Toxoplasma gondii GRA28 is required for specific induction of the regulatory chemokine CCL22 in human and mouse cells
ABSTRACTToxoplasma gondii is an intracellular protozoan pathogen of humans that causes severe disease in immunocompromised patients and in the developing fetus. T. gondii specifically alters production of the immunomodulatory chemokine CCL22 in human placental cells during infection. Using a combination of bioinformatics and molecular genetics, we have now identified T. gondii GRA28 as the gene product required for CCL22 induction. GRA28 is strongly co-regulated at the transcriptional level along with other known secreted effectors and their chaperones. GRA28 is secreted into the host cell where it localizes to the nucleus, and deletion of this gene results in reduced CCL22 secretion from human monocytes and second trimester placental explants. The impact of GRA28 on CCL22 is also conserved in mouse immune and placental cells and the deletion of GRA28 results in increased inflammatory responses and reduced CNS burden during mouse infectionsAUTHOR SUMMARYToxoplasma gondii is a globally ubiquitous pathogen that can cause severe disease in HIV/AIDS patients and can also cross the placenta and infect the developing fetus. We have found that placental and immune cells infected with T. gondii secrete signfiicant amounts of a chemokine (called “CCL22”) that is critical for immune tolerance during pregnancy. In order to better understand whether this is a response by the host or a process that is driven by the parasite, we have identified a T. gondii gene that is absolutely required to induce CCL22 production in human cells, indicating that CCL22 production is a process driven almost entirely by the parasite rather than the host. Consistent with its role in immune tolerance, we also found that T. gondii parasites lacking this gene are less able to proliferate and disseminate throughout the host. Taken together these data illustrate a direct relationship between CCL22 levels in the infected host and a key parasite effector, and provide an interesting example of how T. gondii can directly modulate host signaling pathways in order to facilitate its growth and dissemination.