Moritz Treeck | Group Leader
Broadly speaking, I am really interested to understand how host- pathogen interaction works on multiple levels. The parasites we work with, Plasmodium falciparum and Toxoplasma gondii both evolved to excel at infecting and modifying host cells and a huge proportion of the proteins important for these processes are poorly characterized. I very much enjoy working with a team of talented and enthusiastic individuals in the lab to unravel the complexity of host pathogen interaction. Often this involves the development of new methods to overcome challenges. The scientific environment of the Francis Crick Institute enables us to use the latest technology developments to pursue these goals, often in collaboration with research groups from around the world.
Biography: I was born in the rainy city of Hamburg in northern Germany and I almost ended up as a lawyer. I prepared two applications, one for law and one for biology, and inserted one application blind-folded into the post-box. Law was still in my hands and I am thankful for this until the very day. Throughout my academic career I was interested in parasites and I have tried to attract as many as possible during my travels to Central America and South-East Asia. However, it was not until I met my future PhD advisor Tim Gilberger during a semester in Melbourne, Australia, where I got hooked working with malaria. I spent my PhD thesis at the Bernhard-Nocht Institute for Tropical Medicine in Hamburg, Germany, studying protein trafficking and invasion of red blood cells by the malaria parasite. After that I moved to John Boothroyd’s lab in Stanford, California to learn as much as I could about another really interesting parasite, Toxoplasma. After 4 years I returned to Europe to join the Francis Crick institute, which offered an outstanding research environment in a vibrant city.
Francesca Torelli | Post-doctoral Researcher
What are the common and specific tools different Toxoplasma strains use to succeed in infection? Toxoplasma secretes a large number of proteins that mediate adhesion and invasion, establishment and defence of the parasitophorous vacuole, and influence various host cell pathways. However, most of these secreted proteins have unknown functions. I will be using our arrayed CRISPR library with both in vitro and in vivo selection methods to identify which of those proteins is important for Toxoplasma's success to establish an infection. Furthermore, by performing the screen on strains that differ in virulence, I will identify which of these virulence factors are generic and which are strain-specific. My position as post-doctoral fellow is currently funded by German Research Foundation (DFG).
Francesca completed her PhD in the Seeber lab at the Robert Koch Institute in Berlin, working on the resistance mechanisms of wild rodents to Toxoplasma infection. In future work she aims to explore tolerance mechanisms of parasites to host immune responses.
Identification and characterisation of novel Toxoplasma gondii virulence factors in macrophages using tailored CRISPR screens in vivo
Stephanie Nofal | Wellcome Trust Early Career Fellow
How do P. falciparum gametocytes remodel their host cell? Gametocytes are the only stage of the malaria lifecycle that can be transmitted from humans to mosquitos to sustain disease transmission. Prior to being taken up by mosquitos, immature gametocytes sequester to the bone marrow where they extensively remodel the host cell in which they reside. However, the parasite effectors responsible for these critical remodelling events remain to be identified. I am currently investigating how exported parasite effectors are responsible for subverting the host cell.
Stephanie completed her PhD in David Baker’s lab at the London School of Hygiene & Tropical Medicine, where she worked on cyclic nucleotide signalling and molecular motor function in the malaria parasite.
Signalling pathways in Toxoplasma gondii
Hugo Belda | Post-doctoral Researcher
What is the function of post-translational modification in host cell remodelling by Plasmodium falciparum? P. falciparum exports a large number of proteins out into its host red blood cell. These proteins drive the transformation of red blood cells from oxygen-transporting cells with no nucleus and little of a typical cell’s internal machinery into a parasite-production facility that causes all of malaria’s most severe symptoms. We and others have found that many of these exported proteins are phosphorylated, but the kinases responsible are not currently known and - most importantly - the functional consequences are a mystery. I am using quantitative phoshoproteomic methods and am developing new genetic tools to try and figure out how P. falciparum uses post-translational modification to take over red blood cells and cause disease.
Davies, Belda et al.
An exported kinase family mediates species specific erythrocyte remodelling and virulence in human malaria
Nature Microbiology 2020
Simon Butterworth | PhD Student
How do Toxoplasma effector proteins reprogram the host cell? Toxoplasma secretes a large number of effector proteins into its host cell which inhibit immune responses to the parasite and reprogram host transcription, but how these effectors work in the context of different parasite strains and host cell types is not well understood. I am using our arrayed CRISPR library to design a single-cell RNA-sequencing screen to identify and characterise effector proteins that influence host reprogramming across cell types and parasite strains.
Single cell transcriptomes of Toxoplasma gondii infected human fibroblasts
Eloise Lockyer | PhD Student
How does Toxoplasma disarm the human innate immune response? Humans are ‘accidental’ intermediate hosts for Toxoplasma (unless eaten by a lion). Yet, given the widespread human seroprevalence and incidence of toxoplasmosis it is clear Toxoplasma can evade elimination by the human immune system. Mouse models are commonly used to study Toxoplasma infection in vivo, but the critical mediators of cell-autonomous immunity in mice are absent or altered in human cells. Some of the protein effectors that Toxoplasma secretes to disarm mouse innate immunity have been well characterised, but if and how these effectors operate in human cells is less well studied. I am using our arrayed CRISPR library to identify the key complement of effectors that are essential to Toxoplasma virulence in both mouse and human hosts.
Human macrophages (magenta) infected with Toxopasma gondii (green)
David Jones | PhD Student
How does P. falciparum respond to fever? David is interested in how the parasite Plasmodium falciparum responds and reacts to conditions met in a human host. While we can culture P. falciparum efficiently in human red blood cells, we miss the host environment and predict that the important function of many genes cannot be uncovered under standard cell culture conditions. Dave has identified a controlled response to physiological fever temperatures on the post-translational level that is linked to increased cytoadhesion, the major cause for pathology of this parasite. He is using cell culture models to mimic fever and identify the key regulators of this response. In collaboration with researchers in Africa we want to link cell culture studies to observations in patients.
Gwendolin Fuchs | PhD Student
How are P. falciparum surface antigens trafficked in the host cytosol compartment? Upon invasion of the red blood cell, P. falciparum exports numerous proteins to the host cell surface to interact with its surroundings. This, for example, includes the key virulence factor PfEMP1 which mediates cytoadhesion to endothelial cells preventing splenic clearance of the infected cell. Key structures of protein export like Maurer’s Clefts and the translocon PTEX are well characterised, however, it remains unclear how surface antigens are trafficked in the host cytosol compartment. I am using a proximity labelling approach to identify cytosolic proteins involved in the trafficking of different surface antigens.