Abstract
Francisella tularensis is the causative agent of tularemia and a category A bioterrorism agent. The molecular basis for the extreme virulence of F. tularensis remains unclear. Our recent study found that capBCA, three neighboring genes, are necessary for the infection of F. tularensis live vaccine strain (LVS) in a respiratory infection mouse model. We here show that the capBCA genes are necessary for in vivo growth of F. tularensis LVS in the lungs, spleens, and livers of BALB/c mice. Unmarked deletion of capBCA in type A strain Schu S4 resulted in significant attenuation in virulence although the level of the attenuation in Schu S4 was much less profound than in LVS. We further demonstrated that CapB protein is produced at a low level under the in vitro culture conditions, and capB alone is necessary for in vivo growth of F. tularensis LVS in the lungs of BALB/c mice. Finally, deletional mutations in capB alone or capBCA significantly impaired intracellular growth of F. tularensis LVS in cultured macrophages, thus suggesting that the capBCA genes are necessary for intracellular adaptation of F. tularensis. The requirement of this gene locus in intracellular adaption at least in part explains the significant attenuation of F. tularensis capBCA mutants in virulence.
Highlights
Francisella tularensis is a Gram-negative intracellular bacterium and causative agent of tularemia in humans and many other species (Sjostedt, 2007)
The F. tularensis capBCA genes are among the 95 virulence-associated genes identified in our recent STM study (Su et al, 2007)
Transposon insertions in each of the capBCA genes resulted in significantly impaired growth of F. tularensis live vaccine strain (LVS) in the lungs of BALB/c mice 7 days post-intranasal inoculation
Summary
Francisella tularensis is a Gram-negative intracellular bacterium and causative agent of tularemia in humans and many other species (Sjostedt, 2007). All F. tularensis subspecies are able to cause lethal infection in mice, but only the strains of types A and B are mostly associated with human disease (Keim et al, 2007). F. tularensis live vaccine strain (LVS) is a type B derivative. LVS is relatively avirulent in humans but causes a lethal infection in mice that highly resembles human tularemia (Eigelsbach and Downs, 1961; Anthony and Kongshavn, 1987). Respiratory tularemia has attracted the most attention because inhalation of as few as 10–50 live organisms of F. tularensis type A can cause disease and the mortality rate can be >30% by the respiratory route in the absence of antibiotic therapy (McCrumb, 1961). F. tularensis type A strains are listed as a category A potential agent of bioterrorism (Dennis et al, 2001)
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