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An, Andy Yi

University of British Columbia

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection, which kills 11 million people each year. Sepsis affects the most vulnerable patients, including neonates, the elderly, and the immunosuppressed. Sepsis also has mechanistic parallels to severe COVID-19, which has killed up to 18 million people since the start of the pandemic. Furthermore, survivors of these diseases suffer long-term consequences such as post-sepsis syndrome and “Long COVID”. Therapeutics for sepsis and severe COVID-19 are critically needed but designing them requires understanding of their immune dysfunction, which is highly complex due to its dynamic nature. Longitudinal analyses must be performed to fully comprehend pathophysiological trajectories. In this thesis, I analyzed whole blood gene expression trajectories in three populations: adult sepsis, adult COVID-19, and neonatal sepsis patients. Severe COVID-19 was shown to be a form of viral sepsis, since COVID-19 patients and non-COVID-19 sepsis patients converged into the same pathophysiological mechanisms after a week in the ICU, while the main initial difference was elevated antiviral response in COVID-19. Persistent immune dysfunction, consisting of both inflammatory processes and suppression of adaptive immunity, was identified to be associated with eventual mortality in both severe COVID-19 and non-COVID-19 sepsis patients, and potential immunomodulatory treatments that might reverse this persistence were predicted. These findings were recapitulated in another population of COVID-19 patients, where disease phase-specific mechanisms were analyzed and drugs targeting phase-specific mechanisms were identified to enable personalized treatment. In addition, gene expression trajectories were found to differ between discharged patients with and without “long COVID”, with those without post-COVID symptoms showing resolution of immune and hemostatic processes post-discharge. Gene signatures were developed that could stratify patients into different underlying mechanisms/endotypes of long COVID. Lastly, in neonates, sepsis disrupted immune and metabolic developmental trajectories in the first week of life and HSPH1 was identified as a predictive biomarker for neonatal sepsis. By analyzing trajectories of adult sepsis, neonatal sepsis, and severe COVID-19 disease, I was able to identify the time-dependent pathophysiological mechanisms occurring, leading to the identification of potential therapeutics and diagnostic/prognostic tools, ultimately contributing to improving management of these diseases.

Text

2025-05-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/84771

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/