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Department of Chemical Engineering and Biotechnology

 

Virus assembly and transport are complicated, highly dynamic processes. From a virus perspective, they must be extremely well coordinated in space and time to be successful - all while evading the host's immune defences. Thus, it is even more surprising that viruses are able to produce hundreds of progenies from one infected cell.

I am interested in the question how viruses manage to efficiently assemble and transport new virus particles from infected host cells despite the huge logistical challenge. How do viruses bring the different parts of the new virus particles together? Which infrastructure do they create for optimal assembly by restructuring the host subcellular landscape? What are the timings between the creation of infrastructure, production of the individual structural parts, and their spatial and temporal placement for assembly and transport? On which factors do they depend?

For my research, I employ different modern light microscopy techniques. Subcellar organisation of virus-infected cells is ideally imaged with structured illumination microscopy (SIM) which has been demonstrated to provide optical sectioning and to double the lateral resolution. I have optimised protocols to combine sample expansion (expansion microscopy) with light sheet microscopy. This allows us to quickly screen 3D volumes of infected cells with at least 4x increased spatial resolution in currently up to five colours to study interactions. Furthermore, I am using confocal and widefield imaging as well as single particle tracking to measure protein and virus dynamics in infected cells.

 

Research

Determinants of efficient assembly to optimise LAIV vaccines

AstraZeneca’s FluMist which is a live attenuated influenza vaccine (LAIV) must be optimised every year due to the mutations in the influenza strains. However, to date it cannot be well predicted how the introduced changes in the vaccine affect its efficacy.

We work together with AstraZeneca to find the molecular interactions that determine when LAIV assembly is efficient. Effective assembly has been shown to be a requirement for a good vaccine in previous studies. We compare LAIV strains that are representatives of good and bad vaccines with known differences in their genome. In order to probe for differences in gene segment interactions - one known important driver for virus particle assembly -, we employ RNA FISH in combination with expansion microscopy for 4x increased spatial precision. By specifically labelling the eight different genes of the virus with fluorescent probes, we also screen for variation in gene expression and transport kinetics in the different strains.

 

Dynamics of SARS-CoV-2 infection using pseudotemporal single cell mapping

Despite being the target of extensive research efforts due to the COVID-19 pandemic, relatively little was known about the dynamics of SARS-CoV-2 replication within cells. We have investigated and characterised the tightly orchestrated sequence of events during replication. Our data provide new insights into the spatiotemporal regulation of SARS-CoV-2 assembly and refine current understanding of SARS-CoV-2 replication. Our study has recently been accepted in Science Advances.

As I have previously shown for herpes simplex virus 1 (HSV-1), viral protein expression patterns can serve as an intrinsic timestamp. We used this inherent property for single cell-based classification and pseudotemporal mapping of host cell remodelling and SARS-CoV-2 assembly. Since a high degree of cell-to-cell variability in infection is expected and has been observed for a range of mammalian viruses, such a single cell-based analysis is more informative than the population average.

 

Mechanism of HSV-1 envelopment

Herpesviruses are widespread human pathogens that establish life-long latent infections. In collaboration with Dr Colin Crump, I investigate the molecular mechanisms of the final step of herpes simplex virus 1 (HSV-1) assembly, the envelopment of capsid and tegument into the membrane envelope. Little is known about the dynamics of this process and the roles of different viral proteins are still unresolved. We hypothesise that genetically engineered mutants of viruses that have defective or delayed secondary envelopment exhibit very distinct mobility patterns compared to the wildtype. By recording videos with fast acquisition rate, we perform a motion analysis by tracking single viral particles.

Biography

I am a Research Associate in the group of Clemens Kaminski (Laser Analytics group) at the University of Cambridge where I work on virus-host cell interaction using advanced fluorescence imaging methods. Previously, I was awarded an individual fellowship by the German Research Foundation and investigated the dynamics of herpesvirus assembly and egress and related changes in host-cell morphology.

Before coming to Cambridge in March 2017, I was a postdoc in Tom Shimizu’s lab at the AMOLF institute in Amsterdam studying the organisation of chemotaxis receptors in E. coli. Previously, I completed my PhD in Chemistry under the supervision of Ulrich Kubitscheck at the University of Bonn, where I investigated the mechanisms of the action of antibiotics.

Publications

Key publications: 

(* denotes equal contribution)

Katharina M. Scherer*, Luca Mascheroni*, George W. Carnell, Lucia C. S. Wunderlich, Stanislaw Makarchuk, Marius Brockhoff, Ioanna Mela, Ana Fernandez-Villegas, Max Barysevich, Hazel Stewart, Maria Suau Sans, Charlotte L. George, Jacob R. Lamb, Gabriele S. Kaminski-Schierle, Jonathan L. Heeney, Clemens F. Kaminski. The SARS-CoV-2 nucleocapsid protein associates with the replication organelles before viral assembly at the Golgi/ERGIC and lysosome-mediated egress, bioRxiv 2021.

Katharina M. Scherer, James D. Manton, Timothy Soh, Luca Mascheroni, Colin M. Crump, Clemens F. Kaminski. A fluorescent reporter system enables spatiotemporal analysis of host cell modification during herpes simplex virus-1 replication, Journal of Biological Chemistry 2021, 296.

Luca Mascheroni*, Katharina M. Scherer*, Edward Ward, Oliver Dibben, Clemens F. Kaminski. Combining light sheet microscopy and expansion -microscopy for fast 3D imaging of virus-infected cells with super-resolution, Biomedical Optics Express 2020.

Fabian Grein*, Anna Müller*, Katharina M. Scherer*, Xinliang Liu, Kevin C. Ludwig, Anna Klöckner, Manuel Strach, Hans-Georg Sahl, Ulrich Kubitscheck, Tanja Schneider. Ca2+-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids, Nature Communications 2020, 11, 1455.

Katharina M. Scherer, Jan-Hendrik Spille, Fabian Grein, Hans-Georg Sahl, Ulrich Kubitscheck. The lantibiotic nisin induces formation of large Lipid II aggregates causing membrane instability and vesicle budding, Biophysical Journal 2015, 108, 1114-1124.

Katharina Scherer, Imke Wiedemann, Corinna Ciobanasu, Hans-Georg Sahl, Ulrich Kubitscheck, Aggregates of nisin with various bactoprenol-containing cell wall precursors differ in size and membrane permeation capacity, Biochimica et Biophysica Acta 2013, 1828, 2628-2636.

Other publications: 

Bo Meng*, Pedro P. Vallejo Ramirez*, Katharina M. Scherer, Ezra Bruggeman, Julia C. Kenyon, Clemens F. Kaminski, Andrew M. Lever. EAP45 association with budding HIV-1: Kinetics and domain requirements, Traffic 2021.

Christopher J. Rowlands, Florian Stroehl, Pedro P. V. Ramirez, Katharina M. Scherer, Clemens F. Kaminski. Flat-field super-resolution localization microscopy with a low-cost refractive beam-shaping element, Scientific Reports 2018, 8:5630.

Jacopo Solari, Francois Anquez, Katharina M. Scherer, Thomas S. Shimizu. Bacterial chemoreceptor imaging at high spatiotemporal resolution using photoconvertible fluorescent proteins, Methods in Molecular Biology 2018, 1729, 203-231.

Jan-Hendrik Spille, Tim P. Kaminski, Katharina Scherer, Jennifer S. Rinne, Alexander Heckel, Ulrich Kubitscheck. Direct observation of mobility state transitions in RNA trajectories by sensitive single molecule feedback tracking, Nucleic Acids Research 2015, 34, 2, e14.

Post doc

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