Trophoblast apoptosis through polarization of macrophages induced by Chinese Toxoplasma gondii isolates with different virulence in pregnant mice

Abstract

Toxoplasma gondii is an apicomplexan parasite capable of transplacental transmission to cause spontaneous abortion or significant disease in the surviving neonate. Different from the dominant genotypes of T. gondii strains in European and North American which belong to three distinct clonal lineages, type I, type II, and type III, isolates from China possess the predominant genotype of China 1(ToxoDB#9) with a different virulence. The genotype-associated pathogenesis has been investigated previously. Based on two isolates of T. gondii from Chinese wild cats, a murine model of pregnancy and one transwell system in vitro, here we reported differentially polarized activation of macrophages induced by genotype China 1 strains, TgCtwh3 and TgCtwh6 with different virulence to mice, and its impact on trophoblast apoptosis. The results showed that macrophages were alternatively activated when infected with virulent TgCtwh3 while classically activated when infected with low virulent (cyst-forming) TgCtwh6 both in vitro and in vivo. By the analysis of flow cytometry, the percentage of the Th1 cells in two infection groups decreased significantly, and the Th2 cells from spleen escalated only in the virulent TgCtwh3 group. Interestingly, the high parasite burden was noted in the placenta of TgCtwh3-infected group whereas the inflammatory cells infiltration predominates in the TgCtwh6-infected group. In vivo trophoblast apoptosis in TgCtwh3 group was found to be more obvious when compared with TgCtwh6 although it was present in both. The present observations indicate that polarization of macrophages and modulation of Th subsets induced by the isolates with identical genotype but different virulence could contribute to trophoblast apoptosis through different mechanisms, suggesting a virulence-associated pathogenesis of T. gondii in abnormal pregnant outcome.

M1/M2 Macrophage Polarity in Normal and Complicated Pregnancy

“…The obligate intracellular parasite Toxoplasma gondii can invade the placenta and fetus, resulting in spontaneous abortion, stillbirth, fetal neurological, and ocular damage (104). A virulent strain of T. gondii , TgCtwh3, actively induces M2 polarization in infected macrophages (15). TgCtwh3 rapidly invades the placenta producing a heavy parasite burden with minimal inflammation but a high rate of trophoblast apoptosis (15).…”

“…A virulent strain of T. gondii , TgCtwh3, actively induces M2 polarization in infected macrophages (15). TgCtwh3 rapidly invades the placenta producing a heavy parasite burden with minimal inflammation but a high rate of trophoblast apoptosis (15). On the other hand, less virulent strain TgCtwh6 triggers pro-M1 responses in infected macrophages (15).…”

“…TgCtwh3 rapidly invades the placenta producing a heavy parasite burden with minimal inflammation but a high rate of trophoblast apoptosis (15). On the other hand, less virulent strain TgCtwh6 triggers pro-M1 responses in infected macrophages (15). TgCtwh6 can still invade the placenta, but infection is contained and associated with a profound lymphocytic inflammatory response with trophoblast apoptosis that is less extensive than TgCtwh3 (15).…”

“…Successful pregnancy requires that the macrophage activation state remain regulated throughout pregnancy. Indeed, inappropriate macrophage polarization within the maternal–fetal compartments is associated with spontaneous abortion or miscarriage (12), inadequate remodeling of the uterine vessels during placentation (12–14), and intrauterine parasitic infections (15). In this review, we provide an overview of M1/M2 dynamics relevant to the maternal–fetal interface, the temporal and spatial changes in macrophage M1/M2 within the maternal and fetal compartments during normal pregnancy, and imbalanced M1/M2 dynamics associated with complicated pregnancies.…”

Identification of a TNF-α inducer MIC3 originating from the microneme of non-cystogenic, virulent Toxoplasma gondii

“…Acute T. gondii infection initiates M1-dominant polarization of macrophages, which produce high levels of NO and proinflammatory cytokines such as TNF-α and IL-622232829. M1 macrophages destroy intracellular pathogens by releasing NO, which is known to be a major effector molecule in macrophage-mediated cytotoxicity27.…”