We focus on the role of host defence peptides (HDP; also known as antimicrobial peptides) as modulators of inflammation, immunity, cell differentiation & death in infectious and inflammatory diseases. We have particular interest in diseases of the lungs (including infections with RSV and influenza, and cystic fibrosis) and the skin (including atopic dermatitis), as well as novel approaches to cancer immunotherapy and extending our knowledge of inflammatory processes to the development of novel therapeutics.
We are interested in discovering the importance of HDP to our ability to combat bacterial and viral infections. In addition, we study the potential of HDP (and their synthetic derivatives) in the development of novel therapeutic approaches, with the potential to circumvent problems of microbial resistance to conventional treatments by enhancing natural defences.
Our principal research interests focus on:
- 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:
- Neutrophil NET formation in host defence & the role of calprotectin in the cystic fibrosis lung disease.
- 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.
What are Host Defence Peptides?
Host-defence peptides (HDP; also known as antimicrobial peptides) are a key first line component of the innate host defence against pathogens. These are evolutionarily-conserved, short, cationic, amphipathic peptides, produced by a wide range of cells and found throughout the body. Although initially described as microbicidal agents, we and others have characterised them as modulators of inflammation and immunity. Thus 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 immunomodulatory 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 the Cathelicidin family, but also include research into the immunomodulatory properties of Defensins and novel synthetic analogues.
What are Cathelicidins?
Cathelicidins are multipotent immunomodulatory CHDP
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 remain underdetermined.
We have recently discovered that:
- Cathelicidins are protective against RSV infections in mouse models and 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.
- Beta defensin 2 can enhance skin barrier function and promote wound healing.
Why are we concerned about infectious diseases?
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. In particular we are focused on studying:
- Respiratory syncytial virus lung infection
- Staphylococccus aureus skin infections in atopic dermatitis
- Pseudomonas aeruginosa lung infection (including in cystic fibrosis)
- Influenza lung infection
What are our goals?
- To discover the key functions of HDP in host defence against infectious diseases and establish novel innate antiviral/antibacterial strategies to combat multi-resistant pathogens.
- To deliver excellence in inflammation biology / innate immunity / infectious disease research.
- To nurture the development of young scientific and clinical researchers.
- To disseminate our research findings to the international research community and communicate it accessibly to a broader public forum.