FETAL IMMUNITY TO ZIKA VIRUS

Abstract

In utero infection by ZIKV is associated with congenital disorders, however, little is known about the fetal immune response. Early/primitive fetal hematopoiesis gives rise to primitive macrophages, some of which differentiate into microglia, and mast cells, which are also brain-resident immune cells. These two immune cells emerge during the period of highest risk of developing ZIKV-associated congenital syndrome (ZCS), raising questions of whether they are protective during congenital ZIKV infection and how they respond to different ZIKV strains, since only strains from the Asian but not the African lineage of ZIKV have been linked to microcephaly in humans. Here, I report that both African and Asian lineage strains of ZIKV are capable of infecting fetal microglia and neural progenitors (NPCs) following maternal to fetal transmission of infection. Yet, strains of each lineage showed differential tropism, with African strains preferentially infecting larger proportions of microglia, compared to Asian lineage strains that infected NPCs in higher proportions. Interestingly, the differential tropism was associated with microcephaly of varying severity, contingent on ZIKV lineage. Strains of the African lineage induced less severe phenotypes, as compared to Asian lineage. Furthermore, a representative Asian lineage strain induced more cell death in NPCs in the cortex and the hippocampus, as compared to a representative strain from the African lineage, following microinjection of ZIKV into fetal brain. Consistent with this, the Asian lineage strain infected and recruited more Ly6cHi inflammatory monocytes in different brain regions, compared to the African strain, which infected more microglia cells in various brain regions. Moreover, depletion of fetal microglia resulted in enhancement of infection by both ZIKV lineages, highlighting the importance of microglia in clearing ZIKV infection. In addition to microglia in the brain, I also identified the role of fetal mast cells in the context of congenital ZIKV infection. Mast cells are key sentinel immune cells that play important roles in allergies and in clearing viral infection, however, their role in clearing congenital infection is unknown. For this reason, I optimized a novel mast cell-knock out model that allows fetal but not maternal mast cell ablation. I showed that the presence of fetal mast cells is protective against ZCS, as mast cell-deficient fetuses showed more severe symptoms than mast cell-sufficient littermates. Furthermore, our data suggests that fetal mast cell may mediate infection clearance by promoting the activation of other innate immune cells, such as γδT cells. Taken together, data here shows that both microglia and fetal mast cells protect the fetal brain against ZIKV infection. Although both African and Asian ZIKV strains can induce congenital abnormalities, their severity depends on their cellular tropism in microglia.