Fetal hematopoietic stem cells are activated during acute prenatal infection with Toxoplasma gondii and IFNγ

Abstract

Infection in the adult organism drives cytokine-mediated inflammation that directly influences hematopoietic stem cell (HSC) function and differentiation within the bone marrow, but much less is known about the fetal hematopoietic response to maternal infection during pregnancy. Here, we investigated the fetal hematopoietic response to maternal infection with Toxoplasma gondii (T. gondii). T. gondii is an intracellular parasite that elicits Type II IFNγ-mediated maternal immunity to prevent vertical transmission and promote parasite clearance. The production of excessive IFNγ during maternal infection with T. gondii has dire consequences for the developing fetus, such as reduced birth weights and premature abortion, but the effects on developing hematopoietic cells and the signals that mediate these interactions have not been investigated. Our investigation reveals that the heterogenous fetal HSC pool responds to T. gondii infection with virulence-dependent changes in proliferation, self-renewal potential, and lineage output. We demonstrate that maternal IFNγ crosses the fetal-maternal interface and is perceived directly by fetal HSCs. By directly comparing the effects of maternal IFNγ injection with maternal T. gondii infection, our observations reveal that IFNγ mimics several aspects of the fetal HSC response to infection. Moreover, our data disentangle the role of additional infection-induced inflammatory cytokines in driving the expansion of independent downstream hematopoietic progenitors. Together, our findings illuminate the robust response of fetal hematopoietic stem cells to prenatal infection, and demonstrate that this response is distinct from the adult HSC response to IFNγ-induced inflammation.