Donald J Davidson's lab studies the role of cationic host defence peptides (antimicrobial peptides) as modulators of cell death, inflammation and immunity in infectious and inflammatory lung diseases, and innate immune signalling.
Infectious diseases are a leading cause of death and ill health, increasingly exacerbated by antibiotic-resistant microbes. Pathogens resistant to conventional therapeutics represent an ever-increasing challenge. Greater understanding of innate host defence mechanisms and novel therapeutic approaches are urgently required.
Innate responses are the first line of defence against pathogens, but remain under-researched and under-exploited. Important components of early innate immunity are host-defence peptides (HDP; also known as antimicrobial peptides). Although initially described as microbicidal agents, we and others have characterised them as modulators of inflammation and immunity. HDP can promote innate responses; enhancing protective inflammation and repair. These peptides are emerging as important in diseases affecting multiple organs including in the lung, skin and gastrointestinal tract. However, their specific modulatory roles in defence against bacterial and viral infection remain poorly understood.
In addition, HDP are powerful templates for the development of novel microbicidal immunomodulatory therapeutics, with the capacity to circumvent microbial resistance strategies to conventional therapeutics by enhancing natural defences. However, the full potential of HDP-derived therapeutics is only likely to be realised through greater understanding of the multiple mechanisms employed by naturally-occurring HDP in host defence against specific bacterial and viral infectious diseases.
Our studies are primarily focused on two families of HDP: cathelicidins and defensins.
Cathelicidins are multipotent immunomodulatory HDP. The sole human cathelicidin hCAP-18 (CAMP) is stored in neutrophil-specific granules and is inducible in epithelial cells and macrophages. LL-37 is the predominant active HDP generated from hCAP-18. hCAP-18/LL-37 can be detected in airway surface liquid, plasma, sweat and other body fluids, and is upregulated in infection and inflammation.
The importance of LL-37 to host defence against infection is demonstrated by the increased susceptibility to infection of individuals with morbus Kostmann (in which neutrophils are cathelicidin-deficient), the correlation between LL-37 levels and susceptibility to infection in dermatological pathologies, and the upregulation of hCAP-18/LL-37 observed in infectious lung diseases. Mice deficient in mCRAMP (Camp), the murine hCAP-18 orthologue, have increased susceptibility to bacterial infections of the lung, skin, intestinal tract, cornea and urinary tract. However, the specific protective immunomodulatory mechanisms involved, and the key cellular sources of cathelicidin remain undetermined.
Beta-defensins are also multipotent immunomodulatory HDP, but are expressed principally by epithelial cells and keratinocytes. We are principally interested in human beta-defensin 2, which is induced by inflammation and infection, but under-expressed in the skin of individuals with Atopic Dermatitis. In addition to microbicidal potential, this peptide has modulatory functions that may be critical to maintaining skin barrier.
We have recently discovered that:
Cathelicidins are protective against Respiratory Syncytial Virus infections in mouse models and in humans.
Cathelicidins are protective against influenza infection.
Cathelicidins are protective against pulmonary infection with Pseudomonas aeruginosa via modulatory mechanisms; affecting host neutrophil responses.
Cathelicidins can modulate the function, differentiation and cell death of innate immune effector cells; including induction of cathelicidin-primed dendritic cells.
We are interested in elucidating the physiological importance of host defence peptides to innate and adaptive host defences, and the potential of their synthetic derivatives as future preventative and therapeutic antimicrobial agents.
The importance of host defence modulation and microbicidal activities in cathelicidin-mediated protection against pulmonary viruses (including Respiratory Syncytial Virus and Influenza), and their potential for novel protective and therapeutic interventions.
The role and therapeutic potential of defensins, and related synthetic derivatives, in the treatment of Atopic Dermatitis.
The biological significance and therapeutic potential of cathelicidin-primed dendritic cells in host immunity.
The role of cathelicidin-induced epithelial cell death of bacterially / virally infected cells, as an innate pulmonary defence.
The key cellular sources of cathelicidins and therapeutic inducibility.
Additional and collaborative projects focus on:
The function of cathelicidins as direct modulators of adaptive immune responses.
Novel approaches to imaging HDP interactions with microbes and mammalian cells.
The physiological importance of lipoxins in non-CF bronchiectasis, and potential as therapeutic targets.
The importance of HDP in regulation of the microbiome.
The role of HDP in the female reproductive tract and in premature birth.
Neutrophil NET formation in host defence and the role of calprotectin in the cystic fibrosis lung disease.
Donald Davidson is a medical graduate of the University of Edinburgh who chose to pursue a non-clinical research career. He completed a PhD at the MRC Human Genetics Unit, studying the pathogenesis of cystic fibrosis lung disease, then was awarded a Wellcome Trust Travelling Research Fellowship to undertake post-doctoral training in innate immunity research at the University of British Columbia, Vancouver. After four years in Canada, he was recruited to the MRC / University of Edinburgh Centre for Inflammation Research, where he has developed an independent research group, focused on cationic host defence peptides and pulmonary innate defence mechanisms, funded initially as a Wellcome Trust Research Career Development Fellow, and then as an MRC Senior Non-clinical Fellow.