title: Acute Fetal Demise with First Trimester Maternal Infection Resulting fromListeria monocytogenesin a Nonhuman Primate Model.
abstract: Infection withListeria monocytogenesduring pregnancy is associated with miscarriage, preterm birth, and neonatal complications, including sepsis and meningitis. While the risk of these conditions is thought to be greatest during the third trimester of pregnancy, the determinants of fetoplacental susceptibility to infection, the contribution of gestational age, and thein vivoprogression of disease at the maternal-fetal interface are poorly understood. We developed a nonhuman primate model of listeriosis to better understand antecedents of adverse pregnancy outcomes in early pregnancy. Four pregnant cynomolgus macaques (Macaca fascicularis) received a single intragastric inoculation between days 36 and 46 of gestation with 107CFU of anL. monocytogenesstrain isolated from a previous cluster of human listeriosis cases that resulted in adverse pregnancy outcomes. Fecal shedding, maternal bacteremia, and fetal demise were consistently noted within 7 to 13 days. Biopsy specimens of maternal liver, spleen, and lymph node displayed variable inflammation and relatively low bacterial burden. In comparison, we observed greater bacterial burden in the decidua and placenta and the highest burden in fetal tissues. Histopathology indicated vasculitis, fibrinoid necrosis, and thrombosis of the decidual spiral arteries, acute chorioamnionitis and villitis in the placenta, and hematogenous infection of the fetus. Vascular pathology suggests early impact ofL. monocytogenesinfection on spiral arteries in the decidua, which we hypothesize precipitates subsequent placentitis and fetal demise. These results demonstrate thatL. monocytogenestropism for the maternal reproductive tract results in infection of the decidua, placenta, and the fetus itself during the first trimester of pregnancy.IMPORTANCEAlthough listeriosis is known to cause significant fetal morbidity and mortality, it is typically recognized in the third trimester of human pregnancy. Its impact on early pregnancy is poorly defined. Here we provide evidence that exposure toL. monocytogenesin the first trimester poses a greater risk of fetal loss than currently appreciated. Similarities in human and nonhuman primate placentation, physiology, and reproductive immunology make this work highly relevant to human pregnancy. We highlight the concept that the maternal immune response that protects the mother from serious disease is unable to protect the fetus, a concept relevant to classic TORCH (toxoplasmosis,other,rubella,cytomegalovirus, andherpes) infections and newly illuminated by current Zika virus outbreaks. Studies with this model, using the well-understood organismL. monocytogenes, will permit precise analysis of host-pathogen interactions at the maternal-fetal interface and have broad significance to both recognized and emerging infections in the setting of pregnancy.
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.|Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Bryce
authors.initials: B
authors.lastname: Wolfe
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.|Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Wiepz
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Schotzko
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Gennadiy I
authors.initials: GI
authors.lastname: Bondarenko
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Durning
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Simmons
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Mejia
authors.affiliation: Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Nancy G
authors.initials: NG
authors.lastname: Faith
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Sampene
authors.affiliation: Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Marulasiddappa
authors.initials: M
authors.lastname: Suresh
authors.affiliation: Department of Food, Bioprocessing and Nutrition Sciences, North Carolina State University, Raleigh, North Carolina, USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Kathariou
authors.affiliation: Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Czuprynski
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA golos@primate.wisc.edu.|Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.|Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Thaddeus G
authors.initials: TG
authors.lastname: Golos
mesh_terms: D000825:Animal Structures / Q000382:microbiology / Q000473:pathology; D000818:Animals; D058491:Bacterial Load; D004195:Disease Models, Animal; D005260:Female; D005313:Fetal Death; D008088:Listeriosis / Q000150:complications* / Q000382:microbiology / Q000473:pathology*; D008252:Macaca fascicularis; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000382:microbiology / Q000473:pathology*; D011261:Pregnancy Trimester, First