerebral ischemia. We show that infection-induced systemic inflammation mediates its effects via increasing platelet activation and microvascular coagulation in the brain after cerebral ischemia, as confirmed by reduced brain injury in response to blockade of platelet glycoprotein (GP) Ibα. IL-1 and platelet-mediated signals converge on microglia, as both IL-1Ra and GPIbα blockade reversed the production of IL-1α by microglia in response to cerebral ischemia in infected animals. Interpretation S. pneumoniae infection augments atherosclerosis and exacerbates ischemic brain injury via IL-1 and platelet-mediated systemic inflammation. These mechanisms may contribute to diverse cardio- and cerebrovascular pathologies in humans. © 2014 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
Original languageEnglish
Pages (from-to)670-683
Number of pages13
JournalAnnals of Neurology
Issue number5
Publication statusPublished - May 2014


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