Toxoplasma Effectors that Affect Pregnancy Outcome

Abstract

As an immune-privileged organ, the placenta can tolerate the introduction of antigens without inducing a strong inflammatory response that would lead to abortion. However, for the control of intracellular pathogens, a strong Th1 response characterized by the production of interferon-γ is needed. Thus, invasion of the placenta by intracellular parasites puts the maternal immune system in a quandary: The proinflammatory response needed to eliminate the pathogen can also lead to abortion. Toxoplasma is a highly successful parasite that causes lifelong chronic infections and is a major cause of abortions in humans and livestock. Here, we discuss how Toxoplasma strain type and parasite effectors influence host cell signaling pathways, and we speculate about how this might affect the outcome of gestation.

Keywords: GRA; ROP; Toxoplasma; gestation; placenta.

Figure 1. Key Figure. Immune Response to Toxoplasma Infection during Gestation

After oral infection, Toxoplasma disseminates either as extracellular parasites or by a Trojan horse mechanism and reaches the placenta. (A) In type I strains, rhoptry bulb protein ROP16_I induces sustained activation of signal transducer and activator of transcription (STAT3/6), dampening the production of interleukin (IL)-12, IL-1β, and IL-6, while dense granule protein GRA6_I/III induces the secretion of CC chemokine ligand 2 (CCL2). In the absence of IL-12, an anti-inflammatory profile predominates with M2 macrophages and Th2, CD4, and regulatory T cells (Treg). As a consequence, the uncontrolled parasite multiplication produces tissue damage, which in turn facilitates the invasion of the fetus. The most likely outcomes are late abortion and/or congenital infection during early or late gestation, respectively. (B) Type II strains produce a strong inflammatory environment in the placenta due to the early secretion of IL-12 induced by GRA15. This stimulates the secretion of proinflammatory cytokines [interferon {IFN)-γ, IL-1β, and tumor necrosis factor (TNF)-α], which in turn upregulates the expression of intercellular adhesion molecule 1 (ICAM1) on trophoblasts, facilitating the adhesion of infected cells. The intense proinflammatory response eliminates most of the parasites but produces extensive tissue damage that compromises nutrient/oxygen transport to the fetus. Hence, the most likely outcome is an early, ‘sterile’ abortion without vertical transmission. (C)Similar to type I, ROP16_III limits the initial production of IL-12, delaying the induction of antiparasitic mechanisms and establishing an initial anti-inflammatory response. However, type III strains are not effective at avoiding intracellular killing, and a proinflammatory immune response is eventually mounted when IL-12 is produced by dendritic cells. However, because the control of the parasite is delayed, some parasites can cross the placental barrier and reach the fetus. Therefore, both early and late abortion with or without vertical transmission are possible, depending on the stage of gestation.