Background: A new controlled human infection model of Streptococcus pyogenes pharyngitis promises to provide new insights into host and bacterial factors determining outcomes after exposure. In the initial dose-finding trial, 17/20 (85%) participants at the starting dose level were diagnosed with symptomatic pharyngitis after challenge with emm75 S. pyogenes. The remaining were either not colonised, colonised without symptoms or had likely pharyngitis.
Methods: We extracted total nucleic acid from throat swabs collected at serial timepoints, then profiled host gene expression using NanoString nCounter technology. A panel of 785 immune-response genes were quantified and normalised to housekeeping genes and controls.
Results: Within individuals, there were transient changes in gene expression profiles and modifications of key immune pathways at different timepoints. Furthermore, changes in cell-type specific genes over the course and resolution of infection identify changes in proportions of immune cells such as neutrophils, monocytes, T and B cells at the infection site at different stages. We used hierarchical clustering and principal component analyses to explore patterns of response across individuals with differing clinical outcomes and found a signal of specific innate and adaptive immune responses associated with the development of more severe symptoms after challenge. Responses associated with protection from colonisation were also identified.
Conclusion: Host gene expression profiling in the human challenge model can deliver key insights regarding the mucosal immune response. We will extend this work by comparing these results to those from a paediatric cohort with natural S. pyogenes infections (Bristol, UK).