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Exploring new ways to prevent and treat congenital Cytomegalovirus infection through protein dysregulation studies in neuronal organoids

Hosted by: Professor David Tscharke

Abstract

Our work on congenital Cytomegalovirus infection, and mother to child transmission during pregnancy takes in epidemiological, clinical and basic scientific studies of how this occurs. Through such work, we integrate our findings into studying new antivirals, and how they might be used to prevent congenital CMV. 

Human CMV infection is the leading non-genetic aetiology of congenital malformation in developed countries, causing significant fetal disease, including neurological injury and mental disability. Our current studies explore potential CMV pathogenetic mechanisms of fetal neural malformation using in vitro human cerebral organoids, that are permissive to CMV replication. We have shown CMV infection dysregulates cellular pluripotency and differentiation pathways, with aberrant expression of dual- specificity tyrosine phosphorylation-regulated kinases (DYRK), sonic hedgehog (SHH), pluripotency, neurodegeneration, axon guidance, hippo signalling and dopaminergic synapse pathways. We use culture, RNA seq and protein studies in neuronal cultures, and in tissue from CMV-induced stillbirths. Infection with CMV result in dysregulation of multipole genes, including Autism Spectrum Disorder (ASD)-related genes and pathways. These more recent observations suggest potential links between congenital CMV infection and ASD, which has been observed clinically. Cytomegalovirus infection-related dysregulation of key cerebral cellular pathways in the fetus provides important, modifiable pathogenetic mechanisms for congenital CMV-induced neural malformation and ASD. Using antivirals in the model systems, we show improvements in the CMV-induced malformations, and these more recent unpublished data will also be presented.   

Biography

Professor William David Rawlinson is an infectious diseases clinician and virology scientist researching how viruses cause disease, also known as viral pathogenesis. He has undertaken research and clinical work on Cytomegalovirus (CMV) since 1993 when he completed his PhD at Cambridge University. He also undertakes research into other herpesviruses, respiratory viral infections, congenital infections, and viruses in type 1 diabetes mellitus. He established, and oversees, serology and virology clinical research programs, statewide transplant donor screening, and national quality programs for serology and biosecurity. He is conjoint professor at UNSW with over 700 publications and 29,000 citations, many of which are on CMV basic research, diagnostic and clinical virology.

His initial studies were of models for congenital CMV, and analysis of the DNA sequence of mouse CMV (as a model) and human CMV. He has brought together international researchers and NGOs to produce highly influential guidelines on congenital CMV diagnosis, prevention and treatment. His research group studies all these areas, and has graduated many PhD and honours students studying congenital CMV. He is privileged to be associated with the Congenital CMV Association of Australia and Cerebral Palsy Alliance as an advisor and colleague in reducing the impact of congenital CMV on families.