Ealry steps of viral infection


Modeling Endosomal escape and Virus trafficking

Collaboration: A. Herrmann (Berlin, Germany), O Danos (NY, USA)

Most viruses enter the cell through an endocytic pathway and subsequently travel through the cytoplasm inside an endosomal compartment. To pursue their fate, these viruses have to escape endosomes and deliver their genetic payload in the cytoplasm before being degraded.

Our goal is to study the early steps of viral infection including, trafficking in the cyctoplasm and escape from endosomes until a nuclear pore is reached. To examine the endosomal escape, we have developed biophysical models based on Brownian motion, the narrow escape theory, Markov jump processes and Brownian simulations

These methods allow us to estimate the time for the glycoproteins involved in membrane fusion, to change conformation and reach their fusogenic state, leading to fusion and viral escape. This approach is illustrated with enveloped (influenza) and non-enveloped viruses (Adeno-Associated Virus).

Finally, using our modeling approach, we were able to analyze single particle data and we could now discriminate bindings from crowding in cytoplasmic viral trajectories (coll. C. Sieben and A. Herrmann, Berlin).

It remains many challenges in cellular trafficking that viruses are teaching us: the Virus-host interaction remains a fundamental challenge for us to study.

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images

Legends: Scheme of the gene delivery process: we are currently quantifying the first steps of cytoplasmic trafficking.

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Slide2

Legends: Nonlinear interaction of HA sites.

References:

- T. Lagache, C Sieben, A Hermann, D. Holcman, Part I : Modeling the endosomal escape for enveloped viruses.

- T. Lagache, O. Danos, D. Holcman : Modeling the endosomal step of non-enveloped viruses in cell infection, BJ 2012.

- T. Lagache E. Dauty D. Holcman, Physical principles and models describing intracellular virus particle dynamics, Current Opinion in Microbiology, 12,4 (2009).

- T. Lagache, E. Dauty, D. Holcman, Toward a quantitative analysis of virus and plasmid trafficking in cells, PRE, 79,1,2009

- D. Holcman, Modeling viral DNA trafficking in a biological cell, Journal Stat. Physics 2007 10.1007/s10955-007-9282-4