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dc.contributor.authorGrassel, C.
dc.contributor.authorLipsky, M.
dc.contributor.authorVogel, S.N.
dc.contributor.authorBarry, E.M.
dc.date.accessioned2020-04-14T14:28:51Z
dc.date.available2020-04-14T14:28:51Z
dc.date.issued2020
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85082854005&doi=10.1080%2f21505594.2020.1746557&partnerID=40&md5=950890021459c8102796507b93d6f1f9
dc.identifier.urihttp://hdl.handle.net/10713/12552
dc.description.abstractThere is a need for development of an effective vaccine against Francisella tularensis, as this potential bioweapon has a high mortality rate and low infectious dose when delivered via the aerosol route. Moreover, this Tier 1 agent has a history of weaponization. We engineered targeted mutations in the Type A strain F. tularensis subspecies tularensis Schu S4 in aro genes encoding critical enzymes in aromatic amino acid biosynthesis. F. tularensis Schu S4ΔaroC, Schu S4ΔaroD, and Schu S4ΔaroCΔaroD mutant strains were attenuated for intracellular growth in vitro and for virulence in vivo and, conferred protection against pulmonary wild-type (WT) F. tularensis Schu S4 challenge in the C57BL/6 mouse model. F. tularensis Schu S4ΔaroD was identified as the most promising vaccine candidate, demonstrating protection against high-dose intranasal challenge; it protected against 1,000 CFU Schu S4, the highest level of protection tested to date. It also provided complete protection against challenge with 92 CFU of a F. tularensis subspecies holarctica strain (Type B). Mice responded to vaccination with Schu S4ΔaroD with systemic IgM and IgG2c, as well as the production of a functional T cell response as measured in the splenocyte-macrophage co-culture assay. This vaccine was further characterized for dissemination, histopathology, and cytokine/chemokine gene induction at defined time points following intranasal vaccination which confirmed its attenuation compared to WT Schu S4. Cytokine, chemokine, and antibody induction patterns compared to wild-type Schu S4 distinguish protective vs. pathogenic responses to F. tularensis and elucidate correlates of protection associated with vaccination against this agent. Copyright 2020 The Author(s).en_US
dc.description.sponsorshipThese studies were supported by the National Institutes of Allergy and Infectious Diseases at the National Institutes of Health (grant numbers R01 AI123129, U54 AI57168, U01 AI077909, and R01 AI102966).en_US
dc.description.urihttps://doi.org/10.1080/21505594.2020.1746557en_US
dc.language.isoen_USen_US
dc.publisherTaylor and Francis Inc.en_US
dc.relation.ispartofVirulence
dc.subjectaroDen_US
dc.subjectcytokinesen_US
dc.subjectdisseminationen_US
dc.subjectFrancisella tularensisen_US
dc.subjectpathologyen_US
dc.subjectSchu S4en_US
dc.subjecttularemiaen_US
dc.subjectvaccineen_US
dc.titleCharacterization of Schu S4 aro mutants as live attenuated tularemia vaccine candidatesen_US
dc.typeArticleen_US
dc.identifier.doi10.1080/21505594.2020.1746557
dc.identifier.pmid32241221


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