Abstract
Brucellosis, an infectious disease caused by bacteria of the Brucella genus, is one of the major zoonosis around the globe. Initially an animal disease, the infection can be passed onto humans and increases the risk of obstetrical complications in pregnant infected women. During pregnancy, specialized placental cells called trophoblasts ensure the main functions of the placenta. Several of these functions involve the host protein CD98hc. This surface glycoprotein was shown by our group to be important during Brucella infection in different cell types. In this work, we studied the importance of CD98hc in Brucella infection of human trophoblasts and tried to decipher which specific function(s) of the protein was (were) hijacked by the bacteria. Knocking out the SLC3A2 gene (coding for CD98hc) turned out to be impossible, showing that this gene is essential in human trophoblasts. We could however obtain a cellular clone expressing a CD98hc protein with conformational and glycosylation changes in its C-terminal domain and that seems to be trapped in recycling endosomes. Nonetheless, such modifications were compatible with Brucella infection, giving clues about how bacteria could use CD98hc during infection. In another chapter of this work, we identified Gefitinib, an EGFR inhibitor used in the treatment of non-infectious diseases, as a promising drug to fight against brucellosis. This drug was shown to be effective in vitro against the 3 main zoonotic species of Brucella in human trophoblasts as well as murine macrophages. These findings provide new insights into the role of CD98hc in Brucella infection and new leads toward the development of improved brucellosis treatments.