title: Streptococcus pneumoniae worsens cerebral ischemia via interleukin 1 and platelet glycoprotein Ibα.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary.
authors.forename: Ádám
authors.initials: Á
authors.lastname: Dénes
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Pradillo
authors.forename: Caroline
authors.initials: C
authors.lastname: Drake
authors.forename: Andrew
authors.initials: A
authors.lastname: Sharp
authors.forename: Peter
authors.initials: P
authors.lastname: Warn
authors.forename: Katie N
authors.initials: KN
authors.lastname: Murray
authors.forename: Bazaz
authors.initials: B
authors.lastname: Rohit
authors.forename: David H
authors.initials: DH
authors.lastname: Dockrell
authors.forename: Janet
authors.initials: J
authors.lastname: Chamberlain
authors.forename: Helen
authors.initials: H
authors.lastname: Casbolt
authors.forename: Sheila
authors.initials: S
authors.lastname: Francis
authors.forename: Bernadett
authors.initials: B
authors.lastname: Martinecz
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Rothwell
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Allan
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology*; D018450:Disease Progression; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D007375:Interleukin-1 / Q000009:adverse effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D015539:Platelet Activation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013290:Streptococcal Infections / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology*; D013296:Streptococcus pneumoniae
chemical_list: D007375:Interleukin-1; D019038:Platelet Glycoprotein GPIb-IX Complex