Abstract
Type I and III interferons (IFNs) are immune cytokines secreted upon microbial detection by the host. Type I IFNs signal through the IFN-α-receptor (IFNAR) while type III IFNs signal through the IFN-λ-receptor (IFNLR). Both IFNs induce interferon-stimulated-genes (ISGs) with well-known antiviral functions. However, the roles of type I and III IFN signalling during bacterial infections remain understudied. Additionally, it is not well understood, whether, bacteria, like viruses, can block IFN responses. This study investigates:1. the mechanisms deployed by bacteria to counteract type I and III IFN responses.
2. the dynamics of type I and III IFN responses in the gut during bacterial infection.
3. the impacts of type I and III IFN responses on cecitis/colitis- induced by bacteria.
The work focuses on two intracellular pathogens, Shigella sonnei (S. sonnei) and Salmonella enterica serovar Typhimurium (S. Typhimurium), which cause severe gastroenteritis. The pathogenesis of Shigella and Salmonella relies on their type III secretion systems (T3SS), which inject effector molecules into host cells to manipulate cellular processes and establish a favourable environment for infection. Using molecular techniques, we identified a family of T3SS effectors called the OspC family, that blocks signalling downstream of type I and III IFNs. OspC1 and OspC3 were found to bind to the Ca2+ sensor calmodulin (CaM), which blocked CaM kinase II (CaMKII) and downstream JAK/STAT signalling. Remarkably, infection with a S. sonnei strain lacking OspC effectors resulted in increased phosphorylation of CaMKII and STAT1 and ISG expression compared to infection with the wild-type strain. These findings were also observed in colons recovered from mice infected with OspC-deficient-Shigella strain, indicating the in vivo relevance of these mechanisms.
| Date of Award | 1 Apr 2024 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Charlotte Odendall (Supervisor) & affiliated academic (Supervisor) |