Investigating the genetic basis for bacterial toxin production using functional genomics

Abstract

The genetic networks that regulate bacterial phenotypes are highly complex and incompletely understood in many cases. One such example of this is virulence, which is dependent on a variety of contributors including genetic, environmental and host factors. If we are to continue to develop new treatments and preventative measures against bacterial disease, it will become increasingly important to understand how different pathogens cause disease, and genome sequencing information can be of considerable use in doing so. A key aspect of bacterial virulence is toxicity, which is the production of proteins toxic to host cells that actively damage them to the benefit of the bacteria. This work uses functional genomics to further elucidate the genetic basis for toxicity in two medically important pathogens; Staphylococcus aureus and Streptococcus pneumoniae. Following identification of the cyoE locus as a novel effector of toxicity in S. aureus using a genome-wide association study (GWAS), this gene is shown to be involved in processing haem for incorporation into the electron transport chain during aerobic respiration. In its absence S. aureus respires as if growing in microaerobic conditions and down-regulates toxin production. The functional genomics approach is then extended further in S. pneumoniae, using three different GWAS methods in combination to aid identification of novel effectors of the toxic phenotype. From this, the SPN23F12470 gene is identified as a novel effector of toxicity in the pneumococcus, which encodes a UvrD-like protein with helicase and nuclease domains. Data presented here shows a physical interaction between this protein and regions of the genome either side of the pneumococcal toxin pneumolysin which may be interfering with expression of the toxin gene. Functional genomics is therefore shown to be a useful approach in the identification of novel effectors of toxicity in S. aureus and S. pneumoniae.

Date of Award	23 Jan 2020
Original language	English
Awarding Institution	University of Bristol
Supervisor	Ruth C Massey (Supervisor)