title: Preclinical testing of a vaccine candidate against tularemia.
abstract: Tularemia is caused by a gram-negative, intracellular bacterial pathogen, Francisella tularensis (Ft). The history weaponization of Ft in the past has elevated concerns that it could be used as a bioweapon or an agent of bioterrorism. Since the discovery of Ft, three broad approaches adopted for tularemia vaccine development have included inactivated, live attenuated, or subunit vaccines. Shortcomings in each of these approaches have hampered the development of a suitable vaccine for prevention of tularemia. Recently, we reported an oxidant sensitive mutant of Ft LVS in putative EmrA1 (FTL_0687) secretion protein. The emrA1 mutant is highly sensitive to oxidants, attenuated for intramacrophage growth and virulence in mice. We reported that EmrA1 contributes to oxidant resistance by affecting the secretion of antioxidant enzymes SodB and KatG. This study investigated the vaccine potential of the emrA1 mutant in prevention of respiratory tularemia caused by Ft LVS and the virulent SchuS4 strain in C57BL/6 mice. We report that emrA1 mutant is safe and can be used at an intranasal (i. n.) immunization dose as high as 1x106 CFU without causing any adverse effects in immunized mice. The emrA1 mutant is cleared by vaccinated mice by day 14-21 post-immunization, induces minimal histopathological lesions in lungs, liver and spleen and a strong humoral immune response. The emrA1 mutant vaccinated mice are protected against 1000-10,000LD100 doses of i.n. Ft LVS challenge. Such a high degree of protection has not been reported earlier against respiratory challenge with Ft LVS using a single immunization dose with an attenuated mutant generated on Ft LVS background. The emrA1 mutant also provides partial protection against i.n. challenge with virulent Ft SchuS4 strain in vaccinated C57BL/6 mice. Collectively, our results further support the notion that antioxidants of Ft may serve as potential targets for development of effective vaccines for prevention of tularemia.
authors.affiliation: Department of Microbiology and Immunology, New York Medical College, Valhalla, United States of America.
authors.forename: Ragavan Varadharajan
authors.initials: RV
authors.lastname: Suresh
authors.affiliation: Albany College of Pharmacy and Health Sciences, Albany, United States of America.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, United States of America.
authors.forename: Raju
authors.initials: R
authors.lastname: Sunagar
authors.affiliation: Department of Microbiology and Immunology, New York Medical College, Valhalla, United States of America.
authors.forename: Vivek
authors.initials: V
authors.lastname: Bhatty
authors.affiliation: Department of Microbiology and Immunology, New York Medical College, Valhalla, United States of America.
authors.forename: Sukalyani
authors.initials: S
authors.lastname: Banik
authors.affiliation: Albany College of Pharmacy and Health Sciences, Albany, United States of America.
authors.forename: Sally V
authors.initials: SV
authors.lastname: Catlett
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, United States of America.
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Gosselin
authors.affiliation: Albany College of Pharmacy and Health Sciences, Albany, United States of America.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Malik
authors.affiliation: Department of Microbiology and Immunology, New York Medical College, Valhalla, United States of America.
authors.forename: Chandra Shekhar
authors.initials: CS
authors.lastname: Bakshi
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001426:Bacterial Proteins / Q000235:genetics; D001428:Bacterial Vaccines / Q000276:immunology*; D016207:Cytokines / Q000097:blood; D005260:Female; D005604:Francisella tularensis / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D014406:Tularemia / Q000517:prevention & control*; D014611:Vaccination
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D016207:Cytokines; D008565:Membrane Proteins; C077168:emrA protein, Bacteria