unc93b1 mediates host resistance to infection with toxoplasma gondiiunc93b1介导宿主抗感染刚地弓形虫.pdfVIP

UNC93B1 Mediates Host Resistance to Infection with Toxoplasma gondii 1 1 1 ¨ 2 1 Mariane B. Melo , Pia Kasperkovitz , Anna Cerny , Stephanie Konen-Waisman , Evelyn A. Kurt-Jones , 1 3 2 1,4 1,4,5 Egil Lien , Bruce Beutler , Jonathan C. Howard , Douglas T. Golenbock , Ricardo T. Gazzinelli * 1 University of Massachusetts Medical School, Worcester, Massachusetts, United States of America, 2 Institute for Genetics, University of Cologne, Cologne, Germany, ´ ˜ 3 The Scripps Research Institute, La Jolla, California, United States of America, 4 Centro de Pesquisas Rene Rachou, Fundac¸ao Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil, 5 Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil Abstract UNC93B1 associates with Toll-Like Receptor (TLR) 3, TLR7 and TLR9, mediating their translocation from the endoplasmic reticulum to the endolysosome, hence allowing proper activation by nucleic acid ligands. We found that the triple deficient ‘3d’ mice, which lack functional UNC93B1, are hyper-susceptible to infection with Toxoplasma gondii. We established that while mounting a normal systemic pro-inflammatory response, i.e. producing abundant MCP-1, IL-6, TNFa and IFNc, the 3d mice were unable to control parasite replication. Nevertheless, infection of reciprocal bone marrow chimeras between wild- type and 3d mice with T. gondii demonstrated a primary role of hemopoietic cell lineages in the enhanced