Staphylococcal superantigen-specific IgE reveals functional superantigen production beyond Staphylococcus aureus in CRSwNP.

Abstract

Staphylococcal superantigen-specific IgE (SAg-IgE) correlates with disease severity in patients with type 2 (T2) chronic rhinosinusitis with nasal polyps (CRSwNP). Although Staphylococcus aureus is recognized as a primary source of SAgs, SAg-IgE is detected even in patients with culture-negative S aureus. We sought to identify the source of SAgs in SAg-IgE-positive patients with T2 CRSwNP with culture-negative S aureus. Metagenomic sequencing was conducted in patients with T2 CRSwNP with repeatedly negative S aureus cultures, stratified by SAg-IgE status. We screened clinical isolates for SAg genes and evaluated SAg functionality by measuring SAg-specific T-cell receptor repertoire expansion and T2 inflammatory responses in an ex vivo infection model. The SAg-IgE-positive group showed significantly higher abundances of S epidermidis, S aureus, Lysinibacillus xylanilyticus, and S capitis compared with the SAg-IgE-negative group. Interestingly, in all participants in whom S aureus was detected, S capitis was also present, albeit at low abundance. Redundancy analysis demonstrated clustering of the Staphylococcus genus, SAg-IgE, and IL-5, supporting a potential link between the Staphylococcus genus and SAg-driven immune responses. Notably, a clinical S capitis isolate carried SEA (staphylococcal enterotoxin A) and SEC genes and secreted functional SAgs, which triggered the clonal expansion of SEA/SEC-specific T-cell receptors and exacerbated the T2 inflammatory response via IL-33 induction. Metagenomic sequencing reveals that S capitis, beyond S aureus, produces functional SAg to drive T2 response in SAg-IgE-positive patients with CRSwNP when conventional cultures fail to detect S aureus. Independent of culturable bacterial load, tissue SAg-IgE positivity reliably indicates bacterial colonization and SAg exposure in CRSwNP.