title: Enhancement of vaccine efficacy by expression of a TLR5 ligand in the defined live attenuated Francisella tularensis subsp. novicida strain U112ΔiglB::fljB.
abstract: Oral vaccination with the defined live attenuated Francisella novicida vaccine strain U112ΔiglB has been demonstrated to induce protective immunity against pulmonary challenge with the highly human virulent Francisella tularensis strain SCHU S4. However, this vaccination regimen requires a booster dose in mice and Exhibits 50% protective efficacy in the Fischer 344 rat model. To enhance the efficacy of this vaccine strain, we engineered U112ΔiglB to express the Salmonella typhimurium FljB flagellin D1 domain, a TLR5 agonist. The U112ΔiglB::fljB strain was highly attenuated for intracellular macrophage replication, and although the FljB protein was expressed within the cytosol, it exhibited TLR5 activation in a TLR5-expressing HEK cell line. Additionally, infection of splenocytes and lymphocytes with U112ΔiglB::fljB induced significantly greater TNF-α production than infection with U112ΔiglB. Oral vaccination with U112ΔiglB::fljB also induced significantly greater protection than U112ΔiglB against pulmonary SCHU S4 challenge in rats. The enhanced protection was accompanied by higher IgG2a production and serum-mediated reduction of Francisella infectivity. Thus, the U112ΔiglB::fljB strain may serve as a potential vaccine candidate against pneumonic tularemia.
authors: South Texas Center for Emerging Infectious Disease and the Center for Excellence in Infection Genomics, University of Texas at San Antonio, San Antonio, TX 78249, United States; Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United States.
authors: Aimee L
authors: AL
authors: Cunningham
authors: South Texas Center for Emerging Infectious Disease and the Center for Excellence in Infection Genomics, University of Texas at San Antonio, San Antonio, TX 78249, United States.
authors: Kim Minh
authors: KM
authors: Dang
authors: South Texas Center for Emerging Infectious Disease and the Center for Excellence in Infection Genomics, University of Texas at San Antonio, San Antonio, TX 78249, United States.
authors: Jieh-Juen
authors: JJ
authors: Yu
authors: South Texas Center for Emerging Infectious Disease and the Center for Excellence in Infection Genomics, University of Texas at San Antonio, San Antonio, TX 78249, United States.
authors: M Neal
authors: MN
authors: Guentzel
authors: South Texas Center for Emerging Infectious Disease and the Center for Excellence in Infection Genomics, University of Texas at San Antonio, San Antonio, TX 78249, United States.
authors: Hans W
authors: HW
authors: Heidner
authors: South Texas Center for Emerging Infectious Disease and the Center for Excellence in Infection Genomics, University of Texas at San Antonio, San Antonio, TX 78249, United States.
authors: Karl E
authors: KE
authors: Klose
authors: South Texas Center for Emerging Infectious Disease and the Center for Excellence in Infection Genomics, University of Texas at San Antonio, San Antonio, TX 78249, United States. Electronic address: bernard.arulanandam@utsa.edu.
authors: Bernard P
authors: BP
authors: Arulanandam
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001428:Bacterial Vaccines / Q000276:immunology*; D002460:Cell Line; D005408:Flagellin / Q000276:immunology*; D005604:Francisella tularensis; D006801:Humans; D008024:Ligands; D008264:Macrophages / Q000382:microbiology; D008807:Mice, Inbred BALB C; D011916:Rats, Inbred F344; D051198:Toll-Like Receptor 5 / Q000276:immunology*; D014406:Tularemia / Q000517:prevention & control*; D064166:Vaccine Potency; D014613:Vaccines, Attenuated / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D001428:Bacterial Vaccines; C094427:FljB protein, Salmonella; D008024:Ligands; D051198:Toll-Like Receptor 5; D014613:Vaccines, Attenuated; D005408:Flagellin
keywords: Fischer 344 rat; Flagellin; Francisella tularensis; TLR5; Vaccine