Characterization of Schu S4 aro mutants as live attenuated tularemia vaccine candidates. Issue 1 (1st January 2020)

• Record Type: Journal Article
• Authors: Cunningham, Aimee L.; Mann, Barbara J.; Qin, Aiping; Santiago, Araceli E.; Grassel, Christen; Lipsky, Michael; Vogel, Stefanie N.; Barry, Eileen M.
• Is Part Of: Virulence. Volume 11:Issue 1(2020)
• Page Start: 283
• Page End: 294
• Publication Date: 2020-01-01
• Subjects: Francisella tularensis -- tularemia -- Schu S4 -- vaccine -- aroD -- dissemination -- cytokines -- pathology; Virulence (Microbiology) -- Periodicals; Bacterial diseases -- Periodicals; Molecular microbiology -- Periodicals; 579.05
• DOI: 10.1080/21505594.2020.1746557
• Languages: English
• ISSNs: 2150-5608

Abstract

ABSTRACT: There 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 S4 ΔaroC, Schu S4Δ aroD, and Schu S4Δ aroC Δ aroD 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 S4Δ aroD 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 S4Δ aroD 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.