Cathelicidins as immunomodulators of host defence against infectious diseases
Lead Research Organisation:
University of Edinburgh
Department Name: MRC Centre for Inflammation Research
Abstract
Lung diseases are among the most common causes of ill-heath, accounting for 20% of deaths in the UK, with one third due to infectious diseases. The rise of superbugs is a ever increasing challenge, urgently requiring new treatments and a greater understanding of the body‘s natural protective mechanisms.
Important components of our body‘s early defence system are cationic host-defence peptides (CHDP). Initially studied for their ability to kill bacteria and viruses, we have discovered many ways in which CHDP can alter inflammation, modulating the body‘s response to threat and damage, and the repair systems. CHDP are therefore drug templates with the capacity to kill microbes and enhance our natural protective responses. CHDP also offer the potential to circumvent the strategies that make superbugs resistant to our current conventional treatments.
Building upon the foundation I have established with my recent research, I propose to: 1) determine the cellular pathways involved in the key activities of CHDP (particularly regulating the responses of airway lining cells to infection), 2) determine the role of these activities in protecting against the establishment of infection, and 3) design novel CHDP as potential therapeutics, with a particular focus on the treatment of pathogenic lung viruses, including influenza.
Important components of our body‘s early defence system are cationic host-defence peptides (CHDP). Initially studied for their ability to kill bacteria and viruses, we have discovered many ways in which CHDP can alter inflammation, modulating the body‘s response to threat and damage, and the repair systems. CHDP are therefore drug templates with the capacity to kill microbes and enhance our natural protective responses. CHDP also offer the potential to circumvent the strategies that make superbugs resistant to our current conventional treatments.
Building upon the foundation I have established with my recent research, I propose to: 1) determine the cellular pathways involved in the key activities of CHDP (particularly regulating the responses of airway lining cells to infection), 2) determine the role of these activities in protecting against the establishment of infection, and 3) design novel CHDP as potential therapeutics, with a particular focus on the treatment of pathogenic lung viruses, including influenza.
Technical Summary
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.
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.
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| Donald Davidson (Principal Investigator / Fellow) |