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

43 Citations (Scopus)

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

Fingerprint

Toxoplasmosis
Toxoplasma
Macrophages
Interleukin-12
Toll-Like Receptor 3
Communicable Disease Control
Toll-Like Receptors
Cell Lineage
Vacuoles
Infection
Endoplasmic Reticulum
Nucleic Acids
Interleukin-6
Parasites
Spleen
Bone Marrow
Ligands
Growth
Genes

ASJC Scopus subject areas

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

Cite this

Melo, M. B., Kasperkovitz, P., Cerny, A., Könen-Waisman, S., Kurt-Jones, E. A., Lien, E., ... 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

UNC93B1 mediates host resistance to infection with toxoplasma gondii. / Melo, Mariane B.; Kasperkovitz, Pia; Cerny, Anna; Könen-Waisman, Stephanie; Kurt-Jones, Evelyn A.; Lien, Egil; Beutler, Bruce; Howard, Jonathan C.; Golenbock, Douglas T.; Gazzinelli, Ricardo T.

In: PLoS Pathogens, Vol. 6, No. 8, e1001071, 08.2010, p. 83-84.

Research output: Contribution to journalArticle

Melo, MB, Kasperkovitz, P, Cerny, A, Könen-Waisman, S, Kurt-Jones, EA, Lien, E, Beutler, B, Howard, JC, Golenbock, DT & Gazzinelli, RT 2010, 'UNC93B1 mediates host resistance to infection with toxoplasma gondii', PLoS Pathogens, vol. 6, no. 8, e1001071, pp. 83-84. https://doi.org/10.1371/journal.ppat.1001071
Melo MB, Kasperkovitz P, Cerny A, Könen-Waisman S, Kurt-Jones EA, Lien E et al. UNC93B1 mediates host resistance to infection with toxoplasma gondii. PLoS Pathogens. 2010 Aug;6(8):83-84. e1001071. https://doi.org/10.1371/journal.ppat.1001071
Melo, Mariane B. ; Kasperkovitz, Pia ; Cerny, Anna ; Könen-Waisman, Stephanie ; Kurt-Jones, Evelyn A. ; Lien, Egil ; Beutler, Bruce ; Howard, Jonathan C. ; Golenbock, Douglas T. ; Gazzinelli, Ricardo T. / UNC93B1 mediates host resistance to infection with toxoplasma gondii. In: PLoS Pathogens. 2010 ; Vol. 6, No. 8. pp. 83-84.
@article{7730585a433c4a13a7942187f6c6684a,
title = "UNC93B1 mediates host resistance to infection with toxoplasma gondii",
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.",
author = "Melo, {Mariane B.} and Pia Kasperkovitz and Anna Cerny and Stephanie K{\"o}nen-Waisman and Kurt-Jones, {Evelyn A.} and Egil Lien and Bruce Beutler and Howard, {Jonathan C.} and Golenbock, {Douglas T.} and Gazzinelli, {Ricardo T.}",
year = "2010",
month = "8",
doi = "10.1371/journal.ppat.1001071",
language = "English (US)",
volume = "6",
pages = "83--84",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "8",

}

TY - JOUR

T1 - UNC93B1 mediates host resistance to infection with toxoplasma gondii

AU - Melo, Mariane B.

AU - Kasperkovitz, Pia

AU - Cerny, Anna

AU - Könen-Waisman, Stephanie

AU - Kurt-Jones, Evelyn A.

AU - Lien, Egil

AU - Beutler, Bruce

AU - Howard, Jonathan C.

AU - Golenbock, Douglas T.

AU - Gazzinelli, Ricardo T.

PY - 2010/8

Y1 - 2010/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77958144527&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77958144527&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1001071

DO - 10.1371/journal.ppat.1001071

M3 - Article

C2 - 20865117

AN - SCOPUS:77958144527

VL - 6

SP - 83

EP - 84

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 8

M1 - e1001071

ER -