Acute Fetal Demise with First Trimester Maternal Infection Resulting from Listeria monocytogenes in a Nonhuman Primate Model

Abstract

Infection with Listeria monocytogenes during 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 the in vivo progression 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 107 CFU of an L. monocytogenes strain 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 of L. monocytogenes infection on spiral arteries in the decidua, which we hypothesize precipitates subsequent placentitis and fetal demise. These results demonstrate that L. monocytogenes tropism for the maternal reproductive tract results in infection of the decidua, placenta, and the fetus itself during the first trimester of pregnancy.

Impact of Ferumoxytol Magnetic Resonance Imaging on the Rhesus Macaque Maternal-Fetal Interface

“…This previously published model reported increased numbers of macrophages and granulocytes in the decidua parietalis, however that study did not evaluate the decidua basalis which we hypothesized would be imaged with Ferumoxytol treatment. While our study did not validate the use of Ferumoxytol with this model due to lack of induced inflammation, it is possible that other nonhuman primate models of adverse pregnancy outcomes and MFI inflammation, including maternal infection with Listeria monocytogenes [49] or Zika virus [37,50-52] which have been shown to provoke significant inflammation in the decidua basalis with significant placental pathology, may more productively demonstrate the efficacy of ferumoxytol for detection of inflammation at the MFI. Furthermore, a placenta facing a bacterial or viral insult may have altered placental transporter protein expression, which may affect ferumoxytol’s ability to pass into the fetal blood circulation [53].…”

Listeria Placental Infection

“…This and other placental immune tolerance mechanisms prevent the rejection of the semiallogenic fetus but at the same time may provide a protected sanctuary for the proliferation of intracellular pathogens like L. monocytogenes , ultimately depending on T-cell-mediated immunity for clearance (33). Consistent with the rare cooccurrence of central nervous system (CNS) involvement in maternofetal listeriosis (0.01%) (15), neurological signs were never observed in experimentally infected pregnant macaques (9–11) despite listerial CNS infection having a shorter incubation period (1 to 14 days) (16). In an immunocompetent pregnant mother, this may reflect competition between a permissive placenta and a less permissive blood-brain barrier in allowing the establishment of limited numbers of circulating listeriae (Fig.…”

Animal and Human Tissue Models of Vertical Listeria monocytogenes Transmission and Implications for Other Pregnancy-Associated Infections

“…Immune regulation in NHP placentas is by far the most similar to that in humans (76). Additionally, NHPs express Ecad and c-Met isoforms that interact with InlA and InlB, allowing for L. monocytogenes gastrointestinal infections (77,78), and they are permissive to other important transplacental human pathogens as well, including cytomegalovirus (79), Toxoplasma (80,81), and Trypanosoma cruzi (82). However, there are many disadvantages to NHPs.…”

“…Like humans, pregnant rhesus and cynomolgus macaques do not show overt signs of illness after inoculation (77,85). Further, hematological studies show few changes in leukocyte populations during infections (77,78). However, one of the earliest and most consistent signs of L. monocytogenes infection in NHPs is fecal shedding of L. monocytogenes (78).…”

“…Further, hematological studies show few changes in leukocyte populations during infections (77,78). However, one of the earliest and most consistent signs of L. monocytogenes infection in NHPs is fecal shedding of L. monocytogenes (78).…”