Current anti-inflammatory therapies often utilise a single mechanism of action and come with
a range of side-effects that reduce the scope of therapeutic applications. One such therapy
is the conventional corticosteroid, dexamethasone used to treat the hyperinflammatory
response-induced sepsis associated with severe SARS-CoV-2 infection. This drug has
displayed poor efficacy in early stages of SARS-CoV-2 infection, alongside side effects such
as weight gain, mood changes, vision impairment, osteoporosis, and poor glycaemic control
in diabetic patients - a cohort at greater risk of death from SARS-CoV-2 infection. Herein, I
explore Non-Ionic Surfactant Vesicles (NISV) as an immunomodulatory therapy for the
treatment of viral infection induced sepsis. I compare NISV and dexamethasone by
examining modulation of cytokine production in TLR7 and TLR8 stimulated bone marrow
derived macrophages (BMDM) using ELISA and Cytometric bead array, alongside
transcriptomic and metabolomic analyses. I also investigate NISV size as a factor in their
immunomodulatory effects. I demonstrate that whilst dexamethasone displays broad
immunosuppression of cytokines regardless of TLR stimulation, NISV differentially modulate
cytokine production dependent on specific TLR activation. This effect is generally retained as
NISV size decreases, with a small increase in potency. Whilst NISV effects on energy
metabolism are minor, I observe an increase in phospholipid synthesis and regulation of the
anti-inflammatory TCA cycle metabolite itaconate in treated cells. Finally, I demonstrate that
whilst both NISV and dexamethasone downregulate NF-kB activation, NISV also control
inflammation through downregulation of the non-canonical NLRP3 inflammasome. Here, I
broadly present NISV as an immunomodulatory therapy that can transcriptionally regulate
inflammation-associated gene expression through multiple regulatory pathways in a way that
dexamethasone cannot. These results support further investigation of NISV as an
alternative anti-inflammatory to widely used corticosteroids during virally induced sepsis.
| Date of Award | 4 Apr 2024 |
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| Original language | English |
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| Awarding Institution | - University Of Strathclyde
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| Sponsors | University of Strathclyde |
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| Supervisor | Craig Roberts (Supervisor) & Yvonne Perrie (Supervisor) |
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