The impact of thermally-regulated cell wall modifications on Streptococcus pneumoniae pathogenesis

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.