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Streptococcus pneumoniae worsens cerebral ischemia via interleukin 1 and platelet glycoprotein Ibα
Ádám Dénes1, Jesus M Pradillo, Caroline Drake
1Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary.
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.
Insights
Streptococcus pneumoniae infection worsens stroke outcomes by increasing inflammation and blood clotting. Blocking interleukin-1 (IL-1) and platelet activation reduces brain injury, suggesting new therapeutic targets for stroke patients with infections.
Area of Science:
- Cardiovascular Science
- Neuroscience
- Infectious Disease
Background:
- Bacterial infections, particularly Streptococcus pneumoniae, are common in stroke patients and worsen outcomes.
- The precise mechanisms by which infection impacts stroke severity and clinical outcomes remain unclear.
Purpose of the Study:
- To investigate the impact of Streptococcus pneumoniae infection on vascular and inflammatory responses before and after cerebral ischemia.
- To elucidate the role of interleukin-1 (IL-1) and platelet activation in infection-exacerbated ischemic brain injury.
Main Methods:
- Rodent models were used to induce pulmonary Streptococcus pneumoniae infection.
- Cerebral ischemia was induced to assess the effects of infection on brain injury, vascular responses, and inflammation.
- Interventions included IL-1 receptor antagonist (IL-1Ra) and platelet glycoprotein (GP) Ibα blockade.
Main Results:
- Streptococcus pneumoniae infection accelerated atherosclerosis and increased systemic IL-1 levels.
- Infection significantly exacerbated ischemic brain injury and functional deficits, particularly in older or atherosclerotic animals.
- Blockade of IL-1 and GP Ibα effectively reversed infection-induced brain injury and inflammation by modulating microglial activation and platelet aggregation.
Conclusions:
- Streptococcus pneumoniae infection exacerbates ischemic brain injury through IL-1 and platelet-mediated systemic inflammation.
- These findings highlight potential therapeutic strategies targeting IL-1 and platelet pathways to mitigate stroke severity in infected individuals.
- The identified mechanisms may contribute to various human cardiovascular and cerebrovascular diseases.
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