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.
Highlights
Tularemia is a disease caused by a gram-negative, intracellular bacterial pathogen Francisella tularensis (Ft)
We have recently reported that the emrA1mutant of Ft Live Vaccine Strain (LVS) is highly attenuated for virulence and doses as high as 1x105 or 1x106 CFU administered i.n. do not cause any mortality in Vaccine Potential of the emrA1 mutant of Francisella tularensis infected mice [20]
It was observed that similar to mice infected with Ft LVS, those immunized with the emrA1 mutant did not show any changes in body weight for first three days, which was followed by a sudden weight loss by day 5 post-immunization
Summary
Tularemia is a disease caused by a gram-negative, intracellular bacterial pathogen Francisella tularensis (Ft). Inactivated Ft LVS or SchuS4 vaccines do not protect against virulent Ft [8,15,16] and subunit vaccines have been shown to possess limited protective ability due to the lack of a suitable platform for delivering multiple protective antigens simultaneously [7]. These shortcomings have hampered the development of a suitable vaccine for prevention of tularemia
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