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Cytomegalovirus infection of the fetal brain: intake of aspirin during pregnancy blunts neurodevelopmental pathogenesis in the offspring

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Journal of Neuroinflammation

Published in:

Open Access 01-12-2024 | Acetylsalicylic Acid | Research

Cytomegalovirus infection of the fetal brain: intake of aspirin during pregnancy blunts neurodevelopmental pathogenesis in the offspring

Authors: Sarah Tarhini, Carla Crespo-Quiles, Emmanuelle Buhler, Louison Pineau, Emilie Pallesi-Pocachard, Solène Villain, Saswati Saha, Lucas Silvagnoli, Thomas Stamminger, Hervé Luche, Carlos Cardoso, Jean-Paul Pais de Barros, Nail Burnashev, Pierre Szepetowski, Sylvian Bauer

Published in: Journal of Neuroinflammation | Issue 1/2024

Abstract

Background

Congenital cytomegalovirus (CMV) infections represent one leading cause of human neurodevelopmental disorders. Despite their high prevalence and severity, no satisfactory therapy is available and pathophysiology remains elusive. The pathogenic involvement of immune processes occurring in infected developing brains has been increasingly documented. Here, we have used our previously validated rat model of CMV infection of the fetal brain in utero to test whether the maternal administration of four different drugs with immunomodulatory properties would have an impact on the detrimental postnatal outcome of CMV infection.

Methods

CMV infection of the rat fetal brain was done intracerebroventricularly. Each of the drugs, including acetylsalicylic acid (aspirin, ASA), a classical inhibitor of cyclooxygenases Cox-1 and Cox-2, the two key rate-limiting enzymes of the arachidonic acid-to-prostaglandins (PG) synthesis pathway, was administered to pregnant dams until delivery. ASA was selected for subsequent analyses based on the improvement in postnatal survival. A combination of qRT-PCR, mass spectrometry-based targeted lipidomics, immunohistochemistry experiments, monitoring of neurologic phenotypes and electrophysiological recordings was used to assess the impact of ASA in CMV-infected samples and pups. The postnatal consequences of CMV infection were also analyzed in rats knocked-out (KO) for Cox-1.

Results

Increased PGE2 levels and increased proportions of Cox-1⁺ and Cox-2⁺ microglia were detected in CMV-infected developing brains. Maternal intake of ASA led to decreased proportion of Cox-1⁺ fetal, but not neonatal, microglia, while leaving the proportions of Cox-2⁺ microglia unchanged. Maternal intake of ASA also improved the key postnatal in vivo phenotypes caused by CMV infection and dramatically prevented against the spontaneous epileptiform activity recorded in neocortical slices from CMV-infected pups. In contrast with maternal intake of ASA, Cox-1 KO pups displayed no improvement in the in vivo phenotypes after CMV infection. However, as with ASA administration, the spontaneous epileptiform activity was dramatically inhibited in neocortical slices from CMV-infected, Cox-1 KO pups.

Conclusion

Overall, our data indicate that, in the context of CMV infection of the fetal brain, maternal intake of ASA during pregnancy improved CMV-related neurodevelopmental alterations in the offspring, likely via both Cox-1 dependent and Cox-1 independent mechanisms, and provide proof-of-principle for the use of ASA against the detrimental outcomes of congenital CMV infections.

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Title: Cytomegalovirus infection of the fetal brain: intake of aspirin during pregnancy blunts neurodevelopmental pathogenesis in the offspring
Authors: Sarah Tarhini
Carla Crespo-Quiles
Emmanuelle Buhler
Louison Pineau
Emilie Pallesi-Pocachard
Solène Villain
Saswati Saha
Lucas Silvagnoli
Thomas Stamminger
Hervé Luche
Carlos Cardoso
Jean-Paul Pais de Barros
Nail Burnashev
Pierre Szepetowski
Sylvian Bauer
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Acetylsalicylic Acid
Acetylsalicylic Acid
Human Cytomegalovirus
Published in: Journal of Neuroinflammation / Issue 1/2024
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-024-03276-4

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Cytomegalovirus infection of the fetal brain: intake of aspirin during pregnancy blunts neurodevelopmental pathogenesis in the offspring

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