Abstract
Opportunistic pathogens are a global threat for both immunocompromised and immunocompetent individuals with comorbidities at risk of healthcare-acquired infections. With immune evasion strategies and an arsenal of virulence mechanism to make the human body their replicative niche, these opportunists are extremely resourceful and difficult to treat. To understand how these pathogens successfully conquer the human body, we must also grasp how the body responds to infection. Elucidating the host-pathogen interactions will uncover the virulence mechanisms utilised by opportunistic pathogens, in turn revealing potential targets for antimicrobial treatment.Achromobacter are environmental opportunists that thrive in nosocomial settings, frequently isolated from sterile solutions and medical devices used in patient care. People with Cystic Fibrosis (pwCF) suffer with chronic lung infections of A. xylosoxidans with disease severity and symptoms comparable to Pseudomonas aeruginosa. Enterobacter cloacae complex (Ecc) are opportunistic pathogens commonly associated with outbreaks in adult and neonatal intensive care units. A part of the ESKAPE classification, Ecc are steadily gaining resistance to antibiotics classed as last-resort, necessitating the development of novel antimicrobial strategies.
However, the virulence mechanisms utilised by Achromobacter and Enterobacter to overcome the human body’s defences are only beginning to be understood. To elucidate the host-pathogen interactions of these two opportunists, we must investigate their infection lifestyles. In this thesis, we demonstrate that both Achromobacter and Enterobacter withstand the engulfment by macrophages to survive in modified phagolysosomes. We demonstrate that Achromobacter employs the Type III secretion system to induce pro-inflammatory pyroptotic cell death in macrophages. This is dependent on internalisation and is via activation of the NLRP3 and NLRC4 inflammasomes. Whereas Enterobacter persists in a non-inflammatory approach by not causing overt cytotoxicity to the host cell. Our findings suggest that Enterobacter establishes a protective niche in macrophages to delay detection by the innate immune system, contributing to ongoing persisting infections.
Thesis embargoed until 31st December 2027
| Date of Award | Dec 2025 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Sponsors | Department of Higher and Further Education, Training and Employment, Cystic Fibrosis Foundation & BBSRC |
| Supervisor | Miguel A. Valvano (Supervisor) & Brendan Gilmore (Supervisor) |
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