Silva Holtfreter (Greifswald / DE), Stefan Weiss (Greifswald / DE), Tanja C. Meyer (Greifswald / DE), Frieder Schmiedeke (Greifswald / DE), Clemens Cammann (Greifswald / DE), Marcus Dörr (Greifswald / DE), Stephan B. Felix (Greifswald / DE), Hans J. Grabe (Greifswald / DE), Georg Homuth (Greifswald / DE), Christian Kohler (Greifswald / DE), Cedric Mahncke (Greifswald / DE), Stephan Michalik (Greifswald / DE), Matthias Nauck (Greifswald / DE), Nele Friedrich (Greifswald / DE), Stefanie Samietz (Greifswald / DE), Henry Völzke (Greifswald / DE), Uwe Völker (Greifswald / DE), Barbara Bröker (Greifswald / DE)
Toxic shock syndrome (TSS) is an acute life-threatening disease caused by superantigens (SAg) of the pathobiont Staphylococcus aureus, foremost by toxic shock syndrome toxin-1 (TSST-1). While most adults are protected by TSST-1-neutralizing antibodies, up to 15% of the population remains at risk. Are they unable to mount an effective antibody response to TSST-1? To identify determinants of the anti-TSST-1 antibody response, we examined 976 participants of the German population-based epidemiological Study of Health in Pomerania (SHIP-TREND-0). We profiled the anti-S. aureus antibody response, including anti-TSST-1 antibody levels, using immuno-proteomics, analyzed the nasal colonization with TSST-1-encoding S. aureus strains, and performed a genome-wide association analysis of genetic risk factors. TSST-1-specific serum IgG levels varied over a range of 4.2 logs and were elevated by a factor of 12.3 upon nasal colonization with TSST-1-encoding S. aureus. Moreover, the anti-TSST-1 antibody levels were strongly associated with single nucleotide variants in the HLA class II gene loci. HLA typing revealed that HLA-DRB1*03:01 and HLA-DQB1*02:01 were positively, and HLA-DRB1*01:01 as well as HLA-DQB1*05:01 negatively associated with the anti-TSST-1 antibody levels. We also demonstrate that the HLA haplotype can be accurately determined from array-based genotyping data using the newly published Four-digit Multi-ethnic HLA v2 (2022) algorithm. To conclude, both toxin exposure and HLA alleles affect the human antibody response to TSST-1. These findings suggest that immunizing susceptible individuals with a detoxified TSST‑1 vaccine could provide protection against TSS in the future, encouraging efforts to develop such a vaccine. Moreover, the array-based HLA prediction promises new insights into the genetics of infectious diseases, autoimmune disorders, immune deficiencies, and inflammatory disorders.