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Background   Francisella tularensis  is a highly virulent, facultative intracellular pathogen and the etiologic agent of the zoonotic disease Tularemia. RipA is a cytoplasmic membrane protein that is conserved among  Francisella  species and is required for intracellular growth.  F. tularensis ripA  deletion mutants escape the phagosome of infected cells, but unlike wild type organisms fail to replicate in the host cell cytoplasm.    Results  Further analysis of  ripA  with respect to environmental effects on the growth of mutant strains and expression levels revealed that RipA is required for optimal growth at pH 7.5 but not pH 6.5. Using a combination of RT-PCR,  ripA-lacZ  transcriptional and translational fusions, and a RipA-tetracysteine tag fusion protein we found that both  ripA  transcription and RipA protein levels were elevated in organisms grown at pH 7.5 as compared to organisms grown at pH 5.5. A number of genes, including  iglA , that are required for intracellular growth are regulated by the transcriptional regulators MglA and SspA, and are induced upon infection of host cells. We quantified  ripA  and  iglA  expression at different stages of intracellular growth and found that the expression of each increased between 1 and 6 hours post infection. Given the similar intracellular expression patterns of  ripA  and  iglA  and that MglA and SspA are positive regulators of  iglA  we tested the impact of  mglA  and  sspA  deletions on  ripA  and  iglA  expression. In the deletion mutant strains  iglA  expression was reduced dramatically as expected, however  ripA  expression was increased over 2-fold.    Conclusion  Expression of  ripA  is required for growth at neutral pH, is pH sensitive, and is responsive to the intracellular environment. The intracellular expression pattern of  ripA  coincided with  iglA , which is positively regulated by MglA and SspA. However, in contrast to their positive impact on  iglA  expression, MglA and SspA negatively impacted  ripA  expression  in vitro .

Environmental and intracellular regulation of Francisella tularensis ripA