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.
Highlights
Perinatal and congenital infections cause morbidity and mortality throughout the world
CMV Infection of the Rat Fetal Brain Leads to Postnatal Mortality and to Neurological Manifestations
To determine whether CMV infection and the accompanying immune responses in the developing rat brain could be associated with the emergence of postnatal consequences, recalling those seen in the corresponding human congenital disorder, recombinant rat CMV expressing green fluorescent protein (GFP) was injected icv in embryos from timed-pregnant rats at embryonic day 15 (E15) as previously described (Cloarec et al, 2016)
Summary
Perinatal and congenital infections cause morbidity and mortality throughout the world. Congenital CMV infection can cause severe neurological diseases and defects (Adler and Nigro, 2013). These include microcephaly, polymicrogyria, hearing loss, cerebral palsy, epileptic seizures and intellectual disability, as well as the as-yet elusive influence on the emergence of schizophrenia, autism or epilepsy. Despite the incidence and the medical and socioeconomical burden of congenital CMV, which represents about 1% of all live births, the pathophysiological mechanisms underlying the emergence of neurodevelopmental disorders remain elusive (Cheeran et al, 2009). The pathophysiology of congenital CMV disease is inherently complicated and involves different stages, from maternal CMV primary infection or reactivation and the associated maternal immune responses, to infection and dissemination within the developing brain—not to mention the crossing of the placental and blood-brain barriers
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