Maternal- and Fetal-Encoded Perforin-2 Limits Placental Infection by a Bloodborne Pathogen

Abstract

Placental immune responses are highly regulated to strike a balance between protection and tolerance. For relatively mild infections, protection encompasses both the mother and fetus; however, during worsening conditions, protection becomes exclusively reserved for the mother. Previously, we and others have shown that the host factor perforin-2 plays a central role in protecting mice and cells against infection. In this study, we analyzed perforin-2 activity in the mouse placenta to determine whether perforin-2 plays a similarly protective role. We show that perforin-2 is critical for inhibiting Listeria monocytogenes colonization of the placenta and fetus and that this protection is due to both maternal and fetal-encoded perforin-2. Perforin-2 mRNA is readily detectable in individual immune cells of the decidua, and these levels are further enhanced specifically in decidual macrophages during high-dose infections that result in fetal expulsion. Unexpectedly, inductive perforin-2 expression in decidual macrophages did not occur during milder infections in which fetal viability remained intact. This pattern of expression significantly differed from that observed in splenic macrophages in which inductive perforin-2 expression was observed in both high and mild infection conditions. In the placenta, inductive perforin-2 expression in decidual macrophages was coincident with their polarization from a CD206 + MHC class II lo to CD206 2 MHC class II hi phenotype that normally occurs in the placenta during high-burden infections. Our results suggest that perforin-2 is part of a host response that is protective either for both the mother and fetus in milder infections or exclusively for the mother during high-dose infections.

Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression

“…P-2 KO mice (n=9) were generated and bred at University of Miami (20,65). Mice were shaved and tape-stripped (7 applications) with Transpore tape (3M, Minneapolis, MN, United States) to disrupt the epidermal barrier (20).…”

Breaching the Bacterial Envelope: The Pivotal Role of Perforin-2 (MPEG1) Within Phagocytes

“…Perforin-2 deficient mice infected intravenously with L. monocytogenes have significantly greater loads of the pathogen in their spleens and livers than wild-type mice ( 52 ). In a pregnancy model of infection Perforin-2 deficient mice had significantly higher loads of L. monocytogenes in both the placenta and fetuses ( 76 ). In these models injected bacteria are phagocytosed and killed by splenic and liver macrophages ( 77 ).…”

Innate immune responses to Listeria in vivo

“…Macrophages, through TNF-a and IL-12, signal to decidual NK cells to produce IFNg, increasing their bactericidal activity against Lm [56] (Figure 2). In decidual macrophages, Lm infection induces the expression of Perforin-2, a membrane-attack-complex-perforin-containing factor, that mediates the killing of intracytoplasmic Lm [57]. However, Perforin-2 can also trigger miscarriage.…”