Infectious diseases are characterized by a complex interplay between host and pathogen, but it remains unclear to what extent these interactions impact the host proteome. Here we applied a novel mass spectrometry based proteomics strategy to investigate how the human proteome is influenced by the pathogen Streptococcus pyogenes, with a particular focus on bacterial cleavage of IgG in vivo. In invasive diseases such as sepsis, S. pyogenes evokes a massive host response in blood, whereas during superficial diseases such as tonsillitis, the proteome change is markedly different and characterized by a local leakage of blood plasma at the site of infection, elevating the levels of several plasma proteins including IgG. S. pyogenes produces IdeS, a protease cleaving IgG in the lower hinge region. We find IdeS-cleavage of IgG in samples from a majority of patients with infections caused by S. pyogenes. The results show that the in vivo activity of IdeS is more effective in local IgG poor microenvironments. The results suggest that the local cleavage of IgG by IdeS contributes to the adaptation of S. pyogenes to its normal ecological niches. In addition, the work identifies novel opportunities for pathogen detection and evaluation of the inflammatory status of the human host during S. pyogenes infection.

1.) Serum samples from clinical phase I trial of IdeS. 2.) Plasma or local swabs from patients with S. pyogenes infection together with control samples.