In utero administration of drugs targeting microglia improves the neurodevelopmental outcome following cytomegalovirus infection of the rat fetal brain

Robin Cloarec, Sylvian Bauer, Natacha Teissier, Fabienne Schaller, Hervé Luche, Sandra Courtens, Manal Salmi, Vanessa Pauly, Emilie Bois, Emilie Pallesi-Pocachard, Emmanuelle Buhler, François J. Michel, Pierre Gressens, Marie Malissen, Thomas Stamminger, Daniel Streblow, Nadine Bruneau, Pierre Szepetowski

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Congenital cytomegalovirus (CMV) infections represent one leading cause of neurodevelopmental disorders. Recently, we reported on a rat model of CMV infection of the developing brain in utero, characterized by early and prominent infection and alteration of microglia—the brain-resident mononuclear phagocytes. Besides their canonical function against pathogens, microglia are also pivotal to brain development. Here we show that CMV infection of the rat fetal brain recapitulated key postnatal phenotypes of human congenital CMV including increased mortality, sensorimotor impairment reminiscent of cerebral palsy, hearing defects, and epileptic seizures. The possible influence of early microglia alteration on those phenotypes was then questioned by pharmacological targeting of microglia during pregnancy. One single administration of clodronate liposomes in the embryonic brains at the time of CMV injection to deplete microglia, and maternal feeding with doxycyxline throughout pregnancy to modify microglia in the litters’ brains, were both associated with dramatic improvements of survival, body weight gain, sensorimotor development and with decreased risk of epileptic seizures. Improvement of microglia activation status did not persist postnatally after doxycycline discontinuation; also, active brain infection remained unchanged by doxycycline. Altogether our data indicate that early microglia alteration, rather than brain CMV load per se, is instrumental in influencing survival and the neurological outcomes of CMV-infected rats, and suggest that microglia might participate in the neurological outcome of congenital CMV in humans. Furthermore this study represents a first proof-of-principle for the design of microglia-targeted preventive strategies in the context of congenital CMV infection of the brain.

Original languageEnglish (US)
Article number55
JournalFrontiers in Cellular Neuroscience
Volume12
DOIs
StatePublished - Mar 6 2018

Fingerprint

Cytomegalovirus Infections
Microglia
Drug Delivery Systems
Brain
Cytomegalovirus
Muromegalovirus
Doxycycline
Epilepsy
Clodronic Acid
Phenotype
Pregnancy
Survival
Cerebral Palsy
Phagocytes
Infection
Liposomes
Hearing
Weight Gain
Body Weight
Mothers

Keywords

  • Cytomegalovirus
  • Fetal brain
  • Microglia
  • Neurological outcome
  • Rat model

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

In utero administration of drugs targeting microglia improves the neurodevelopmental outcome following cytomegalovirus infection of the rat fetal brain. / Cloarec, Robin; Bauer, Sylvian; Teissier, Natacha; Schaller, Fabienne; Luche, Hervé; Courtens, Sandra; Salmi, Manal; Pauly, Vanessa; Bois, Emilie; Pallesi-Pocachard, Emilie; Buhler, Emmanuelle; Michel, François J.; Gressens, Pierre; Malissen, Marie; Stamminger, Thomas; Streblow, Daniel; Bruneau, Nadine; Szepetowski, Pierre.

In: Frontiers in Cellular Neuroscience, Vol. 12, 55, 06.03.2018.

Research output: Contribution to journalArticle

Cloarec, R, Bauer, S, Teissier, N, Schaller, F, Luche, H, Courtens, S, Salmi, M, Pauly, V, Bois, E, Pallesi-Pocachard, E, Buhler, E, Michel, FJ, Gressens, P, Malissen, M, Stamminger, T, Streblow, D, Bruneau, N & Szepetowski, P 2018, 'In utero administration of drugs targeting microglia improves the neurodevelopmental outcome following cytomegalovirus infection of the rat fetal brain', Frontiers in Cellular Neuroscience, vol. 12, 55. https://doi.org/10.3389/fncel.2018.00055
Cloarec, Robin ; Bauer, Sylvian ; Teissier, Natacha ; Schaller, Fabienne ; Luche, Hervé ; Courtens, Sandra ; Salmi, Manal ; Pauly, Vanessa ; Bois, Emilie ; Pallesi-Pocachard, Emilie ; Buhler, Emmanuelle ; Michel, François J. ; Gressens, Pierre ; Malissen, Marie ; Stamminger, Thomas ; Streblow, Daniel ; Bruneau, Nadine ; Szepetowski, Pierre. / In utero administration of drugs targeting microglia improves the neurodevelopmental outcome following cytomegalovirus infection of the rat fetal brain. In: Frontiers in Cellular Neuroscience. 2018 ; Vol. 12.
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abstract = "Congenital cytomegalovirus (CMV) infections represent one leading cause of neurodevelopmental disorders. Recently, we reported on a rat model of CMV infection of the developing brain in utero, characterized by early and prominent infection and alteration of microglia—the brain-resident mononuclear phagocytes. Besides their canonical function against pathogens, microglia are also pivotal to brain development. Here we show that CMV infection of the rat fetal brain recapitulated key postnatal phenotypes of human congenital CMV including increased mortality, sensorimotor impairment reminiscent of cerebral palsy, hearing defects, and epileptic seizures. The possible influence of early microglia alteration on those phenotypes was then questioned by pharmacological targeting of microglia during pregnancy. One single administration of clodronate liposomes in the embryonic brains at the time of CMV injection to deplete microglia, and maternal feeding with doxycyxline throughout pregnancy to modify microglia in the litters’ brains, were both associated with dramatic improvements of survival, body weight gain, sensorimotor development and with decreased risk of epileptic seizures. Improvement of microglia activation status did not persist postnatally after doxycycline discontinuation; also, active brain infection remained unchanged by doxycycline. Altogether our data indicate that early microglia alteration, rather than brain CMV load per se, is instrumental in influencing survival and the neurological outcomes of CMV-infected rats, and suggest that microglia might participate in the neurological outcome of congenital CMV in humans. Furthermore this study represents a first proof-of-principle for the design of microglia-targeted preventive strategies in the context of congenital CMV infection of the brain.",
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AU - Salmi, Manal

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AU - Michel, François J.

AU - Gressens, Pierre

AU - Malissen, Marie

AU - Stamminger, Thomas

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