Selected publications with comments
• Fisch D, Bando H, Clough B, Hornung V, Yamamoto M, Shenoy, AR, Frickel EM. Human GBP1 is a microbe‐specific gatekeeper of macrophage apoptosis and pyroptosis. The EMBO journal, e100926
• Fisch D, Yakimovich Y, Clough B, Wright J, Bunyan M, Howell M, Mercer J, Frickel EM. Defining host–pathogen interactions employing an artificial intelligence workflow. eLife 8, e40560
• Napolitano A, van der Veen AG, Bunyan M, Borg A, Frith D, Howell S, Kjaer S, Beling A, Snijders AP, Knobeloch KP, Frickel EM. Cysteine-Reactive Free ISG15 Generates IL-1b-Producing CD8a+-Dendritic Cells at the Site of Infection. J Immunol. 2018 Jun 11. pii: ji1701322. doi: 10.4049/jimmunol.1701322
We show that cysteines in the ubiquitin-like ISG15 are critical when this protein is generated extracellularly during an acute Toxoplasma infection. Free ISG15 enables CD8a+ DCs to produce IL-1b at the site of Toxoplasma infection.
• Sanecka A, Yoshida N, Kolawole EM, Patel H, Evavold BD, Frickel EM. T Cell Receptor–Major Histocompatibility Complex Interaction Strength Defines Trafficking and CD103+ Memory Status of CD8 T Cells in the Brain. Frontiers in Immunology 9, 1290. doi: 10.3389/fimmu.2018.01290
3 clones with different binding strengths to the same MHC-epitope combination fare differently in the chronic phase of Toxoplasma infection.
• REVIEW: Saeij JP, Frickel EM. Exposing Toxoplasma gondii hiding inside the vacuole: a role for GBPs, autophagy and host cell death. Curr Opin Microbiol. 2017 Dec;40:72-80. doi: 10.1016/j.mib.2017.
Our summary of how the host responds to infection with the Toxoplasma tachyzoite. Mouse and human cells react differently and the main players are GTPases, autophagy and the ability of the host cell to commit suicide.
• REVIEW: Yoshida N, Frickel EM, Mostowy S. Macrophage-Microbe Interactions: Lessons from the Zebrafish Model. Front Immunol. 2017 Dec 1;8:1703. doi: 10.3389/fimmu.2017.01703.
The zebrafish is a fantastic model when it comes to studying in vivoinnate immune control of pathogens – it is translucent and thus provides for amazing microscopy and it is genetically accessible enabling molecular studies of host defence molecules. We summarise host macrophage-pathogen interaction studies conducted with the zebrafish in this review.
• Foltz C, Napolitano A, Khan R, Clough B, Hirst EM, Frickel EM. TRIM21 is critical for survival of Toxoplasma gondii infection and localises to GBP-positive parasite vacuoles. Sci Rep. 2017 Jul 12;7(1):5209. doi: 10.1038/s41598-017-05487-7.
In mice, the E3 ubiquitin ligase TRIM21 is essential for controlling the infection with Toxoplasma. TRIM21 mediates some of the K63-linked ubiquitin that is deposited around the GBP-marked PV and controls parasite replication and adequate cytokine production. How exactly all of this works we do not know yet!
• REVIEW: Clough, B and Frickel, E-M (2017) The Toxoplasma parasitophorous vacuole: an evolving host-parasite frontier. Trends Parasitol. 2017 Jun;33(6):473-488. doi: 10.1016/j.pt.2017.02.007
Our summary of what happens at the vacuole which is the border between the Toxoplasma parasite and the host cell. Lots of host defence mechanisms targeting the vacuole while the parasite has learnt to fight back!
• Clough, B; Wright, JD; Pereira, PM; Hirst, EM; Johnston, AC; Henriques, R and Frickel, E-M (2016) K63-linked ubiquitination targets Toxoplasma gondii for endo-lysosomal destruction in IFNγ-stimulated human cells. PLOS Pathogens 12, e1006027. doi: 10.1371/journal.ppat.1006027
Human Toxoplasma vacuoles are also ubiquitinated! This ubiquitination targets the parasite for destruction by acidification in the endo-lysosomal system. Important: autophagy seems to not play a dominant role and acidic destruction is specific for type II parasites.
• Johnston, AC; Piro, A; Clough, B; Siew, M; Virreira Winter, S; Coers, J and Frickel, E-M (2016) Human GBP1 does not localize to pathogen vacuoles but restricts Toxoplasma gondii. Cellular Microbiology 18, 1056-1064
Human GBP1 can restrict the replication of Toxoplasma, but not Salmonella or Chlamydia in epithelial A549 cells. It does this without localising to the Toxo vacuole. We are still wondering how…
• Sanecka, A; Yoshida, N; Dougan, SK; Jackson, J; Shastri, N; Ploegh, H; Blanchard, N and Frickel, E-M (2016) Transnuclear CD8 T cells specific for the immunodominant epitope Gra6 lower acute-phase Toxoplasma gondii burden. Immunology 149, 270-279. doi: 10.1111/imm.1264
The transnuclear CD8 T cells specific to the immunodominant epitope Gra6 are fully functional and can actively lower the parasite burden. These CD8 T cells could be useful to study further details of the host response to Toxoplasma or properties of potential vaccine strategies.
• Swee, LK; Tan, ZW; Sanecka, A; Yoshida, N; Patel, H; Grotenbreg, G; Frickel, E-M and Ploegh, HL (2016) Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions. Open Biology 6, 160293. pii: 160293
3 CD8 T cell clones with different T cell receptor sequences all recognising the same MHC I-epitope combination: they exhibit a responsiveness to the epitope that is driven by the responsiveness to self peptide rather than strictly to the hierarchy of TCR-MHC binding strength. Never before have people been able to study 3 different T cell clones that react to the same endogenous epitope peptide.
• Haldar, AK; Foltz, C; Finethy, R; Piro, AS; Feeley, EM; Pilla-Moffett, DM; Komatsu, M; Frickel, E-M and Coers, J (2015) Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins. Proceedings of the National Academy of Sciences of the United States of America 112, E5628-E5637. doi: 10.1073/pnas.1515966112
We contributed to this study that for the first time demonstrates ubiquitin around the Toxoplasma vacuole – in IFNg-stimulated murine cells. Some of the ubiquitin is deposited by Traf6, which in turn recruits p62 and subsequently GBPs. Important: IRGs are the seeds of this pathway! Ubiquitin is at the centre of the host defence cascade to Toxoplasma!