Human cytomegalovirus infection is associated with increased expression of the lissencephaly gene PAFAH1B1 encoding LIS1 in neural stem cells and congenitally infected brains

Maude Rolland (1) , Hélène Martin (1) , Mathilde Bergamelli (1) , Yann Sellier (2, 3) , Bettina Bessières (2, 3) , Jacqueline Aziza (4) , Alexandra Benchoua (5) , Marianne Leruez‐ville (2, 3) , Daniel Gonzalez‐dunia (1) , Stéphane Chavanas (1)

1 Infinity - Institut Toulousain des Maladies Infectieuses et Inflammatoires
2 Hôpital Necker - Enfants Malades [AP-HP]
3 UFR Médecine UPCité - UFR Médecine [Santé] - Université Paris Cité
4 Service Anatomie et cytologie pathologiques [CHU Toulouse]
5 CECS - Centre d'Etude des Cellules Souches

Congenital infection of the central nervous system by human cytomegalovirus (HCMV) is a leading cause of permanent sequelae, including mental retardation or neurodevelopmental abnormalities. The most severe complications include smooth brain or polymicrogyria, which are both indicative of abnormal migration of neural cells, although the underlying mechanisms remain to be determined. To gain better insight on the pathogenesis of such sequelae, we assessed the expression levels of a set of neurogenesis-related genes, using HCMV-infected human neural stem cells derived from embryonic stem cells (NSCs). Among the 84 genes tested, we found dramatically increased expression of the gene PAFAH1B1, encoding LIS1 (lissencephaly-1), in HCMV-infected versus uninfected NSCs. Consistent with these findings, western blotting and immunofluorescence analyses confirmed the increased levels of LIS1 in HCMV-infected NSCs at the protein level. We next assessed the migratory abilities of HCMV-infected NSCs and observed that infection strongly impaired the migration of NSCs, without detectable effect on their proliferation. Moreover, we observed increased immunostaining for LIS1 in brains of congenitally infected fetuses, but not in control samples, highlighting the clinical relevance of our findings. Of note, PAFAH1B1 mutations (resulting in either haploinsufficiency or gain of function) are primary causes of hereditary neurodevelopmental diseases. Notably, mutations resulting in PAFAH1B1 haploinsufficiency cause classic lissencephaly. Taken together, our findings suggest that PAFAH1B1 is a critical target of HCMV infection. They also shine a new light on the pathophysiological basis of the neurological outcomes of congenital HCMV infection, by suggesting that defective neural cell migration might contribute to the pathogenesis of the neurodevelopmental sequelae of infection.

Mots clés: DCX; LIS1; PAFAH1B1; congenital infection; cytomegalovirus; neuronal migration

Domaines: Sciences du Vivant [q-bio]

Maude Rolland, Hélène Martin, Mathilde Bergamelli, Yann Sellier, Bettina Bessières, et al.. Human cytomegalovirus infection is associated with increased expression of the lissencephaly gene PAFAH1B1 encoding LIS1 in neural stem cells and congenitally infected brains. Journal of Pathology, 2021, ⟨10.1002/path.5640⟩. ⟨hal-03258562⟩