UNC93B1 mediates host resistance to infection with Toxoplasma gondii.
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, TNFα and IFNγ, 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 susceptibility of UNC93B1 mutant mice. The protective role mediated by UNC93B1 to T. gondii infection was associated with impaired IL-12 responses and delayed IFNγ by spleen cells. Notably, in macrophages infected with T. gondii, UNC93B1 accumulates on the parasitophorous vacuole. Furthermore, upon in vitro infection the rate of tachyzoite replication was enhanced in non-activated macrophages carrying mutant UNC93B1 as compared to wild type gene. Strikingly, the role of UNC93B1 on intracellular parasite growth appears to be independent of TLR function. Altogether, our results reveal a critical role for UNC93B1 on induction of IL-12/IFNγ production as well as autonomous control of Toxoplasma replication by macrophages.
Melo
Mariane B
MB
University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Kasperkovitz
Pia
P
Cerny
Anna
A
Könen-Waisman
Stephanie
S
Kurt-Jones
Evelyn A
EA
Lien
Egil
E
Beutler
Bruce
B
Howard
Jonathan C
JC
Golenbock
Douglas T
DT
Gazzinelli
Ricardo T
RT
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D002469:Cell Separation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology; D014122:Toxoplasma / Q000235:genetics / Q000276:immunology; D014124:Toxoplasmosis, Animal / Q000235:genetics* / Q000276:immunology*
D026901:Membrane Transport Proteins; D051193:Toll-Like Receptors; C512254:UNC93B1 protein, mouse; D018664:Interleukin-12; D007371:Interferon-gamma