The role of RNA elements that control flagellar biosynthesis during infection
Lead Research Organisation:
University of Cambridge
Department Name: Pathology
Abstract
PhD project strategic theme: Understanding the rules of life
Understanding host responses to pathogen infection is critical for guiding the development of intervention strategies. Changes in gene expression are commonly observed upon infection, as exemplified by numerous transcriptomic studies. However, techniques to analyse genome-wide responses at the level of protein synthesis have only recently become available with ribosome profiling, permitting a more sophisticated interrogation of host-pathogen interaction at the level of translation.
This project will focus on the synthesis of flagellin in the food-borne enteric pathogen Salmonella enterica Typhimurium. Flagellin is a major virulence factor as it helps the bacterium swim to its preferred site of infection inside the host and is also a key antigen for the host innate immune system. The flagellar filament consists of thousands of copies of flagellin monomer protein. Salmonella undergoes phase-switching to produce two types of flagellin-FliC in phase 1 or FljB in phase 2-with each phase being beneficial in different circumstances. Indeed, it was shown that while phase 2 flagella confer a motility advantage in highly viscous liquids (Yamaguchi et al., 2020, Biomolecules), phase 1 has a selective advantage in gastrointestinal colonization as well as systemic infection (Horstmann et al., 2017, Cellular microbiology; Ikeda et al., 2001, Infection and Immunity). This alternative expression of the two flagellins is achieved by control of the fljBA operon, which encodes FljB and FljA. The repressor protein FljA controls expression of the distally located fliC through direct binding of fliC 5' UTR, direct-ly impeding FliC synthesis (Aldridge et al., 2006, PNAS; Yamamoto & Kutsukake, 2006, Jour-nal of Bacteriology). However, the exact role of the 5' UTR in fliC expression is less clear, and whether FljA regulates other mRNAs in a similar manner is unknown. In addition to addressing these unknowns, the project will investigate how gene expression is regulated during Salmonella infection.
Understanding host responses to pathogen infection is critical for guiding the development of intervention strategies. Changes in gene expression are commonly observed upon infection, as exemplified by numerous transcriptomic studies. However, techniques to analyse genome-wide responses at the level of protein synthesis have only recently become available with ribosome profiling, permitting a more sophisticated interrogation of host-pathogen interaction at the level of translation.
This project will focus on the synthesis of flagellin in the food-borne enteric pathogen Salmonella enterica Typhimurium. Flagellin is a major virulence factor as it helps the bacterium swim to its preferred site of infection inside the host and is also a key antigen for the host innate immune system. The flagellar filament consists of thousands of copies of flagellin monomer protein. Salmonella undergoes phase-switching to produce two types of flagellin-FliC in phase 1 or FljB in phase 2-with each phase being beneficial in different circumstances. Indeed, it was shown that while phase 2 flagella confer a motility advantage in highly viscous liquids (Yamaguchi et al., 2020, Biomolecules), phase 1 has a selective advantage in gastrointestinal colonization as well as systemic infection (Horstmann et al., 2017, Cellular microbiology; Ikeda et al., 2001, Infection and Immunity). This alternative expression of the two flagellins is achieved by control of the fljBA operon, which encodes FljB and FljA. The repressor protein FljA controls expression of the distally located fliC through direct binding of fliC 5' UTR, direct-ly impeding FliC synthesis (Aldridge et al., 2006, PNAS; Yamamoto & Kutsukake, 2006, Jour-nal of Bacteriology). However, the exact role of the 5' UTR in fliC expression is less clear, and whether FljA regulates other mRNAs in a similar manner is unknown. In addition to addressing these unknowns, the project will investigate how gene expression is regulated during Salmonella infection.
Organisations
People |
ORCID iD |
| Betty Chung (Primary Supervisor) | |
| Filip Lastovka (Student) |