The impact of thermally-regulated cell wall modifications on Streptococcus pneumoniae pathogenesis
Lead Research Organisation:
University of Dundee
Department Name: School of Life Sciences
Abstract
Streptococcus pneumoniae (SPN) is a natural coloniser of the upper airways (the nasopharynx) but also a major cause of bacterial pneumonia and serious invasive infections, including sepsis and meningitis. We only have partial understanding of the processes that cause asymptomatic nasopharyngeal infection to progress into symptomatic disease, but it has long been known that viral infections of the respiratory tract are associated with elevated risk of developing SPN pneumonia. One factor that might contribute to this association is the effect that the host response to viral infection has on SPN. The elevated body temperature during fever is detected by SPN and this environmental sensing leads to changes in the bacteria that might promote their ability to cause disease.
SPN are able to respond to temperature changes, in part, due to the action of RNA thermosensors. These regulatory elements prevent gene transcripts from being translated into proteins. When the temperature rises, structural changes in the RNA removes this break on translation and protein production can resume. Only a small number of SPN genes are subject to this mechanism of thermoregulation, with the production of their protein products tied to temperature changes. Thermosensors have been described in SPN genes that encode proteins playing important roles in the interaction of pathogen with host. When the temperature rises, more of these proteins are produced.
We have identified an RNA thermosensor in a gene encoding a protein that modifies the SPN cell wall. Evolutionary studies with SPN have suggested that genes in this same pathway might play important roles in colonisation of host tissues. The cell wall is an important interface between pathogen and host, and changes in cell wall structures may promote or lessen virulence (disease-causing potential) in SPN. We aim to understand how thermal regulation of cell wall modifications in SPN are achieved and what the implications are for our understanding of diseases caused by this pathogen. The natural home of SPN in the nasopharynx is cooler (~33C) than the disease sites of lung, blood or brain (37C), so temperature-induced changes in the cell wall may contribute to virulence in these environments. If similar changes are induced by fever, then this may partially explain the association of respiratory viral infection with susceptibility to SPN pneumonia. Understanding the role of temperature in modulating SPN virulence will help us explain the link between viral infection and bacterial pneumonia and why outbreaks of SPN disease occur in places subject to heatwaves and extremes of temperature. In the future, the information gained will help in identification of SPN proteins suitable as vaccine targets.
We will determine whether the production of the SPN cell-wall modifying enzyme CapD is regulated by temperature. We will define the mechanism by which this thermoregulation is achieved and explore how the modifications to the cell wall influence the interactions between pathogen and host. Using infection models, we will determine whether thermal regulation of the cell wall influences infection outcomes, making symptomatic disease more likely when SPN moves from nasopharynx to the warmer environment of lungs or when fever raises the body temperature.
SPN are able to respond to temperature changes, in part, due to the action of RNA thermosensors. These regulatory elements prevent gene transcripts from being translated into proteins. When the temperature rises, structural changes in the RNA removes this break on translation and protein production can resume. Only a small number of SPN genes are subject to this mechanism of thermoregulation, with the production of their protein products tied to temperature changes. Thermosensors have been described in SPN genes that encode proteins playing important roles in the interaction of pathogen with host. When the temperature rises, more of these proteins are produced.
We have identified an RNA thermosensor in a gene encoding a protein that modifies the SPN cell wall. Evolutionary studies with SPN have suggested that genes in this same pathway might play important roles in colonisation of host tissues. The cell wall is an important interface between pathogen and host, and changes in cell wall structures may promote or lessen virulence (disease-causing potential) in SPN. We aim to understand how thermal regulation of cell wall modifications in SPN are achieved and what the implications are for our understanding of diseases caused by this pathogen. The natural home of SPN in the nasopharynx is cooler (~33C) than the disease sites of lung, blood or brain (37C), so temperature-induced changes in the cell wall may contribute to virulence in these environments. If similar changes are induced by fever, then this may partially explain the association of respiratory viral infection with susceptibility to SPN pneumonia. Understanding the role of temperature in modulating SPN virulence will help us explain the link between viral infection and bacterial pneumonia and why outbreaks of SPN disease occur in places subject to heatwaves and extremes of temperature. In the future, the information gained will help in identification of SPN proteins suitable as vaccine targets.
We will determine whether the production of the SPN cell-wall modifying enzyme CapD is regulated by temperature. We will define the mechanism by which this thermoregulation is achieved and explore how the modifications to the cell wall influence the interactions between pathogen and host. Using infection models, we will determine whether thermal regulation of the cell wall influences infection outcomes, making symptomatic disease more likely when SPN moves from nasopharynx to the warmer environment of lungs or when fever raises the body temperature.
Technical Summary
Streptococcus pneumoniae (SPN) is a leading cause of bacterial pneumonia and severe invasive diseases. SPN pneumonia can occur secondary to viral respiratory infection. This association may relate, in part, to the effect of virus-induced fever responses on SPN. RNA thermosensors (RNAT) have been described in the 5' untranslated regions of several SPN genes, including those encoding virulence factors. Thermally-induced changes in SPN have implications for disease outcomes.
We identified an RNAT-like element in the 5' UTR of the SPN gene capD, predicted to play a role in cell wall modification through teichoic acids (TA) biosynthesis. Experimental evolution work undertaken with SPN in infection models demonstrates that aatB, functioning in the same biosynthesis pathway, is under strong selective pressure during colonisation and disease.
We hypothesise that cell wall TA modifications modulate colonisation and virulence in SPN and that these pathways are under temperature-dependent regulation. These processes may contribute to the high incidence of SPN pneumonia and invasive disease in those with respiratory viral co-infections or who live in areas of exposure to extreme temperatures. The project will determine the significance of the capD thermosensor in SPN colonisation and disease, by:
1. Defining the molecular mechanism of thermosensing in capD, via biochemical analysis in cell-free systems.
2. Investigating thermally-regulated cell wall changes in SPN, including changes in surface TA, phosphorycholine and choline-binding protein expression.
3. Determining how thermoregulation affects host-pathogen interactions and infection outcomes, in in vitro and in vivo models.
These objectives will further our understanding of SPN colonisation and disease and the relationship between viral infection and secondary bacterial pneumonia.
We identified an RNAT-like element in the 5' UTR of the SPN gene capD, predicted to play a role in cell wall modification through teichoic acids (TA) biosynthesis. Experimental evolution work undertaken with SPN in infection models demonstrates that aatB, functioning in the same biosynthesis pathway, is under strong selective pressure during colonisation and disease.
We hypothesise that cell wall TA modifications modulate colonisation and virulence in SPN and that these pathways are under temperature-dependent regulation. These processes may contribute to the high incidence of SPN pneumonia and invasive disease in those with respiratory viral co-infections or who live in areas of exposure to extreme temperatures. The project will determine the significance of the capD thermosensor in SPN colonisation and disease, by:
1. Defining the molecular mechanism of thermosensing in capD, via biochemical analysis in cell-free systems.
2. Investigating thermally-regulated cell wall changes in SPN, including changes in surface TA, phosphorycholine and choline-binding protein expression.
3. Determining how thermoregulation affects host-pathogen interactions and infection outcomes, in in vitro and in vivo models.
These objectives will further our understanding of SPN colonisation and disease and the relationship between viral infection and secondary bacterial pneumonia.
