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

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

doi:10.1002/ana.24146

Abstract

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. 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. 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. 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.

Highlights

We present evidence that sustained pulmonary S. pneumoniae infection, the most common cause of bacterial community-acquired pneumonia, generates an IL-1– mediated systemic inflammatory response involving granulocytosis and platelet activation that accelerates atherogenesis and leads to cerebrovascular inflammation
There is clinical evidence to show that S. pneumoniae contributes to atherogenesis,[11,12] the efficacy of antibiotic treatment on heart disease is controversial.[32]
No experimental studies have addressed the role of sustained S. pneumoniae infection in plaque growth or plaque rupture to date

Summary

Objective

Bacterial infection contributes to diverse noninfectious diseases and worsens outcome after stroke. 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. Clinical data indicate that S. pneumoniae, together with other common infections such as Chlamydia pneumoniae and Haemophilus influenzae, contributes to impaired outcome, prolonged hospitalization, and death after stroke.[5] Experimental stroke in mice propagates pneumonia.[13,14] it is not known if sustained bacterial infections preceding an acute cerebrovascular event could trigger stroke or contribute to increased stroke pathophysiology. We suggest that complications after acute vascular events is preceded by a rapid systemic inflammatory response and excessive coagulation induced by pre-existing infection that profoundly impairs outcome This could be prevented by treatment with IL-1 receptor antagonist (IL-1Ra)

Materials and Methods

Results

Discussion