Human placental syncytiotrophoblasts restrictToxoplasma gondiivertical transmission at two distinct stages and induce CCL22 in response to infection

Abstract

52Toxoplasma gondii is a major source of congenital disease worldwide, but the cellular and 53 molecular factors associated with its vertical transmission are largely unknown. In humans, the 54 placenta forms the key interface between the maternal and fetal compartments and forms the 55 primary barrier that restricts the hematogenous spread of microorganisms. Here, we utilized 56 primary human trophoblast (PHT) cells isolated from full-term placentas and human mid-gestation 57 chorionic villous explants to determine the mechanisms by which human trophoblasts restrict and 58 respond to T. gondii infection. We show that placental syncytiotrophoblasts, multinucleated cells 59 that are in direct contact with maternal blood, restrict T. gondii infection at distinct stages of the 60 parasite lytic cycle-at the time of attachment and also during intracellular replication. Utilizing 61 comparative RNAseq transcriptional profiling, we also show that human placental trophoblasts at 62 both mid-and late-stages of gestation induce the chemokine CCL22 in response to T. gondii 63 infection, which relies on the secretion of parasite effector(s). Collectively, our findings provide 64 new insights into the mechanisms by which the human placenta restricts the vertical transmission 65 of T. gondii at early and late stages of human pregnancy, and demonstrate the existence of at 66 least two interferon-independent pathways that restrict T. gondii access to the fetal compartment. 67 68 Significance statement 69 Toxoplasma gondii is a major source of congenital disease worldwide and must breach the 70 placental barrier to be transmitted from maternal blood to the developing fetus. The events 71 associated with the vertical transmission of T. gondii are largely unknown. Here, we show that 72 primary human syncytiotrophoblasts, the fetal-derived cells that comprise the primary placental 73 barrier, restrict T. gondii infection at two distinct stages of the parasite life cycle and respond to 74 infection through the induction of the chemokine CCL22. Collectively, our findings provide 75 important insights into the mechanisms by which human syncytiotrophoblasts restrict T. 76 3 gondii infection at early and late stages of human pregnancy and identify the placental-77 enriched signaling pathways induced in response to infection. Toxoplasma gondii is a major source of congenital disease, with ~200,000 global cases 104 of congenital toxoplasmosis reported each year (1). In the majority of instances (~80%), in utero 105 infections by T. gondii result in a range of severe birth defects, including ocular disease and 106 developmental delays, and can also result in fetal death (2). However, despite the clear impact of 107 T. gondii infections on fetal health, the mechanisms by which the parasite is transmitted from the 108 maternal bloodstream into the fetal compartment are largely unknown. 109In eutherian organisms, the placenta serves as the sole source of gas, nutrient, and waste 110 exchange from the fetal compartment and acts as a key barrie...

Crosstalk between Neospora caninum and the bovine host at the maternal-foetal interface determines the outcome of infection

“…In vitro infections showed that trophoblasts are the niche for parasite proliferation, whereas caruncular cells seem to restrict the infection, acting as a barrier to parasite transmission [10]. Parallel results in human placentas infected with Toxoplasma gondii have also been observed [35]. In the present study, immunohistochemical labelling revealed an increase in the immune cell populations associated with the maternal compartment of the placentome.…”

Participação de quinase regulada por sinais extracelulares (ERK)-1/2 e IL-6 na susceptibilidade de diferentes populações de células trofoblásticas humanas à infecção por Toxoplasma gondii

“…Quando a infecção por T. gondii acomete embriões ou fetos, esta é conhecida como toxoplasmose congênita, e são relatados cerca de 200.000 casos no mundo a cada ano (ANDER et al, 2018). Nesse tipo de infecção ocorre a transmissão vertical da toxoplasmose quando a mulher adquire a infecção durante a gestação e encontra-se na fase aguda desta infecção (REMINGTON et al, 2001;KODJIKIAN, 2010), ou pode ser ocasionada quando a infecção na gestante ocorre antes da concepção (VOGEL et al, 1996;CHEMLA et al, 2002, BARBOSA et al, 2008CHAUDHRY et al, 2014).…”