Streptococcus pyogenes transforms the salivary proteome during controlled human infection

Streptococcus pyogenes (Group A Streptococcus, GAS) is among the leading causes of infectious mortality and primarily manifests as acute pharyngitis. The development of an effective vaccine continues to be hindered by an incomplete understanding of the host immune response, particularly in the oropharynx. Here, we provided detailed insights into the dynamic salivary proteome during acute illness in a human clinical trial of controlled infection of 20 healthy adults (CHIVAS-M75 trial). Deep profiling of salivary proteins via mass spectrometry revealed a striking increase in pro-inflammatory plasma proteins such as alpha1-antitrypsin and elements of the complement system during peak infection as a clear indication of the acute phase response in the oral environment. Many of these proteins, such as fibrinogen, are well-defined targets of key streptococcal virulence factors, with others, such as vitronectin, suggested to play a role in the host-pathogen relationship. Several salivary proteins with known antimicrobial properties, such as mucin-7 and cystatin, decreased universally across the infected cohort. For the first time, we have described the local and immediate protein response to acute pharyngitis in the oral cavity, highlighting a general host inflammatory signature and an abundance of GAS virulence targets infiltrating to the site of infection.