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We previously reported that vaccination of BALB\/c mice with<jats:italic>Mycoplasma pneumoniae<\/jats:italic>(<jats:italic>Mp<\/jats:italic>) lipid-associated membrane proteins (LAMPs) resulted in lipoprotein-dependent vaccine enhanced disease after challenge with virulent<jats:italic>Mp<\/jats:italic>, though the immune responses underpinning this phenomenon remain poorly understood. Herein, we report that lipoprotein-induced VED in a mouse model is associated with elevated inflammatory cytokines TNF-\u03b1, IL-1\u03b2, IL-6, IL-17A, and KC in lung lavage fluid and with suppurative pneumonia marked by exuberant neutrophilia in the pulmonary parenchyma. Whole-lung-digest flow cytometry and RNAScope analysis identified multiple cellular sources for IL-17A, and the numbers of IL-17A producing cells were increased in LAMPs-vaccinated\/<jats:italic>Mp<\/jats:italic>-challenged animals compared to controls. Specific IL-17A or neutrophil depletion reduced disease severity in our VED model\u2014indicating that<jats:italic>Mp<\/jats:italic>lipoproteins induce VED in an IL-17A-dependent manner and through exuberant neutrophil recruitment. IL-17A neutralization reduced levels of TNF-\u03b1, IL-1\u03b2, IL-6, and KC, indicating that IL-17A preceded other inflammatory cytokines. Surprisingly, we found that IL-17A neutralization impaired bacterial clearance, while neutrophil depletion improved it\u2014indicating that, while IL-17A appears to confer both maladaptive and protective responses, neutrophils play an entirely maladaptive role in VED. Given that lipoproteins are found in virtually all bacteria, the potential for lipoprotein-mediated maladaptive inflammatory responses should be taken into consideration when developing vaccines against bacterial pathogens.<\/jats:p>","DOI":"10.1038\/s41541-022-00513-w","type":"journal-article","created":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T12:03:39Z","timestamp":1659096219000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Vaccination with Mycoplasma pneumoniae membrane lipoproteins induces IL-17A driven neutrophilia that mediates Vaccine-Enhanced Disease"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9823-5243","authenticated-orcid":false,"given":"Arlind B.","family":"Mara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3014-4166","authenticated-orcid":false,"given":"Tyler D.","family":"Gavitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2682-5145","authenticated-orcid":false,"given":"Edan R.","family":"Tulman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy M.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wu","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily M.","family":"Reinhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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