Investigating the immunomodulatory effects of Non-Ionic Surfactant Vesicles to combat viral sepsis

MacKie, Logan

Thesis

Investigating the immunomodulatory effects of Non-Ionic Surfactant Vesicles to combat viral sepsis

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Creator

MacKie, Logan

Rights statement

Strathclyde Thesis Copyright

Awarding institution

University of Strathclyde

Date of award

2024

Thesis identifier

T16893

Person Identifier (Local)

202061198

Qualification Level

Doctoral (Postgraduate)

Qualification Name

Doctor of Philosophy (PhD)

Department, School or Faculty

Strathclyde Institute of Pharmacy and Biomedical Sciences

Abstract

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.

Advisor / supervisor