Toxin expression during Staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacy
Abstract Staphylococcus aureus infections are a major public health issue, and a vaccine is urgently needed. Despite a considerable promise in preclinical models, all vaccines tested thus far have failed to protect humans against S. aureus. Unlike laboratory mice, humans are exposed to S. aureus thr...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-01-01
|
| Series: | npj Vaccines |
| Online Access: | https://doi.org/10.1038/s41541-022-00598-3 |
| _version_ | 1797641670245744640 |
|---|---|
| author | Omid Teymournejad Zhaotao Li Pavani Beesetty Ching Yang Christopher P. Montgomery |
| author_facet | Omid Teymournejad Zhaotao Li Pavani Beesetty Ching Yang Christopher P. Montgomery |
| author_sort | Omid Teymournejad |
| collection | DOAJ |
| description | Abstract Staphylococcus aureus infections are a major public health issue, and a vaccine is urgently needed. Despite a considerable promise in preclinical models, all vaccines tested thus far have failed to protect humans against S. aureus. Unlike laboratory mice, humans are exposed to S. aureus throughout life. In the current study, we hypothesized that prior exposure to S. aureus “imprints” the immune response to inhibit vaccine-mediated protection. We established a mouse model in which S. aureus skin and soft tissue infection (SSTI) is followed by vaccination and secondary SSTI. Unlike naïve mice, S. aureus-sensitized mice were incompletely protected against secondary SSTI by vaccination with the inactivated α-hemolysin (Hla) mutant HlaH35L. Inhibition of protection was specific for the HlaH35L vaccine and required hla expression during primary SSTI. Surprisingly, inhibition occurred at the level of vaccine-elicited effector T cells; hla expression during primary infection limited the expansion of T cells and dendritic cells and impaired vaccine-specific T cell responses. Importantly, the T cell-stimulating adjuvant CAF01 rescued inhibition and restored vaccine-mediated protection. Together, these findings identify a potential mechanism for the failure of translation of promising S. aureus vaccines from mouse models to clinical practice and suggest a path forward to prevent these devastating infections. |
| first_indexed | 2024-03-11T13:49:02Z |
| format | Article |
| id | doaj.art-3feb11fedb804e5f94c47581fdde9591 |
| institution | Directory Open Access Journal |
| issn | 2059-0105 |
| language | English |
| last_indexed | 2024-03-11T13:49:02Z |
| publishDate | 2023-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Vaccines |
| spelling | doaj.art-3feb11fedb804e5f94c47581fdde95912023-11-02T09:30:16ZengNature Portfolionpj Vaccines2059-01052023-01-018111310.1038/s41541-022-00598-3Toxin expression during Staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacyOmid Teymournejad0Zhaotao Li1Pavani Beesetty2Ching Yang3Christopher P. Montgomery4Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s HospitalCenter for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s HospitalCenter for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s HospitalCenter for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s HospitalCenter for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s HospitalAbstract Staphylococcus aureus infections are a major public health issue, and a vaccine is urgently needed. Despite a considerable promise in preclinical models, all vaccines tested thus far have failed to protect humans against S. aureus. Unlike laboratory mice, humans are exposed to S. aureus throughout life. In the current study, we hypothesized that prior exposure to S. aureus “imprints” the immune response to inhibit vaccine-mediated protection. We established a mouse model in which S. aureus skin and soft tissue infection (SSTI) is followed by vaccination and secondary SSTI. Unlike naïve mice, S. aureus-sensitized mice were incompletely protected against secondary SSTI by vaccination with the inactivated α-hemolysin (Hla) mutant HlaH35L. Inhibition of protection was specific for the HlaH35L vaccine and required hla expression during primary SSTI. Surprisingly, inhibition occurred at the level of vaccine-elicited effector T cells; hla expression during primary infection limited the expansion of T cells and dendritic cells and impaired vaccine-specific T cell responses. Importantly, the T cell-stimulating adjuvant CAF01 rescued inhibition and restored vaccine-mediated protection. Together, these findings identify a potential mechanism for the failure of translation of promising S. aureus vaccines from mouse models to clinical practice and suggest a path forward to prevent these devastating infections.https://doi.org/10.1038/s41541-022-00598-3 |
| spellingShingle | Omid Teymournejad Zhaotao Li Pavani Beesetty Ching Yang Christopher P. Montgomery Toxin expression during Staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacy npj Vaccines |
| title | Toxin expression during Staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacy |
| title_full | Toxin expression during Staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacy |
| title_fullStr | Toxin expression during Staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacy |
| title_full_unstemmed | Toxin expression during Staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacy |
| title_short | Toxin expression during Staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacy |
| title_sort | toxin expression during staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacy |
| url | https://doi.org/10.1038/s41541-022-00598-3 |
| work_keys_str_mv | AT omidteymournejad toxinexpressionduringstaphylococcusaureusinfectionimprintshostimmunitytoinhibitvaccineefficacy AT zhaotaoli toxinexpressionduringstaphylococcusaureusinfectionimprintshostimmunitytoinhibitvaccineefficacy AT pavanibeesetty toxinexpressionduringstaphylococcusaureusinfectionimprintshostimmunitytoinhibitvaccineefficacy AT chingyang toxinexpressionduringstaphylococcusaureusinfectionimprintshostimmunitytoinhibitvaccineefficacy AT christopherpmontgomery toxinexpressionduringstaphylococcusaureusinfectionimprintshostimmunitytoinhibitvaccineefficacy |