Toxoplasma gondii is a parasite, which can pass through the placenta to the unborn baby in the womb. Infection during pregnancy can result in a number of detrimental consequences including abortion, or neurological defects in the offspring, depending on which stage of pregnancy infection first occurs. Many studies have focussed on the direct effect of the parasite on the fetus, however little is known about fetal damage caused as a consequence of excessive inflammation within the placenta. This study will focus on a receptor called ACKR2 (also known as D6) which is highly expressed within the placenta. ACKR2 has been shown to limit inflammation in many other disease states by scavenging proteins called chemokines which otherwise attract inflammatory immune cells.
Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite, with approximately a third of the world’s population seropositive for infection. Despite this, immunocompetent individuals are usually asymptomatic. The infection is particularly dangerous for those individuals with immunodeficiencies, such as HIV patients, and for those infected during pregnancy, as it can lead to congenital toxoplasmosis in the fetus.
The endocrine and immunological changes that occur throughout pregnancy to prevent fetal rejection are suggested to contribute to the ability of this parasite to cross the placenta. Chemokines are small secreted proteins which play crucial roles in the initiation, maintenance and resolution of inflammatory responses, as well as regulating homeostatic immune cell trafficking and differentiation. ACKR2, the focus of this project, binds and regulates many inflammatory CC chemokines, including those produced in response to T. gondii stimulation (CCL2, 3, 4, 5). ACKR2 acts as a chemokine scavenger by binding, internalising and degrading CC chemokines through its constitutive trafficking to and from the cell surface. In doing so, it acts to limit chemokine bioavailability, thereby suppressing the recruitment of immune cells.
The potential role of ACKR2 in controlling infection with T. gondii is, however, further complicated by the fact that the innate sensing of T. gondii occurs through binding of surface GPI anchors to TLR2 and TLR4. Studies have shown that TLR2 stimulation can lead to downregulation of inflammatory chemokine receptors24, and TLR4 stimulation with LPS can lead to a reduction in ACKR2 expression25. This project will explore the possibility that T. gondii may act to modulate the immune response during primary infection to influence ACKR2 expression by trophoblasts. We hypothesise that T. gondii will act to promote chemokine production and reduce ACKR2- mediated chemokine regulation to facilitate congenital toxoplasmosis and propose to explore this hypothesis using in vitro model systems.