Supervisor: Prof. Dr. Ulrich Schwarz (BioQuant & Institute for Theoretical Physics)
Experimental partner: Prof. Dr. Hans-Georg Kräusslich (University Hospital Heidelberg)

Background and scientific question:

Virus infections are among the most imminent threats to human health, as dramatically demonstrated by the 2014 Ebola outbreak in West Africa. Heidelberg is a world-wide known center for research on infectious diseases, including HIV (human immunodeficiency virus) and HCV (hepatitis C virus). An infection by an animal virus starts with the binding of the virus particle to cell surface receptors. Next it has to surpass two physical barriers: the plasma membrane and the actin cortex underlying it. Often viruses exploit endocytotic pathways to solve these tasks, including the assembly of clathrin or caveolin cages. Once inside the cell, they use molecular motor-based transport along microtubules to travel towards the microtubule-organizing center (MTOC) at the cell nucleus. The actin cytoskeleton also shapes this process by affecting the spatial organization of the microtubule system and by providing a barrier to particle transport. After replication, the viral coat is assembled and the virus leaves the cell by again crossing the physical barriers presented by actin cortex and plasma membrane. Although it is clear that the cytoskeleton (actin and microtubules) play an essential role during the journey of a virus through the cell, both as a barrier and as a supporting scaffold for movement, the importance of the spatial organization of the cytoskeleton for virus infection has not been investigated much. In recent years, there has been several major experimental advances which today make it much more feasible to tackle this important issue, including the availability of appropriate cell culture systems, the breakthroughs in super-resolution and single-molecule microscopy (e.g. to track single viruses), and new ways to systematically change the properties of the viruses and the cytoskeleton (using e.g. the CRISPR/Cas system or optogenetics).

Project goal:

In this project, we will develop a systems-level model for the interactions between HIV and the cytoskeleton, in close collaboration with our experimental partner from the Department of Infectious Diseases (Hans-Georg Kräusslich) and other Heideberg groups working on host-virus interactions (Barbara Müller and Oliver Fackler from the same Department, John Briggs at EMBL, Steeve Boulant at DKFZ). We will focus on three features that can be addressed both by modeling and with experiments: (i) the nature of the stochastic virus trajectories inside the host cell; (ii) the typical time for completion of each of the different stages (a mean first passage time problem in stochastic dynamics); (iii) the relation between these readouts and the structural organization of the cytoskeleton (spatial and mechanical modeling).

Planned work and collaboration within the RTG:

Building on our earlier work on the organization of the actin cytoskeleton (Weichsel and Schwarz, 2010, Rahman et al. 2014), we will develop a mathematical model for how HIV-related factors trigger changes in the actin cytoskeleton that facilitate virus entry and exit. We then will build on our earlier work on motor-based particle transport (Korn et al. 2009) to model the transport processes along microtubules, with a special focus on the dynamic interactions between the microtubule and actin networks. As an important third element, we will use our expertise on the stochastic dynamics of viral capsids (Baschek et al. 2012, Böttcher et al. 2015) to investigate how capsid (dis)assembly is coupled to transport and barrier crossing. Together, the combination of these different modelling approaches will allow us to develop a systems level understanding of how viruses interact with the cytoskeleton, which can be compare directly with microscopy data from our collaborators (single particle trajectories, ensemble averages, correlation with structure). For future work, we envision to extend these approaches to study also other roles of the cytoskeleton for virus infection, including the way HIV affects cell migration and cell-cell contacts, e.g. to induce a virological synapse. Within the RTG, we will benefit strongly by interactions with the groups of Niels Grabe and Anna Marciniak-Czochra on spatial and agent-based modeling, and with the groups of Ilka Bischofs-Pfeifer, Thomas Höfer and Ursula Kummer on kinetic modeling of regulation.

Keywords:

Spatial modeling, reaction-diffusion systems, stochastic processes, mechanics.

Profile of candidate¹s qualification:

The prospective candidate should have a solid education in mathematics and physics, and possibly experience with statistical physics and theoretical biophysics.

List of relevant publications:

1. Boettcher MA, Klein HCR, and Schwarz US (2015) Physical Biology, 12:016014.
2. Rahman SA, Koch P, Weichsel J, Godinez WJ, Schwarz U, Rohr K, Lamb DC, Kraeusslich H-G
and Mueller B (2014) J. Virology, 88: 7904-7914.
3. Baschek JE, Klein HCR, and Schwarz US (2012) BMC Biophysics, 5:22.
4. Weichsel J and Schwarz US (2010). Proc. Natl. Acad. Sci. USA, 107:6304-9.
5. Korn C, Klumpp S, Lipowsky R, and Schwarz US (2009). J. Chem. Phys. 131:245107.

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