Human cytomegalovirus in congenital infections and embryonal malignancies of the nervous system

Abstract: Cytomegalovirus (CMV) is a herpesvirus that may cause severe or even fatal disease in immunocompromised patients as well as severe developmental disturbances in foetuses infected in utero. In contrast, only mild symptoms are generally observed in immunocompetent individuals. Virus infections are very common in and the global prevalence is 70-90%. After a primary infection, the virus establishes latency, from which it can be reactivated by stress, inflammation or concomitant diseases. Most likely, a reactivated infection is controlled by a functioning immune response. However, due to the virus sophisticated strategies, the infection will never be cleared but remain in the host throughout life. In the western world, 0.15-2.0% of all live births are congenitally infected by CMV. The virus can transfer across placenta at any time during pregnancy and cause a wide range of symptoms from foetal death to mild concentration disorders. Clinical observations and data from studies in vitro and in animals suggest that neural stem and progenitor cells (NPCs) are vulnerable targets for CMV infection and that it is the damage in these cells that cause the developmental disorders of the brain. In paper I and II, we demonstrate that NPCs were readily infected by CMV and expressed both immediate early (IE) and late (L) CMV proteins. Interestingly, infected NPCs were unable to differentiate into neuronal or astrocytic lineage cells. Moreover, CMV decreased proliferation and induced apoptosis in infected cells. Our data points to that the clinical findings of microcephaly and disturbed migration in a CMV infected brain may be caused by cell loss due to infection of NPCs. CMV has ways of manipulating its host cell into the perfect viral residence. Many of these strategies are also causing the host cell to increase proliferation, change migration patterns, counteract apoptotic signals and more. This makes CMV a good candidate for oncogenicity and in the 70 s it was proposed to be an oncogenic virus. In recent years new evidence of CMV as a player in tumour development has come forth. CMV proteins and nucleic acids are found in tumour tissue and CMV infected cancer cells are reported to grow more aggressively than uninfected cells. In paper III and IV we show that CMV proteins and DNA are found in 97% and 87% of neuroblastoma and medulloblastoma tumours, respectively. These tumours are reported to express high levels of cyclooxygenase-2 (COX-2) and treatment by COX-2 inhibitors have resulted in significantly reduced tumour growth in vivo and in vitro. CMV also causes upregulation of COX-2 expression with subsequent high levels of the end product, prostaglandin E2 (PGE2). We confirmed that both neuroblastoma and medulloblastoma cells increase COX-2 levels in vitro in response to infection, most likely due to IE or early gene expression. Therefore, we investigated whether treatment with antiviral drug ganciclovir and COX-2 inhibitor celecoxib inhibited tumour growth in vitro and in vivo. We found that when combining the two drugs, tumour growth was decreased significantly both in vivo and in vitro in both tumour types. Our observations may lead to more effective treatments against severe paediatric malignancies.