Dr Daniel Humphreys

Principal Investigator
Centre for Membrane Interactions and Dynamics
University of Sheffield
Western Bank
Sheffield S10 2TN
United Kingdom

Room: C08 Florey Building
Telephone: +44(0) 114 222 4632
Email: d.humphreys@sheffield.ac.uk

Research Overview

Manipulation of mammalian host cell biology by bacterial toxins and virulence effectors

ENDOCYTOSIS & CYTOSKELETONTo establish infections within mammalian hosts, bacterial pathogens have evolved sophisticated strategies to exploit host cell biology. They deploy toxins and virulence effector proteins into our
cells that hijack cellular processes to promote pathogen survival, replication and dissemination, and interfere with the host immune response.

We are interested in the cell biology subverted by bacterial pathogens and how this ultimately contributes to diseases that can have devastating consequences to the health of humans and
animals. Understanding host-pathogen interactions is especially important when considering the human health threat posed by many bacterial pathogens that continue to develop multidrug
resistance.


Bacterial manipulation of host cell biology

Bacterial pathogens are known to inject virulence effectors that hijack the actin cytoskeleton. For example, enteropathogenic and enterohaemorrhagic Escherichia coli generate ‘actin pedestals’ to colonise the host cell surface whilst Salmonella and Shigella invade cells by generating ‘membrane ruffles’.

Once inside cells, Salmonella survives within a vacuole and ‘evades destruction within lysosomes’. Shigella on the other hand uses ‘actin-based propulsion to ‘’rocket’ through the cell and even propel itself into uninfected neighbouring cells for dissemination. Salmonella, E.coli and Shigella also secrete cytolethal distending toxins that cause DNA damage to induce ‘cell cycle arrest’ and interfere with immune cell signalling.

Selected Publications
  1. Humphreys D*. Singh V, Koronakis V*. (2016).
    Inhibition of WAVE Regulatory Complex activation by a bacterial virulence effector counteracts pathogen phagocytosis.
    Cell Reports
    . 17 (3) 697-707. *co-corresponding authors. http://www.cell.com/cell-reports/fulltext/S2211-1247(16)31278-5
  2. Davidson AC., Humphreys D., Brooks, ABE., Hume, PJ., and Koronakis V. (2015).
    The Arf GTPase-Activating Protein family is exploited by Salmonella enterica serovar Typhimurium to invade non-phagocytic host cells.
    mBio. 6(1):e02253-14. PMID 25670778
  3. Hume, PJ., Humphreys, D., and Koronakis, V. (2014).
    WAVE Regulatory complex activation at the membrane.
    Methods in Enzymology. 540, 363-79. PMID: 24630117
  4. Humphreys D, Davidson AC, Hume PJ, Makin LE, Koronakis V. (2013)
    Arf6 coordinates actin assembly through the WAVE complex, a mechanism usurped by Salmonella to invade host cells.
    Proceedings of the National Academy of Sciences of the United States of America. 110(42):16880-16885. PMID: 24085844
  5. Humphreys, D., Liu T, Davidson, AC., Hume, PJ., and Koronakis V. (2012)
    Drosophila Arf1 homologue Arf79F is essential for lamellipodia formation.
    Journal of Cell Science 125, 5621-5629. PMID: 22992458
  6. Humphreys D, Davidson AC, Hume PJ, Koronakis V. (2012)
    Salmonella SopE and host GEF ARNO cooperate to recruit and activate WAVE to trigger bacterial invasion.
    Cell Host & Microbe 11, 129-39. PMID: 22341462
  7. Koronakis V, Hume PJ, Humphreys D, Liu T, Horning O, Jensen ON, McGhie EJ. (2011)
    WAVE regulatory complex activation by cooperating GTPases Arf and Rac1.
    Proceedings of the National Academy of Sciences of the United States of America 108(35):14449-54. PMID: 21844371
  8. Smith, K., Humphreys, D., Hume, P.J., and Koronakis, V. (2010)
    Enteropathogenic Escherichia coli recruits the cellular inositol phosphatase SHIP2 to regulate actin-pedestal formation.
    Cell Host & Microbe 7, 13-24. PMID: 20114025

Editors choice: Highlighted in Cell Host & Microbe (2010) 7, 1-2