Location: Animal Parasitic Diseases LaboratoryTitle: Toxoplasma gondii GRA28 is required for specific induction of the regulatory chemokine CCL22 in human and mouse cells
|RUDZKI, ELIZABETH - University Of Pittsburgh|
|COOMBS, RACHEL - University Of Pittsburgh|
|ANDER, STEPHANIE - University Of Pittsburgh|
|BLANK, MATTHEW - University Of Pittsburgh|
|GUITIERREZ-MELO, NICK - University Of Pittsburgh|
|COYNE, CAROLYN - University Of Pittsburgh|
|BOYLE, JON - University Of Pittsburgh|
Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/1/2020
Publication Date: 10/14/2020
Citation: Rudzki, E.N., Coombs, R.S., Ander, S.E., Blank, M.L., Guitierrez-Melo, N., Dubey, J.P., Coyne, C.C., Boyle, J.P. 2020. Toxoplasma gondii GRA28 is required for specific induction of the regulatory chemokine CCL22 in human and mouse cells. Nature Communications. https://doi.org/10.1101/2020.10.14.335802.
Interpretive Summary: Most pregnant women in the United States lack immunity to the parasite that causes toxoplasmosis, placing them at risk of miscarriage or of transmitting the infection to their newborns, which can result in severe brain defects and blindness. Understanding how the parasite evades immunity and causes congenital harm might offer ways to prevent these devastating outcomes. Here, USDA in Beltsville, MD working with researchers working with biologists and pediatricians in Pittsburgh, discovered that a particular substance secreted by the parasite regulates its growth in placental tissue by subverting host immune responses. In cultured human cells and in pregnant mice, immune responses were improved and fetal brain infections were reduced by preventing secretion of this factor. These results will be of great interest to physicians, immunologists, cell biologists, public health officials, parasitologists, and all those concerned with maternal and fetal health.
Technical Abstract: Toxoplasma 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, and is secreted into the host cell where it localizes to the host cell nucleus. Deletion of this gene results in reduced CCL22 secretion from human monocytes and second trimester placental explants, and the impact of GRA28 on CCL22 is conserved in mouse immune and placental cells. Finally deletion of GRA28 results in increased inflammatory responses and reduced CNS burden during mouse infections.