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

• Published in: The EMBO journal Vol. 42; no. 14; pp. e112693 - n/a
• Main Authors: López, Diego A, Otsuka, Kelly S, Apostol, April C, Posada, Jasmine, Sánchez‐Arcila, Juan C, Jensen, Kirk DC, Beaudin, Anna E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-07-2023; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Cell Differentiation; Congenital infection; Cytokines; Differentiation; EMBO11; EMBO23; Female; Fetuses; Hematopoiesis; hematopoietic stem cell; Hematopoietic Stem Cells; Hemopoiesis; Humans; Infections; Inflammation; Injection; Investigations; Life Sciences; Parasites; Pregnancy; Prenatal experience; Progenitor cells; Stem cells; Toxoplasma; Toxoplasma gondii; Toxoplasmosis - metabolism; Virulence; γ-Interferon; hematopoietic stem cell; hematopoiesis; congenital infection; inflammation; Toxoplasma gondii
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2022112693

Infection directly influences adult hematopoietic stem cell (HSC) function and differentiation, but the fetal hematopoietic response to infection during pregnancy is not well‐studied. Here, we investigated the fetal hematopoietic response to maternal infection with
Toxoplasma gondii
(
T. gondii
), an intracellular parasite that elicits Type II IFNγ‐mediated maternal immunity. While it is known that maternal infection without direct pathogen transmission can affect fetal immune development, the effects of maternal IFNγ 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. Furthermore, maternal IFNγ crosses the fetal–maternal interface, where it is perceived by fetal HSCs. By comparing the effects of maternal IFNγ injection with maternal
T. gondii
infection, we reveal that the effects of IFNγ treatment mimic some aspects of the fetal HSC response to infection. Moreover, our findings illuminate that the fetal HSC response to prenatal infection is distinct from the adult HSC response to IFNγ‐induced inflammation. Altogether, our data disentangle the role of infection‐induced inflammatory cytokines in driving the expansion of downstream hematopoietic progenitors.
Synopsis
Infection has been shown to instruct adult hematopoiesis, but the effects on the fetal hematopoietic response have not been investigated. This study demonstrates that a congenital infection or single cytokine injection impacts fetal hematopoietic stem cell self‐renewal and differentiation.
Prenatal infection with
T. gondii
directly affects fetal hematopoietic stem and progenitor cell (HSPC) function in a virulence‐dependent manner.
Prenatal infection invokes a cytokine response across the maternal–fetal barrier that is distinct from the adult response.
Maternal IFNγ exposure alone affects fetal HSPC function.
The response of fetal HSCs and multipotent progenitors is differently regulated by the IFNγ receptor.
Graphical Abstract
Prenatal infection and cytokine transfer across the maternal–fetal barrier induces a distinct fetal hematopoietic response.