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, 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.
Highlights
Toxoplasma gondii is a widespread obligate intracellular protozoan parasite, which establishes itself in the brain and muscle tissues, persisting for life in humans and other vertebrate hosts [1]
We found that the 3d mice are highly susceptible to infection with T. gondii, suggesting the possibility that the combined action of TLR3, TLR7 and TLR9 is critical for host resistance to infection with T. gondii
UNC93B1 is a critical mediator of the translocation of nucleotidesensing TLR3, TLR7 and TLR9 from the endoplasmic reticulum (ER) to endolysosomes [22]
Summary
Toxoplasma gondii is a widespread obligate intracellular protozoan parasite, which establishes itself in the brain and muscle tissues, persisting for life in humans and other vertebrate hosts [1]. One of the most distinctive aspects of T. gondii life cycle is the establishment of an often benign chronic infection, which is dependent on the parasite’s ability to elicit a strong and persistent cell-mediated immunity [1]. Cytokines that activate macrophage effector functions, such as IFNc and TNFa, are critical in mediating host resistance to T. gondii infection [2]. Studies employing MyD882/2 mice, which are deficient in the function of most TLRs (except for TLR3), suggest that TLRs are critical in many aspects of host:protozoan parasite interaction, including the initiation of the pro-inflammatory cytokine response and the expression of costimulatory molecules [5,6,7]. The deficiency of each of these TLRs, and even the loss of two TLRs, as is the case with TLR2/TLR4 double knockout mice, leads to a relatively minor phenotype after T. gondii infection, as compared to the results obtained with infected MyD882/2 mice [6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
