The Staphylococcus aureus Cell Wall-Anchored Protein Clumping Factor A Is an Important T Cell Antigen.

Keenan A Lacey,John M Leech,Niamh Mccormack,Joan A Geoghegan,Rachel M Mcloughlin,Stephen J Lalor

doi:10.1128/iai.00549-17

Abstract

ABSTRACTStaphylococcus aureus has become increasingly resistant to antibiotics, and vaccines offer a potential solution to this epidemic of antimicrobial resistance. Targeting of specific T cell subsets is now considered crucial for next-generation anti-S. aureus vaccines; however, there is a paucity of information regarding T cell antigens of S. aureus. This study highlights the importance of cell wall-anchored proteins as human CD4+ T cell activators capable of driving antigen-specific Th1 and Th17 cell activation. Clumping factor A (ClfA), which contains N1, N2, and N3 binding domains, was found to be a potent human T cell activator. We further investigated which subdomains of ClfA were involved in T cell activation and found that the full-length ClfA N123 and N23 were potent Th1 and Th17 activators. Interestingly, the N1 subdomain was capable of exclusively activating Th1 cells. Furthermore, when these subdomains were used in a model vaccine, N23 and N1 offered Th1- and Th17-mediated systemic protection in mice upon intraperitoneal challenge. Overall, however, full-length ClfA N123 is required for maximal protection both locally and systemically.

Highlights

Staphylococcus aureus has become increasingly resistant to antibiotics, and vaccines offer a potential solution to this epidemic of antimicrobial resistance
To confirm that cell wall-anchored (CWA) proteins have the capacity for human T cell activation, the heat-inactivated LAC::lux wild-type (WT) strain or the LAC::lux srtA mutant strain, which lacks all surface-bound CWA proteins, was incubated with CD4ϩ T cells isolated from healthy adults and autologous irradiated antigen-presenting cells (APCs)
We found that heat-inactivated S. aureus was a potent human CD4ϩ T cell activator; when CWA proteins were absent in the SrtA-deficient mutant, CD4ϩ T cell activation was significantly reduced

Summary

Introduction

Staphylococcus aureus has become increasingly resistant to antibiotics, and vaccines offer a potential solution to this epidemic of antimicrobial resistance. Targeting of specific T cell subsets is considered crucial for next-generation anti-S. aureus vaccines; there is a paucity of information regarding T cell antigens of S. aureus. The N1 subdomain was capable of exclusively activating Th1 cells When these subdomains were used in a model vaccine, N23 and N1 offered Th1- and Th17-mediated systemic protection in mice upon intraperitoneal challenge. Targeting individual T cell subsets is considered an important strategy for next-generation anti-S. aureus vaccines [8]. It has recently been shown that the majority of adults possess significant levels of circulating antigen-specific memory T cells, indicative of their previous exposure to S. aureus through either commensal colonization or previous subclinical infection [9]. We have further demonstrated that heat-inactivated S. aureus, washed to remove all secreted factors, elicits a robust T cell response, suggesting surface-located factors of S. aureus are important for T cell activation [5]

Methods

Results

Conclusion