Cutting-edge research on congenital viral infections and the advent of new antiviral interventions

Prof. Dana Wolf, M.D.

Human cytomegalovirus (HCMV) is a DNA virus belonging to the herpesvirus family. It is a major pathogen in immunocompromised patients (such as transplant patients and patients with AIDS), and the leading cause of congenital infections, being transmitted from mothers to their babies during pregnancy. Women infected for the first time during pregnancy are especially likely to transmit the virus to their fetuses. Throughout the world, approximately 1% of newborns are born with congenital HCMV infection, which is associated with a range of neuro-developmental abnormalities, including microcephaly, mental retardation, cerebral palsy, and hearing impairment. Recently, Zika virus (ZIKV), a mosquito-borne virus of the flaviviruses family, has emerged as a cause of severe birth defects, microcephaly, a range of brain anomalies, and fetal loss. Unfortunately, although prenatal diagnosis of congenital infections is possible, there are currently no prenatal predictive markers for the occurrence of disease, and no vaccines and antiviral treatments are available for prevention of congenital HCMV or ZIKV.

These many affected children and the associated public health and economic burden are a compelling argument for the development of preventive interventions against congenital HCMV and ZIKV. This goal could reach its full potential once we learn the fundamental mechanisms of viral transmission and damage in the maternal-fetal interface. Yet, our current understanding of congenital HCMV transmission and pathogenesis is largely limited by the absence of animal models for HCMV. In fact, knowledge is also very limited with regard to the specific mechanisms by which the placenta shields the developing fetus and the strategies used by some viruses to bypass and/or weaken the placental barrier.

Prof. Dana Wolf, Head of the Clinical Virology Unit from the Dept. of Microbiology and infectious Diseases, has recently embarked on the development of a novel experimental approach to tackle these most challenging viral infections. Her objective is “to defeat invading viral pathogens while exploring the innate protective mechanisms and preventing injury of the placenta; an injured placenta can significantly contribute to the subsequent fetal intrauterine growth retardation and disease.”

Prof. Wolf and her research team aim is to understand the mechanisms involved in viral transmission from the mother to the fetus and in the development of fetal disease. To this end, she has developed in her lab a unique 3D ex vivo model of the human placenta, and, together with research collaborators from the Hadassah Hebrew University Medical School and the OBGYN department, Prof. Wolf and her team have been able to witness and understand in real time how the virus spreads from maternal to fetal cells within the human placenta, and how the placenta responds to the viral invasion. Employing state-of-the-art genomic and imaging technologies, she has further showed how the virus alters the delicate immunologic balance at the maternal-fetal interface, thereby discovering how the virus inflicts a specific pattern of placental damage once transmission takes place. They are currently in the process of investigating how the virus further manages to circumvent the innate protective placental barriers. They are also comparing ZIKV and HCMV infection processes, showing for the first time that these two viruses utilize different modes of spread and damage within the human placenta.

These findings provide new insights into the previously unexplored initial events of congenital infection. They pave the way to the development of new preventive approaches against the adverse outcomes of both ongoing and emerging congenital infections

Prof. Wolf's research has already been successful in identifying a novel compound which is highly active against HCMV. This newly discovered antiviral drug has recently formed the basis for the foundation of a new biotech company dedicated to uncovering new antiviral drug targets and development of agents for the prevention and treatment of severe and potentially life-threatening infectious diseases.