{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T07:58:28Z","timestamp":1776326308867,"version":"3.50.1"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p><jats:italic>Staphylococcus aureus<\/jats:italic> is a leading cause of skin and soft tissue infections (SSTI) and pneumonia. Recurrence is common and treatment is complicated by antimicrobial resistance; therefore, it is necessary to understand the mechanisms by which the host develops protective immunity against <jats:italic>S. aureus<\/jats:italic>. We previously reported that SSTI, but not pneumonia, elicits strong <jats:italic>S. aureus<\/jats:italic>-specific antibody and T cell responses and protection against recurrent infection; these findings suggested that site-specific elicited immune responses drive protective immunity. Because <jats:italic>S. aureus<\/jats:italic> is rapidly cleared from the lung but persists in the skin, we hypothesized that bacterial persistence in the lung is necessary to elicit protective antibody and T cell responses. In this study, we tested this hypothesis using a newly described mouse model of persistent pneumonia. Indeed, persistent pneumonia and SSTI elicited strong toxin-specific antibody and CD4<jats:sup>+<\/jats:sup> IL-17<jats:sup>+<\/jats:sup> and IFN\u03b3<jats:sup>+<\/jats:sup> T cell responses, whereas transient pneumonia did not. Persistence of <jats:italic>S. aureus<\/jats:italic> in the lung was accompanied by durable systemic T and B cell expansion observed as early as 9 days after infection. Consistent with important roles for antibodies and T cells in protective immunity, SSTI and persistent pneumonia, but not transient pneumonia, elicited protection against secondary SSTI and pneumonia. Taken together, these results demonstrate that bacterial persistence in infected tissues is necessary to elicit protective immunity against recurrent infections. These findings have important implications in better understanding the mechanisms of natural immunity against <jats:italic>S. aureus<\/jats:italic>.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1587018","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T05:30:29Z","timestamp":1758173429000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Staphylococcus aureus persistence in the lung is necessary to elicit systemic protective immunity"],"prefix":"10.3389","volume":"16","author":[{"given":"Usha Vyshnavi","family":"Chidella","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaotao","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maureen","family":"Kleinhenz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher P.","family":"Montgomery","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1080\/14760584.2016.1179583","article-title":"Staphylococcus aureus: the current state of disease, pathophysiology and strategies for prevention","volume":"15","author":"Dayan","year":"2016","journal-title":"Expert Rev Vaccines"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)02185-7","article-title":". Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019","volume":"400","author":"Ikuta","year":"2022","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciu943","article-title":"Staphylococcus aureus skin infection recurrences among household members: an examination of host, behavioral, and pathogen-level predictors","volume":"60","author":"Miller","year":"2015","journal-title":"Clin Infect Dis"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cit123","article-title":"A serologic correlate of protective immunity against community-onset Staphylococcus aureus infection","volume":"56","author":"Fritz","year":"2013","journal-title":"Clin Infect Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.795792","article-title":"Tissue specificity drives protective immunity against Staphylococcus aureus infection","volume":"13","author":"Beesetty","year":"2022","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.04970-22","article-title":"In vitro persistence level reflects in vivo antibiotic survival of natural pseudomonas aeruginosa isolates in a murine lung infection model","volume":"11","author":"Verstraete","year":"2023","journal-title":"Microbiol Spectr"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2011.01.078","article-title":"Generation of Salmonella-specific Th1 cells requires sustained antigen stimulation","volume":"29","author":"Griffin","year":"2011","journal-title":"Vaccine"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1086\/315046","article-title":"The effect of doxycycline treatment on the development of protective immunity in a murine model of chlamydial genital infection","volume":"180","author":"Su","year":"1999","journal-title":"J Infect Dis"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00256-09","article-title":"The arginine catabolic mobile element is not associated with enhanced virulence in experimental invasive disease caused by the community-associated methicillin-resistant Staphylococcus aureus USA300 genetic background","volume":"77","author":"Montgomery","year":"2009","journal-title":"Infect Immun"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0000000000000156","article-title":"Host factors that contribute to recurrent staphylococcal skin infection","volume":"28","author":"Montgomery","year":"2015","journal-title":"Curr Opin Infect Dis"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3791\/53824","article-title":"An efficient and high yield method for isolation of mouse dendritic cell subsets","volume":"110","author":"Arora","year":"2016","journal-title":"J Vis Exp"},{"key":"B12","article-title":"Immunobiology: the immune system in health and disease","volume-title":"The immune system in health and disease","author":"Janeway","year":"2001"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-01122-w","article-title":"The T cell immune response against SARS-CoV-2","volume":"23","author":"Moss","year":"2022","journal-title":"Nat Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1128\/aac.02270-21","article-title":"Antibiotic treatment of staphylococcus aureus infection inhibits the development of protective immunity","volume":"66","author":"Kleinhenz","year":"2022","journal-title":"Antimicrobial Agents Chemotherapy"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.12.6833","article-title":"Early programming of T cell populations responding to bacterial infection","volume":"165","author":"Mercado","year":"2000","journal-title":"J Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20042521","article-title":"Antigen persistence is required throughout the expansion phase of a CD4(+) T cell response","volume":"201","author":"Obst","year":"2005","journal-title":"J Exp Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1172\/JCI130728","article-title":"Staphylococcus aureus toxin suppresses antigen-specific T cell responses","volume":"130","author":"Lee","year":"2020","journal-title":"J Clin Invest"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e34390","DOI":"10.1371\/journal.pone.0034390","article-title":"Host immune transcriptional profiles reflect the variability in clinical disease manifestations in patients with Staphylococcus aureus infections","volume":"7","author":"Banchereau","year":"2012","journal-title":"PloS One"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/82_2016_1","article-title":"Adaptive immunity against staphylococcus aureus","volume":"409","author":"Karauzum","year":"2017","journal-title":"Curr Top Microbiol Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nri3010","article-title":"Immunity against Staphylococcus aureus cutaneous infections","volume":"11","author":"Miller","year":"2011","journal-title":"Nat Rev Immunol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"3580","DOI":"10.1038\/s41598-018-22044-y","article-title":"Protective humoral and CD4+ T cellular immune responses of Staphylococcus aureus vaccine MntC in a murine peritonitis model","volume":"8","author":"Yu","year":"2018","journal-title":"Sci Rep"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/femsre\/fuv024","article-title":"Phagocyte subsets and lymphocyte clonal deletion behind ineffective immune response to Staphylococcus aureus","volume":"39","author":"Pozzi","year":"2015","journal-title":"FEMS Microbiol Rev"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis033","article-title":"Challenges for a universal Staphylococcus aureus vaccine","volume":"54","author":"Proctor","year":"2012","journal-title":"Clin Infect Dis"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.705360","article-title":"Staphylococcus aureus vaccine research and development: the past, present and future, including novel therapeutic strategies","volume":"12","author":"Clegg","year":"2021","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e0147767","DOI":"10.1371\/journal.pone.0147767","article-title":"One Dose of Staphylococcus aureus 4C-Staph Vaccine Formulated with a Novel TLR7-Dependent Adjuvant Rapidly Protects Mice through Antibodies, Effector CD4+ T Cells, and IL-17A","volume":"11","author":"Mancini","year":"2016","journal-title":"PloS One"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.658141","article-title":"Staphylococcus aureus \u03b2-hemolysin up-regulates the expression of IFN-\u03b3 by human CD56(bright) NK cells","volume":"11","author":"Guan","year":"2021","journal-title":"Front Cell Infect Microbiol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01558","article-title":"Biology of interleukin-17 and its pathophysiological significance in sepsis","volume":"11","author":"Ge","year":"2020","journal-title":"Front Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1587018\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T05:30:31Z","timestamp":1758173431000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1587018\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,18]]},"references-count":27,"alternative-id":["10.3389\/fimmu.2025.1587018"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1587018","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,18]]},"article-number":"1587018"}}