Neuro-Immune and Neuronal Alterations caused by Cytomegalovirus Infection of the Developing Brain

Congenital cytomegalovirus (CMV) infection is one leading cause of human neurodevelopmental disorders (brain malformations, autism, cognitive impairment, deafness, epilepsy, cerebral palsy etc.). Despite its severity and prevalence (1% of all living birth worldwide), neuropathogenesis of congenital CMV remains poorly known and no satisfactory treatment is available.

In our team, we have developed a rat model of CMV infection of the developing brain in utero, characterized by early cellular and molecular neuroimmune alterations and by severe postnatal phenotypes comparable to what occurs in humans.

Pharmacological knock-down or depletion of fetal microglia (the brain resident immune cells) prevented against most severe neurologic manifestations. Consistent with the crucial role of microglia in brain development, our data indicate a pivotal role for fetal microglia in CMV-related neuropathogenesis.

Still using this robust in vivo model, we now aim at:

i/ getting more precise information on microglia alterations at the functional and molecular levels, using electrophysiological techniques (microglia recordings) and RNA sequencing;

ii/ describing the morphoanatomical and functional consequences of such alterations on neurons and neuronal networks, using immunohistochemistry and electrophysiological recordings;

iii/ evaluating (neurologic phenotypes, flow cytometry analyses) novel rescue strategies targeting:
- fetal microglia ;
- viral chemokines of interest.

In this overall context, the present Master 2 project will address a subset of the questions as listed above, with a likely focus on microglia alterations and on their impact on the development of the infected fetal brain.

The project is inherently multidisciplinary and involves partnerships at multiple levels, including Virology labs (Ulm University, Germany; Oregon University, Portland, USA), Immunology centre (CIPHE/CIML, Luminy campus, Marseille), and Neuro-pediatrics department (Marseille University Hospital).