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Targeting intracellular bacteria with novel lipid-based drug delivery systems
Secondary Supervisor(s): Dr Alan Goddard
University of Registration: Aston University
BBSRC Research Themes: Understanding the Rules of Life (Immunology, Microbiology)
Project Outline
Intracellular pathogens use host cells for protection, representing some of the most challenging infectious agents to detect and treat. Of all intracellular pathogens, Mycobacterium tuberculosis (Mtb) is the deadliest, causing 1.3 million deaths in 2022, and infecting 1.8 billion people globally. Mtb’s success is partly driven by its ability to reprogram the macrophage host to form an environment conducive to replication and eventually transmission.
Current treatments for Mtb infection rely on prolonged antibiotic treatments, lasting several months, or years for antibiotic resistant strains – which are on the rise. Targeted therapeutic delivery offers several advantages over current antibiotic regimens, potentially reducing treatment times and associated toxic side effects. Additionally, host-directed therapies can negate the issue of antimicrobial resistance and strain diversity completely.
This project will utilise the modulated plasma membrane proteome of macrophages infected with Mtb. Due to their plasma membrane localisation, these protein biomarkers represent accessible candidates for detection of intracellular bacteria, and targeted delivery of therapeutics.
Through lipid-based drug delivery systems, such as functionalised lipid nanoparticles, the project will optimise preferential targeting for infected host cell or bacterial clearance.
Objectives and Methods
This project will test lipid-based delivery systems for improved targeting of infected macrophages, functionalising these based on hits from methods optimised to isolate plasma membrane proteins. As abundance may not correlate with function, the project will further validate the spatiotemporal localisation of these membrane proteins using super-resolution microscopy.
After validating protein hits, lipid-based drug delivery systems will be functionalised against these proteins to test the preferential targeting of Mtb infected cells. These lipid-based systems will then be loaded with either host-directed or bacteria-directed therapies.
Host directed therapies offer a route to circumvent the growing challenge of antimicrobial resistance. pro-apoptotic treatments can be delivered into infected cells, clearing both host and bacteria in a controlled manner compared to the pathogen driven inflammatory cell death pathways. Alternatively, macrophages can be reprogrammed back to a more inflammatory phenotype to enable bacterial clearance.
Mtb-directed therapies, delivered directly into infected macrophages, offer a targeted approach to tip the host-pathogen balance in favour of the host. These antimicrobial treatments can include antibiotics, to test if a targeted approach improves drug efficacy, or siRNA technologies against Mtb virulence factors (e.g. ESAT-6).
Using imaging and RNA extraction methods of intracellular Mtb will lead to an understanding of how host-directed treatments affect both the bacteria and its host.
Overall, this project aims to combine bespoke methods to improve detection and targeting of intracellular bacteria, using the infected hosts own plasma membrane signature.