Investigating the mechanisms of infection induced thromboinflammation

Lamerton, Rachel Emma ORCID: 0000-0002-8931-7279 (2024). Investigating the mechanisms of infection induced thromboinflammation. University of Birmingham. Ph.D.

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Abstract

Dysregulated host responses to infection can turn the immune system from being the hero that wins the battle against harmful invading pathogens, to the enemy within that has the capacity to kill the host it was supposed to be protecting. This is the case in sepsis, which contributed to approximately 20% of worldwide deaths in 2017, and also in severe COVID-19, which killed over 5 million people up to December 2021. This thesis aimed to study the inflammatory responses involved in host immune system dysregulation.
One of the major problems in this dysregulation is the formation of thrombi by platelets and other blood components, which can lead to blockage of blood vessels, starving organs of oxygen. Invasive non-typhoidal Salmonella is a bloodstream infection estimated to cause >75,000 deaths per year, predominantly in sub-Saharan Africa. Whilst many different bacterial strains have been shown to interact with human platelets leading to their aggregation, whether Salmonella Typhimurium can do this was unknown. In this thesis I studied the interactions between Salmonella Typhimurium and platelets using platelet aggregometry, revealing Salmonella Typhimurium can indirectly activate platelets in a donor dependent manner, linked to the level of antibodies recognising Salmonella in the donor plasma. Platelet aggregates also form under physiological flow conditions over Salmonella.
Investigating the broader environment of the blood vessel by bringing endothelial cells into the study revealed binding interactions between these cells and Salmonella Typhimurium, which was strengthened upon the addition of IgG. Platelet adhesion occurred on Salmonella primed endothelial cells under both venous and arterial flow conditions, at sites distal to the Salmonella.
This thesis also investigated inflammatory responses to SARS-CoV-2, the pandemic of which was still severely disrupting the world at the start of this PhD. We found that SARS-CoV-2 protein-antibody complexes activate the classical complement pathway, with levels of complement activation differing between convalescent COVID-19 patients who did not require hospital treatment versus those that did.
Overall, this thesis investigates and argues that three major components in blood vessels: platelets, endothelial cells, and complement, are all capable of contributing to the dysregulated host immune responses leading to severe damage.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):