Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Influenza A Infection Increases Severity of Acute Ischemic Stroke Through Neutrophil Activation and Hypercoagulability

Haupeltshofer, Steffen LU ; Steinbach, Philine ; Wenzek, Christina ; Szepanowski, Rebecca D. ; Mausberg, Anne K. ; Blusch, Alina LU ; Hansmann, Christina ; Casas, Ana I. ; Hansen, Wiebke and Westendorf, Astrid M. , et al. (2025) In Stroke 56(12). p.3500-3511
Abstract

BACKGROUND: Respiratory viruses, such as influenza viruses and SARS-CoV-2, cause severe infections of the respiratory system. Cohort studies and clinical observations indicate that patients with severe influenza A virus (IAV) infections are at an increased risk of developing an ischemic stroke event. However, the underlying mechanisms remain elusive. To this end, we investigated the consequences of IAV infection on cerebral damage in a mouse model of ischemic stroke. METHODS: We intranasally inoculated male C57BL6/N mice with the mouse-adapted IAV strain A/Puerto Rico 8/34 or PBS as a vehicle control. At 3, 7, and 10 days post-infection, mice were subjected to transient middle cerebral artery occlusion, followed by sacrifice 24 hours... (More)

BACKGROUND: Respiratory viruses, such as influenza viruses and SARS-CoV-2, cause severe infections of the respiratory system. Cohort studies and clinical observations indicate that patients with severe influenza A virus (IAV) infections are at an increased risk of developing an ischemic stroke event. However, the underlying mechanisms remain elusive. To this end, we investigated the consequences of IAV infection on cerebral damage in a mouse model of ischemic stroke. METHODS: We intranasally inoculated male C57BL6/N mice with the mouse-adapted IAV strain A/Puerto Rico 8/34 or PBS as a vehicle control. At 3, 7, and 10 days post-infection, mice were subjected to transient middle cerebral artery occlusion, followed by sacrifice 24 hours after reperfusion for subsequent analysis. The anticoagulant drug acetylsalicylic acid was administered as treatment 1 day before transient middle cerebral artery occlusion. RESULTS: Our research demonstrated a time-dependent deterioration of cerebral ischemia after transient middle cerebral artery occlusion, resulting in increased infarct volume and a worsened neurological outcome at the propagation and inflammation phases of infection. Our observations revealed an elevation in procoagulant activity and an increase in thrombosis within the microvasculature after infection and stroke. This effect was attributed to an infection-mediated inflammatory milieu and accelerated neutrophil response. Upon infection, the release of increased neutrophil extracellular traps by neutrophils had detrimental consequences for transient middle cerebral artery occlusion development. Administration of acetylsalicylic acid or control antiviral therapy prevented the IAV-induced exacerbation of stroke and reduced brain damage by reducing NETosis and coagulation. CONCLUSIONS: These findings suggest that IAV infections enhance the systemic propensity for NETosis and foster a procoagulant state, thereby increasing the risk of cerebral damage and thrombosis following stroke. Targeting a combination of neutrophils and coagulation molecules simultaneously represents a promising treatment approach for clinical stroke.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
blood platelets, influenza A virus, ischemic stroke, neutrophils, thrombosis
in
Stroke
volume
56
issue
12
pages
3500 - 3511
publisher
American Heart Association
external identifiers
  • scopus:105014610512
ISSN
0039-2499
DOI
10.1161/STROKEAHA.125.052967
language
English
LU publication?
yes
id
ac4dfd5d-d10d-43c0-9d14-801453804bb0
date added to LUP
2025-11-17 10:03:44
date last changed
2026-01-16 08:54:42
@article{ac4dfd5d-d10d-43c0-9d14-801453804bb0,
  abstract     = {{<p>BACKGROUND: Respiratory viruses, such as influenza viruses and SARS-CoV-2, cause severe infections of the respiratory system. Cohort studies and clinical observations indicate that patients with severe influenza A virus (IAV) infections are at an increased risk of developing an ischemic stroke event. However, the underlying mechanisms remain elusive. To this end, we investigated the consequences of IAV infection on cerebral damage in a mouse model of ischemic stroke. METHODS: We intranasally inoculated male C57BL6/N mice with the mouse-adapted IAV strain A/Puerto Rico 8/34 or PBS as a vehicle control. At 3, 7, and 10 days post-infection, mice were subjected to transient middle cerebral artery occlusion, followed by sacrifice 24 hours after reperfusion for subsequent analysis. The anticoagulant drug acetylsalicylic acid was administered as treatment 1 day before transient middle cerebral artery occlusion. RESULTS: Our research demonstrated a time-dependent deterioration of cerebral ischemia after transient middle cerebral artery occlusion, resulting in increased infarct volume and a worsened neurological outcome at the propagation and inflammation phases of infection. Our observations revealed an elevation in procoagulant activity and an increase in thrombosis within the microvasculature after infection and stroke. This effect was attributed to an infection-mediated inflammatory milieu and accelerated neutrophil response. Upon infection, the release of increased neutrophil extracellular traps by neutrophils had detrimental consequences for transient middle cerebral artery occlusion development. Administration of acetylsalicylic acid or control antiviral therapy prevented the IAV-induced exacerbation of stroke and reduced brain damage by reducing NETosis and coagulation. CONCLUSIONS: These findings suggest that IAV infections enhance the systemic propensity for NETosis and foster a procoagulant state, thereby increasing the risk of cerebral damage and thrombosis following stroke. Targeting a combination of neutrophils and coagulation molecules simultaneously represents a promising treatment approach for clinical stroke.</p>}},
  author       = {{Haupeltshofer, Steffen and Steinbach, Philine and Wenzek, Christina and Szepanowski, Rebecca D. and Mausberg, Anne K. and Blusch, Alina and Hansmann, Christina and Casas, Ana I. and Hansen, Wiebke and Westendorf, Astrid M. and Knuschke, Torben and Langhauser, Friederike and Kleinschnitz, Christoph}},
  issn         = {{0039-2499}},
  keywords     = {{blood platelets; influenza A virus; ischemic stroke; neutrophils; thrombosis}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{3500--3511}},
  publisher    = {{American Heart Association}},
  series       = {{Stroke}},
  title        = {{Influenza A Infection Increases Severity of Acute Ischemic Stroke Through Neutrophil Activation and Hypercoagulability}},
  url          = {{http://dx.doi.org/10.1161/STROKEAHA.125.052967}},
  doi          = {{10.1161/STROKEAHA.125.052967}},
  volume       = {{56}},
  year         = {{2025}},
}