Dr Daniel Humphreys
Host-pathogen interactions with our genome and its role in disease
To combat infectious disease in the face of increasing antibiotic resistance, we need to understand the host-pathogen interaction. Our research focuses on the mechanisms by which multi-drug resistant bacterial pathogens establish infections that can have devastating consequences to the health of humans and animals (Figure). This is exemplified by the intracellular bacterial pathogen Salmonella enterica that causes gastroenteritis and typhoid fever worldwide. The Salmonella problem is exacerbated by the rise of antibiotic strains that are spreading across the globe.
Cellular function depends on DNA integrity, yet our DNA is damaged on a daily basis often generating double strand breaks. The aberrant DNA structures are flagged and targeted for repair by a coordinated DNA damage response (DDR), and malfunction results in many pathologies including cancer. Unsurprisingly given its importance, many bacterial pathogens target the DDR to establish infections and cause disease. Salmonella targets our genome during infection by releasing virulence effector proteins and a unique virulence protein called the typhoid toxin that causes the symptoms of typhoid fever through DNA damage and DDR manipulation. We combine molecular cell biology, biochemical and infection approaches to understand how Salmonella virulence effectors and toxins manipulate our genome, and how this contributes to infection. Our research aims to reveal important fundamental cell biology whilst also discovering virulence mechanisms underlying diseases of global importance.
- Brooks, A.B.E*, Humphreys, D*., Vikash, S., Arden, S., Buss, F., and Koronakis V. (2017). MYO6 is targeted by Salmonella virulence effectors to trigger PI3-kinase signaling and pathogen invasion into host cells. 114 (15) 3915-3920. *co-first authors.
- 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.
- 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. 110(42):16880-16885.
- 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.