UNC93B1 mediates host resistance to infection with toxoplasma gondii

Mariane B. Melo, Pia Kasperkovitz, Anna Cerny, Stephanie Könen-Waisman, Evelyn A. Kurt-Jones, Egil Lien, Bruce Beutler, Jonathan C. Howard, Douglas T. Golenbock, Ricardo T. Gazzinelli

Research output: Contribution to journalArticle

44 Scopus citations

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 stablished 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 wildtype 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 IFNc 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 nonactivated 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/IFNc production as well as autonomous control of Toxoplasma replication by macrophages.

Original languageEnglish (US)
Article numbere1001071
Pages (from-to)83-84
Number of pages2
JournalPLoS pathogens
Volume6
Issue number8
DOIs
StatePublished - Aug 2010

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Melo, M. B., Kasperkovitz, P., Cerny, A., Könen-Waisman, S., Kurt-Jones, E. A., Lien, E., Beutler, B., Howard, J. C., Golenbock, D. T., & Gazzinelli, R. T. (2010). UNC93B1 mediates host resistance to infection with toxoplasma gondii. PLoS pathogens, 6(8), 83-84. [e1001071]. https://doi.org/10.1371/journal.ppat.1001071