Listeria monocytogenes cytoplasmic entry induces fetal wastage by disrupting maternal Foxp3+ regulatory T cell-sustained fetal tolerance.
Although the intracellular bacterium Listeria monocytogenes has an established predilection for disseminated infection during pregnancy that often results in spontaneous abortion or stillbirth, the specific host-pathogen interaction that dictates these disastrous complications remain incompletely defined. Herein, we demonstrate systemic maternal Listeria infection during pregnancy fractures fetal tolerance and triggers fetal wastage in a dose-dependent fashion. Listeria was recovered from the majority of concepti after high-dose infection illustrating the potential for in utero invasion. Interestingly with reduced inocula, fetal wastage occurred without direct placental or fetal invasion, and instead paralleled reductions in maternal Foxp3(+) regulatory T cell suppressive potency with reciprocal expansion and activation of maternal fetal-specific effector T cells. Using mutants lacking virulence determinants required for in utero invasion, we establish Listeria cytoplasmic entry is essential for disrupting fetal tolerance that triggers maternal T cell-mediated fetal resorption. Thus, infection-induced reductions in maternal Foxp3(+) regulatory T cell suppression with ensuing disruptions in fetal tolerance play critical roles in pathogenesis of immune-mediated fetal wastage.
Department of Pediatrics and Microbiology, Center for Infectious Disease and Microbiology Translational Research, University of Minnesota School of Medicine, Minneapolis, Minnesota, United States of America.
Jared H
JH
Rowe
James M
JM
Ertelt
Lijun
L
Xin
Sing Sing
SS
Way
D000818:Animals; D003593:Cytoplasm / Q000276:immunology / Q000382:microbiology; D005260:Female; D005327:Fetal Resorption / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051858:Forkhead Transcription Factors; D007108:Immune Tolerance; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D008088:Listeriosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse