The Bhagirath Singh Early Career Prize in Infection and Immunity: Hematopoietic stem cell sequelae in fetuses and offspring exposed to in utero Zika infection

Zika virus (ZIKV) emerged in the Americas in 2015 and posed ongoing public health concerns. The outcomes of ZIKV infection are fetal death, brain lesions, and life-long impairment in children. Alarmingly, the majority of fetal infections are mild with no easily identifiable birth defects; however, later health complications in initially asymptomatic ZIKV-affected offspring were demonstrated in our animal model studies and studies in humans. It is not known, however, how abnormalities acquired during fetal infection are sustained and endure in offspring. Our preliminary studies suggest that mild ZIKV infection in fetuses causes systemic inflammation deteriorating fetal hematopoietic stem cells (HSCs)-long-living cells that maintain the immune system for the life span. Fetal HSCs affected during a developmental period in the maternal womb may sustain acquired pathology after birth causing long-term HSC abnormalities and enduring dysfunction of immunity in offspring. We will use state-of-the-art molecular techniques and advanced large animal models to understand better how ZIKV affects HSCs and their ability to maintain the immune system. A better understanding of long-term effects caused by mild in utero infection will support the development of therapeutic strategies. Importantly, in addition to ZIKV infection, the new knowledge may be applied to other viruses that are known to cause mild fetal infections. Our studies may help to reduce health sequelae in offspring and treatment required after birth. It will be highly-rewarding for patients, families, and society and will decrease the social and economic burden associated with congenital infections.