Structural biology of host-pathogen interactions

Thilo Stehle

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  • Ph.D. in Chemistry 1992, University of Freiburg
  • Postdoctoral training 1992-1997, Harvard University
  • Assistant Professor 1997-2004, Harvard Medical School
  • Professor of Biochemistry since 2005

Research Interest

The long-range goal of our research is to advance an understanding of the interactions between pathogens and hosts, in order to describe mechanisms of pathogen engagement of target cells and to provide a basis for vaccine and drug design. We study viruses as well as bacterial pathogens. We use protein crystallography, in combination with other structural approaches and associated biochemical techniques, to establish the three-dimensional structures and function of bacterial and viral proteins, often in complex with cognate ligands such as cellular receptors or substrates.

A particular emphasis is placed on understanding basic principles of protein-protein and protein-carbohydrate interactions. Many such interactions are well characterized at a functional level, yet poorly understood at the molecular or atomic level. However, such knowledge is needed to develop compounds that are able to modulate or block biological interactions. For example, by studying the determinants of viral attachment to host cells and establishing principles of attachment, one can develop molecules that interfere with binding. Likewise, unravelling the structures and mechanisms of bacterial enzymes enables us to interfere with reactions that are critical for bacterial survival and fitness.

  • thilo bothfig 18 sp 2
    click to enlarge

Left: Adenovirus capsid protein bound to sialic acid receptor (see Lenman et al., PNAS 2018 for details).

Right: Detailed view of interactions in the active site of the S. aureus glycosyltransferase TarP (see Gerlach et al., Nature 2018 for details).

Available PhD Projects

We have projects available that focus on virus-glycan interactions and on reaction mechanisms of bacterial glycosyltransferases. In both cases, we are particularly interested in advancing knowledge that will enable us to modulate and/or interfere with interactions and reaction mechanisms.

Selected Reading

1) Stencel-Baerenwald JE, Reiss K, Reiter DM, Stehle T, Dermody TS. The sweet spot: defining virus-sialic acid interactions. Nat Rev Microbiol 2014; 12:739-49.

2) Lenman A, et al. Polysialic acid is a cellular receptor for human adenovirus 52. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4264-E4273.; 1:285-306.

3) Gerlach D, et al. Methicillin-resistant Staphylococcus aureus alters cell wall glycosylation to evade immunity. Nature, 2018, in press.