Dr Eva Frickel PhD

Dr Eva Frickel

School of Biosciences
Senior Wellcome Trust Fellow
Reader

Contact details

The Frickel lab studies interferon gamma-driven human host responses to infection and inflammation. We specifically focus on pathways driven by host guanylate binding proteins (GBPs) and ubiquitin. The pathogens we are most interested in are Toxoplasma gondii and Salmonella typhimurium. Our lab has a strong interest in automated artificial-intelligence-driven image analysis

Qualifications

PhD Biochemistry – ETH Zurich, Switzerland (2004)

MSc Biochemistry – Uppsala University, Sweden (2000)

BSc Chemistry – Freiburg University, Germany (1998)

Biography

Eva grew up in Germany and the United States and obtained a BSc in chemistry from the University of Freiburg in Germany before moving to Uppsala University in Sweden to study enzyme kinetics and completing an MSc in Biochemistry. After a short research assistant position in a protein crystallography lab in Auckland, New Zealand, Eva pursued a PhD with Ari Helenius at the ETH Zurich in Switzerland. She studied glycoprotein folding in the endoplasmic reticulum and was interested in the mechanisms of glycoprotein chaperones and their associated thiol-disulfide oxidoreductase.

Thinking about protein folding led to thinking about protein degradation and the immunologically useful consequence of protein degradation products - antigen processing and presentation. Eva joined the laboratory of Hidde Ploegh at the Whitehead Institute at MIT to exploit the plethora of techniques available to study questions pertaining to immune surveillance of Toxoplasma gondii and the generation of parasite epitopes for recognition by CD8 T cells. Eva was funded by the Swiss National Science Foundation and the Human Frontier Science Program during her time in Boston.

Eva was awarded a Research Career Development Fellowship and the Wellcome-Beit Prize both from the Wellcome Trust to transfer her research to an independent position at the National Institute of Medical Research (NIMR) in Mill Hill, London in 2011. The NIMR merged into the Francis Crick Institute in 2016 and Eva’s lab moved to central London. During her time in the UK, the lab’s focus has converged on IFNg-driven host defence to intracellular infection with a special emphasis on Toxoplasma gondii and host ubiquitin and guanylate binding proteins. In 2020, Eva was awarded a Senior Wellcome Trust Fellowship to transfer her lab to the University of Birmingham.

Eva has a family with two young children and is passionate about women in STEM and equal opportunity for all.

Teaching

BIOM23 Host-Pathogen Interaction

BIO388 Molecular and Cellular Immunology

Research

Host defence to Toxoplasma gondii

The protozoan parasite Toxoplasma gondii infects a broad range of hosts, with a seroprevalence in man of about 30 per cent. It is unclear how Toxoplasma maintains the intricate balance between survival and host defense.

IFNγ, the main cytokine responsible for its control, activates cells to restrict intracellular parasite replication or to kill intracellular Toxoplasma. The outcome of an infection with Toxoplasma is determined not only by the host’s immune status, but also by the genotype of the infecting strain. The major cause of Toxoplasma pathogenesis results from parasite burden, concurrent with an over-stimulation of the immune system in the form of high levels of T helper cell type 1 cytokines, increased apoptosis and organ damage.

Our long-term goal is to identify IFNγ-driven novel pathways of host resistance to Toxoplasma in human cells. We are studying how the parasitophorous vacuole (PV) is remodeled within host cells to limit parasite replication. Additionally, we are interested in IFNγ-dependent immune defence mechanisms that in general can limit Toxoplasma viability. The pathways we study often also impact bacterial or other eukaryotic pathogens as well as Toxoplasma. Therefore, the Frickel lab strives to uncover human IFNγ-dependent host defence pathways of broad relevance to eukaryotic and bacterial pathogens.

Cellular immune pathways regulated by guanylate binding proteins (GBPs)

Human GBPs are a family of seven large (ca 65kDa) GTPases whose expression is upregulated by IFNg. Some GBPs can undergo C-terminal lipidation and traffic to microbial compartments. There, they drive access of microbial ligands to cytosolic sensors and/or directly assist in caspase activation leading to host cell death. We discovered that human GBP1 promotes the detection of Gram-negative lipopolysaccharide (LPS) and Toxoplasma DNA.

While direct targeting of pathogens by GBPs is recognised as a hallmark for their host defense function, it remains to be investigated how GBPs regulate protozoan and bacteria pathogen control distal from the infection. For example, we have described that in human epithelial cells, GBP1 can control Toxoplasma replication without localising to the parasite. The mechanism of this phenomenon is unclear.

We are defining the broader function of GBPs during infection and inflammation. Our goal is to further understand how this protein family controls cell intrinsic immunity in diverse human cells and in response to different insults.

Automated artificial-intelligence-driven image analysis

We have a strong interest in automated quantification of host-pathogen image experiments, combining classical image segmentation with artificial intelligence algorithms to substitute for biased manual assessment by the user. To this end we have created an adaptable workflow, capable of processing large quantities of fluorescent image data. We can now analyse and assess infection parameters on a single cell and single pathogen level amounting to the quantification of thousands of infection events.

HRMAn enables you to automatically analyse parameters of host-pathogen interaction derived from immunofluorescent experiments. HRMAn is a custom-built open-source analysis solution based in KNIME. HRMAn uses artificial intelligence to assess host protein recruitement to pathogens.

All downloads and tutorials can be found here: www.hrman.org

Publications

Selected publications:

1: Fisch D, Clough B, Domart MC, Encheva V, Bando H, Snijders AP, Collinson LM, Yamamoto M, Shenoy AR, Frickel EM. Human GBP1 Differentially Targets Salmonella and Toxoplasma to License Recognition of Microbial Ligands and Caspase-Mediated Death. Cell Rep. 2020 Aug 11;32(6):108008. doi: 10.1016/j.celrep.2020.108008. PMID: 32783936; PMCID: PMC7435695.

2: Yoshida N, Domart MC, Peddie CJ, Yakimovich A, Mazon-Moya MJ, Hawkins TA, Collinson L, Mercer J, Frickel EM, Mostowy S. The zebrafish as a novel model for the in vivo study of Toxoplasma gondii replication and interaction with macrophages. Dis Model Mech. 2020 Jul 20;13(7):dmm043091. doi: 10.1242/dmm.043091. PMID: 32461265; PMCID: PMC7390642.

3: Frickel EM. One gene to rule them all in a chronic brain infection. Nature. 2020 Mar;579(7797):34-35. doi: 10.1038/d41586-020-00564-w. PMID: 32123364.

4: Fisch D, Clough B, Frickel EM. Human immunity to Toxoplasma gondii. PLoS Pathog. 2019 Dec 12;15(12):e1008097. doi: 10.1371/journal.ppat.1008097. PMID: 31830133; PMCID: PMC6907746.

5: Fisch D, Yakimovich A, Clough B, Mercer J, Frickel EM. Image-Based Quantitation of Host Cell-Toxoplasma gondii Interplay Using HRMAn: A Host Response to Microbe Analysis Pipeline. Methods Mol Biol. 2020;2071:411-433. doi: 10.1007/978-1-4939-9857-9_21. PMID: 31758464. 

6: Clough B, Finethy R, Khan RT, Fisch D, Jordan S, Patel H, Coers J, Frickel EM. C57BL/6 and 129 inbred mouse strains differ in Gbp2 and Gbp2b expression in response to inflammatory stimuli in vivo. Wellcome Open Res. 2019 Aug 20;4:124. doi: 10.12688/wellcomeopenres.15329.1. PMID: 31544161; PMCID: PMC6749937.

7: 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. EMBO J. 2019 Jul 1;38(13):e100926. doi: 10.15252/embj.2018100926. Epub 2019 Jun 3. PMID: 31268602; PMCID: PMC6600649.

8: Evans RJ, Sundaramurthy V, Frickel EM. The Interplay of Host Autophagy and Eukaryotic Pathogens. Front Cell Dev Biol. 2018 Sep 13;6:118. doi: 10.3389/fcell.2018.00118. PMID: 30271774; PMCID: PMC6146372.

9: 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. Front Immunol. 2018 Jun 5;9:1290. doi: 10.3389/fimmu.2018.01290. PMID: 29922298; PMCID: PMC5996069.

10: 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-1β-Producing CD8α<sup>+</sup> Dendritic Cells at the Site of Infection. J Immunol. 2018 Jul 15;201(2):604-614. doi: 10.4049/jimmunol.1701322. Epub 2018 Jun 11. PMID: 29891555; PMCID: PMC6036233.

11: Encheva V, Foltz C, Snijders AP, Frickel EM. Murine Gbp1 and Gbp2 are ubiquitinated independent of Toxoplasma gondii infection. BMC Res Notes. 2018 Mar 6;11(1):166. doi: 10.1186/s13104-018-3267-z. PMID: 29510761; PMCID: PMC5840767.

12: 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. PMID: 29250076; PMCID: PMC5717010.

13: 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.2017.10.021. Epub 2017 Nov 12. PMID: 29141239; PMCID: PMC7004510.

14: 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. PMID: 28701773; PMCID: PMC5507857.

15: Clough B, Frickel EM. 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. Epub 2017 Mar 19. PMID: 28330745.

16: Clough B, Wright JD, Pereira PM, Hirst EM, Johnston AC, Henriques R, Frickel EM. K63-Linked Ubiquitination Targets Toxoplasma gondii for Endo-lysosomal Destruction in IFNγ-Stimulated Human Cells. PLoS Pathog. 2016 Nov 22;12(11):e1006027. doi: 10.1371/journal.ppat.1006027. PMID: 27875583; PMCID: PMC5119857.

17: Sanecka A, Yoshida N, Dougan SK, Jackson J, Shastri N, Ploegh H, Blanchard N, Frickel EM. Transnuclear CD8 T cells specific for the immunodominant epitope Gra6 lower acute-phase Toxoplasma gondii burden. Immunology. 2016 Nov;149(3):270-279. doi: 10.1111/imm.12643. Epub 2016 Aug 17. PMID: 27377596; PMCID: PMC5046057.

18: Johnston AC, Piro A, Clough B, Siew M, Virreira Winter S, Coers J, Frickel EM. Human GBP1 does not localize to pathogen vacuoles but restricts Toxoplasma gondii. Cell Microbiol. 2016 Aug;18(8):1056-64. doi: 10.1111/cmi.12579. Epub 2016 Mar 10. PMID: 26874079; PMCID: PMC4961618.

19: Sanecka A, Frickel EM. Use and abuse of dendritic cells by Toxoplasma gondii. Virulence. 2012 Nov 15;3(7):678-89. doi: 10.4161/viru.22833. Epub 2012 Nov 15. PMID: 23221473; PMCID: PMC3545950.

20: Virreira Winter S, Niedelman W, Jensen KD, Rosowski EE, Julien L, Spooner E, Caradonna K, Burleigh BA, Saeij JP, Ploegh HL, Frickel EM. Determinants of GBP recruitment to Toxoplasma gondii vacuoles and the parasitic factors that control it. PLoS One. 2011;6(9):e24434. doi: 10.1371/journal.pone.0024434. Epub 2011 Sep 8. PMID: 21931713; PMCID: PMC3169597.

All publications:

https://pubmed-ncbi-nlm-nih-gov.ezproxyd.bham.ac.uk/?term=frickel+em&sort=date

Culture and collections

Schools, institutes and departments

Services and facilities