Title: Cathelicidins as immunomodulators of host defence against infectious diseases
Funder: Medical Research Council

Abstract: Respiratory diseases are among the most common causes of morbidity, and account for one in five deaths in the UK, with one third due to acute respiratory infections, influenza or pneumonia. Pathogens resistant to conventional treatments represent an growing challenge. Greater understanding of natural protective mechanisms and novel treatments are urgently required. Innate responses are the first line of defence, but remain under-researched and under-exploited. Important components of early innate immunity are cationic host-defence peptides (CHDP; e.g., cathelicidins). Initially described as directly microbicidal agents, we have discovered multiple roles for CHDP as modulators of inflammation and immunity; thus, they represent exciting templates for novel therapeutics with the capacity to circumvent existing microbial resistance strategies. Although clearly important in health and disease, their specific roles in defence against infectious diseases remain poorly understood. The central tenet of this proposal is that the full potential of CHDP-derived antimicrobial therapeutics is only likely to be realised through greater understanding of the multiple mechanisms employed by naturally-occurring CHDP in host defence against specific bacterial and viral infectious diseases. Building upon the foundation I established during my Research Career Development Fellowship, I intend to address the central hypothesis that cathelicidins are key components of innate host defence against infection, that they mediate a recently-described pro-inflammatory caspase 1-dependent cell death (pyroptosis) of infected epithelial cells, with protective innate and adaptive immune consequences, and that cathelicidins represent promising templates for novel microbicidal immunomodulatory strategies for drug-resistant bacteria and viruses. I propose to: 1) determine the mechanisms and significance of cathelicidin-mediated pyroptosis of airway epithelial cells infected with invasive bacteria or viruses, and investigate the role of the inflammasome and caspase 1 (including using infection models in vitro and in vivo, live-cell confocal imaging, state-of-the-art in vivo imaging and proteomic analyses); 2) establish the adaptive immune consequences of dendritic cell interaction with infected epithelial cells previously induced to undergo cathelicidin-mediated pyroptosis (including using influenza and Pseudomonas aeruginosa infection models and mutant recombinant virus); and 3) determine the antiviral activities of cathelicidins against respiratory viral pathogens, and the potential for peptide modification in therapeutics (including the use of influenza and respiratory syncytial virus infection models in vitro and in vivo, cryo-electron microscopy and the design of novel CHDP). This research will elucidate new roles of CHDP in infectious lung disease, and enable development of a novel innate immunity-based strategy with application for viral and bacterial infections at epithelial surfaces.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION