Mouse Strain-Dependent Difference Toward the Staphylococcus aureus Allergen Serine Protease-Like Protein D Reveals a Novel Regulator of IL-33

Front Immunol. 2020 Sep 25;11:582044. doi: 10.3389/fimmu.2020.582044. eCollection 2020.


Staphylococcus aureus (S. aureus) can secrete a broad range of virulence factors, among which staphylococcal serine protease-like proteins (Spls) have been identified as bacterial allergens. The S. aureus allergen serine protease-like protein D (SplD) induces allergic asthma in C57BL/6J mice through the IL-33/ST2 signaling axis. Analysis of C57BL/6J, C57BL/6N, CBA, DBA/2, and BALB/c mice treated with intratracheal applications of SplD allowed us to identify a frameshift mutation in the serine (or cysteine) peptidase inhibitor, clade A, and member 3I (Serpina3i) causing a truncated form of SERPINA3I in BALB/c, CBA, and DBA/2 mice. IL-33 is a key mediator of SplD-induced immunity and can be processed by proteases leading to its activation or degradation. Full-length SERPINA3I inhibits IL-33 degradation in vivo in the lungs of SplD-treated BALB/c mice and in vitro by direct inhibition of mMCP-4. Collectively, our results establish SERPINA3I as a regulator of IL-33 in the lungs following exposure to the bacterial allergen SplD, and that the asthma phenotypes of mouse strains may be strongly influenced by the observed frameshift mutation in Serpina3i. The analysis of this protease-serpin interaction network might help to identify predictive biomarkers for type-2 biased airway disease in individuals colonized by S. aureus.

Keywords: IL-33; S. aureus; SplD; allergy; asthma; type 2 immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens / immunology*
  • Animals
  • Asthma / immunology
  • Bacterial Proteins / immunology*
  • Female
  • Frameshift Mutation / immunology
  • Interleukin-33 / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Inbred DBA
  • Peptide Hydrolases / immunology
  • Serine Endopeptidases / immunology
  • Serine Proteases / immunology*
  • Serpins / immunology
  • Staphylococcal Infections / immunology*
  • Staphylococcus aureus / immunology*


  • Allergens
  • Bacterial Proteins
  • Il33 protein, mouse
  • Interleukin-33
  • Serpins
  • Peptide Hydrolases
  • Serine Proteases
  • Serine Endopeptidases
  • mast cell protease 4