TRIM21 is critical for survival of Toxoplasma gondii infection and localises to GBP-positive parasite vacuoles

Foltz, Clémence; Napolitano, Anna; Khan, Rabia; Clough, Barbara; Hirst, Elizabeth; Frickel, Eva‐Maria

doi:10.1038/s41598-017-05487-7

Cited by 57 publications

(59 citation statements)

References 75 publications

(120 reference statements)

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“…with data from Foltz et al, 28 who identified TRIM21 as a critical factor in the defense against the obligate intracellular parasite Toxoplasma gondii. Furthermore, Trim21 À/À BMDMs were hyporesponsive to TLR2 stimulation by both the synthetic ligand PAM3CSK4 and M. bovis BCG, indicating that TRIM21 also plays an important role in response to more complex stimuli.…”

Section: Discussionmentioning

confidence: 64%

TRIM21 controls Toll‐like receptor 2 responses in bone‐marrow‐derived macrophages

et al. 2019

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TRIM21 is an interferon-stimulated E3 ligase that controls the activity of pattern-recognition signaling via ubiquitination of interferon regulatory factors and DDX41. Previous studies on the role of TRIM21 in innate immune responses have yielded contradictory results, suggesting that the role of TRIM21 is cell specific. Here, we report that bone-marrow-derived macrophages (BMDMs) generated from Trim21 À/À mice have reduced expression of mature macrophage markers. Reflecting their reduced differentiation in response to macrophage colony-stimulating factor (M-CSF), Trim21 À/À BMDMs had decreased expression of M-CSF signature genes. Although Trim21 À/À BMDMs responded normally to Toll-like receptor 9 (TLR9) activation, they produced lower levels of pro-inflammatory cytokines in response to the TLR2 agonist PAM3CSK4. In line with this, the response to infection with the Bacillus Calmette-Gu erin strain of Mycobacterium bovis was also diminished in Trim21 À/À BMDMs. Our results indicate that TRIM21 controls responses to TLR2 agonists.

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Section: Discussionmentioning

confidence: 64%

TRIM21 controls Toll‐like receptor 2 responses in bone‐marrow‐derived macrophages

et al. 2019

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“…12,15,21 It is, however, still not known how mGBPs specifically target the T. gondii PCV and distinguish it from other cell's membranes. For example, some studies suggest that TRAF6, p62, and TRIM21 are recruited to the T. gondii-containing vacuole, which favors its ubiquitination and might elicit p62-mediated recruitment of mGBP2, 26,27 whereas other studies argue that mGBP recruitment is p62-independent and PCV ubiquitination might be a consequence of mGBP-mediated vacuolar lysis. 28 In addition, it remains to be addressed how the GBP multimers destabilize the membrane of the PCV and of the parasite itself.…”

Section: Gbps In the Defense Against Protozoa And Virusesmentioning

confidence: 99%

Sensing of invading pathogens by GBPs: At the crossroads between cell-autonomous and innate immunity

Santos

Brož

2018

Journal of Leukocyte Biology

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Guanylate-binding proteins (GBPs) are conserved family of IFN-inducible GTPases that play an important role in the host immunity against bacterial, viral, and protozoan pathogens. GBPs protect the host by associating with intracellular microbes, their vacuolar niche or, in the case of viruses, with their replication complex. This association results in a restriction of the respective pathogen, yet the exact molecular mechanisms of the antimicrobial functions of GBPs are still unclear. Recent work has linked the GBPs with the activation of inflammasomes, multi-protein complexes that assemble upon recognition of pathogen- or host-derived signals and that drive the release of cytokines and host cell death. Here, we will focus on the most recent findings that have started to unravel the manifold restriction mechanism controlled by GBPs in mouse and human cells, and that shed light on the molecular cues that control GBP recruitment to bacterial membranes.

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“…Splenic NK cells were selected as, upon adoptive transfer, they have been shown to recirculate through all organs ordinarily containing NK cells 31. Previous studies showed that tachyzoites are detected in lymphoid tissues early after infection (between 2 and 6 days),4, 12, 32, 33 while parasites were detected in the brains of infected animals by 7 dpi 4, 8, 30, 34. We therefore decided to evaluate the parasite burden in the spleen and the brain of infected animals by PCR at 4 and 7 dpi.…”

Section: Resultsmentioning

confidence: 99%

Parasitized Natural Killer cells do not facilitate the spread of Toxoplasma gondii to the brain

Petit-Jentreau

Glover

Coombes

2018

Parasite Immunology

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Summary Toxoplasma gondii is a protozoan parasite capable of invading immune cells and co‐opting their migratory pathways to disseminate through the host. Natural Killer (NK) cells can be directly invaded by the parasite and this invasion alters NK cell migration, producing a hypermotile phenotype. However, the consequences of this hypermotile phenotype for the dissemination of T. gondii to the brain remain unknown. To address this, C57BL6/J mice were infected with freshly egressed tachyzoites (type II Prugniaud strain) or with parasitized NK cells. Under both conditions, parasite loads in the brain were comparable, indicating that parasitized NK cells were not able to facilitate spread of T. gondii to the brain. Consistent with this, we found no evidence for the recruitment of endogenous NK cells to the brain at early time points post‐infection, nor any changes in the expression of α4β1 integrin, involved in recruitment of NK cells to the brain. We therefore found no evidence for a role for hypermotile NK cells in delivery of parasites to the brain during acute infection with T. gondii.

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TRIM21 is critical for survival of Toxoplasma gondii infection and localises to GBP-positive parasite vacuoles

Cited by 57 publications

References 75 publications

TRIM21 controls Toll‐like receptor 2 responses in bone‐marrow‐derived macrophages

TRIM21 controls Toll‐like receptor 2 responses in bone‐marrow‐derived macrophages

Sensing of invading pathogens by GBPs: At the crossroads between cell-autonomous and innate immunity

Parasitized Natural Killer cells do not facilitate the spread of Toxoplasma gondii to the brain

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