{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T05:04:09Z","timestamp":1780549449209,"version":"3.54.1"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI134681"],"award-info":[{"award-number":["R01AI134681"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Background<\/jats:title>\n \n The formalin-inactivated\n Coxiella burnetii<\/jats:italic>\n virulent phase I vaccine (PIV) has been shown to be more protective than the avirulent phase II vaccine (PIIV) against virulent\n C. burnetii<\/jats:italic>\n challenge in animal models. However, the cellular and molecular mechanisms underlying the differential ability of PIV and PIIV to induce protective immunity remain unclear.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n PIV and PIIV were generated from axenic (ACCM-D) cultures and administered to mice using single or multiple immunization regimens. Protective efficacy was evaluated following challenge with virulent\n C. burnetii<\/jats:italic>\n . Humoral immune responses were assessed by measuring phase I\u2013specific IgM and IgG antibodies. Bulk RNA sequencing and flow cytometry were used to compare immune responses in PIV- and PIIV-vaccinated mice. The role of neutrophils in vaccine-mediated protection was examined through neutrophil depletion prior to challenge.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Regardless of single or multiple immunizations, PIV and PIIV generated from axenic (ACCM-D) cultures retained their differential protective efficacies, with PIV providing robust protection but PIIV did not. PIV elicited earlier phase I-specific IgM responses and sustained higher IgG responses compared to PIIV, indicating differences in immunogenicity. Cellular and transcriptomic analyses revealed that PIV induced a prolonged neutrophil response in the spleen, accompanied by upregulation of genes involved in neutrophil degranulation, metal sequestration, and TLR-dependent innate immune pathways. In contrast, the neutrophil response induced by PIIV was transient and did not persist into later stages of vaccination. Depletion of neutrophils in PIV-vaccinated mice prior to challenge significantly reduced the protective efficacy of PIV.<\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n These findings demonstrate that PIV-induced protection against\n C. burnetii<\/jats:italic>\n infection is partially dependent on sustained neutrophil activation. This study provides novel evidence that modulation of neutrophil-mediated effector functions plays a critical role in PIV-mediated protective immunity.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1809423","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T04:30:13Z","timestamp":1780547413000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Systems biology approach unveils the cellular and molecular mechanisms of formalin-inactivated whole cell vaccine-induced protective immunity against Coxiella burnetii infection in mice"],"prefix":"10.3389","volume":"17","author":[{"given":"Venkatesh","family":"Kumaresan","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Texas at San Antonio","place":["San Antonio, TX, United 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