IFNγ and acute prenatal infection with Toxoplasma gondii activate fetal hematopoietic stem cells

Abstract

Infection directly influences adult hematopoietic stem cell (HSC) function and differentiation, but much less is known about the fetal hematopoietic response to infection during pregnancy. Here, we investigated the fetal hematopoietic response to maternal infection with Toxoplasma gondii (T. gondii), an intracellular parasite that elicits Type II IFN{gamma}-mediated maternal immunity. The effects of maternal IFN{gamma} on developing HSCs and the signals that mediate these interactions have not been investigated. Our investigation reveals that the fetal HSCs respond to T. gondii infection with virulence-dependent changes in proliferation, self-renewal potential, and lineage output. We demonstrate that maternal IFN{gamma} crosses the fetal-maternal interface and is perceived by fetal HSCs. By comparing the effects of maternal IFN{gamma} injection with maternal T. gondii infection, our observations reveal that IFN{gamma} mimics aspects of the fetal HSC response to infection. Moreover, our data disentangle the role of infection-induced inflammatory cytokines in driving the expansion of downstream hematopoietic progenitors. Our findings illuminate that the fetal HSC response to prenatal infection is distinct from the adult HSC response to IFN{gamma}-induced inflammation.