Assessing the role of TICAM1 in human viral diseases
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Author(s)
Sabli, Ira Kartika Dewi
Type
Thesis or dissertation
Abstract
Host genetic factors play a crucial role in determining an individual's vulnerability to specific infections and the outcomes of diseases caused by otherwise common pathogens. In particular, severe infectious diseases such as herpes simplex encephalitis (HSE) can be attributed to inborn errors of immunity (IEI). This thesis aimed to assess 50 different TICAM1 variants present in individuals associated with severe viral illnesses. Firstly, we identified three variants (T4I, S60C, and Q392K) in TICAM1 that result in a loss of function, impairing type I interferon signaling and contributing to the development of severe COVID-19 pneumonia. Secondly, our research extended beyond COVID-19 to discover a rare TICAM1 variant linked to Mollaret's meningitis, highlighting its impact on the TLR3-TICAM1-IFN pathway. Specifically, the rare E429X TICAM1 variant exhibited a loss of protein expression and a loss-of-function phenotype, increasing susceptibility to HSV-2 infection. Lastly, our study introduced an innovative approach, utilising cerebral organoids derived from human pluripotent stem cells (PSCs) as models for investigating viral infections. These 3D models provide insights into the intricate cellular environment of the human central nervous system (CNS) and offer a valuable platform for studying HSV-1 infection. Reprogramming induced pluripotent stem cells (iPSCs) from a patient with a potential defect in the TLR3-IFN pathway enabled the assessment of HSV-1 infection processes within iPSCs-derived CNS cells. Overall, this work aimed to understand the impact of novel genetic variants in TICAM1 and TRL3 pathway on susceptibility to and the severity of infectious diseases.
Version
Open Access
Date Issued
2024-03-08
Date Awarded
2024-07-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Sancho-Shimizu, Vanessa
O'Hare, Peter
Sponsor
Brunei. Ministry of Education
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)