Optimisation of a novel murine model to investigate pathophysiological mechanisms underlying early congenital human cytomegalovirus infection

Abstract

Human cytomegalovirus (hCMV) is a major cause of congenital abnormalities in foetuses worldwide. These affected infants typically develop neurological sequelae, and present with dysfunctions in brain development that may lead to either severe cognitive impairment or hearing loss. The vertical transmission of hCMV from mother to foetus is primarily the result of a primary infection acquired by the mother during pregnancy. In addition, the severity of brain abnormalities has been reported to be directly proportional to the precedency of infection during gestation. Whilst animal (in particular murine) models of congenital hCMV have been developed to study the pathophysiological mechanisms underlying this disease; however, none of the previously reported studies modelled the congenital hCMV infection during the first trimester of pregnancy. Thus, the current literature is limited from further insights into hCMV-induced pathophysiological mechanisms early during pregnancy. Therefore, we decided to (develop / optimise / validate) a mouse model that phenocopies, as closely as possible, the congenital hCMV infection acquired during the first trimester of pregnancy. For this purpose, we injected the murine cytomegalovirus (mCMV) directly into the placental labyrinth of each murine embryo at embryonic day 10.5 (E10.5), whose stage of brain development corresponds to a human foetus during the first trimester. We then monitored the effects of mCMV infection on the health of pregnant mice, as well as the development of murine embryos and pups. We report findings that demonstrate mCMV infection of murine embryos via intraplacental injection at E10.5 shares similarities with congenital hCMV infection. Despite the phenocopy of previously reported human and murine signs and symptoms in our current animal model: health of pregnant mice, microcephaly and microencephaly in infected embryos and pups, recruitment of microglial cells in the embryonic brains, we intend to proceed with detailed spatio-temporal histo-cytologcal analyses to further validate our murine CMV model. In conclusion, we demonstrate a novel mouse model for a more comprehensive study of the pathophysiological mechanisms underlying congenital hCMV infection.