Anthrax SET protein: a potential virulence determinant that epigenetically represses NF-κB activation in infected macrophages.

Toxins play a major role in the pathogenesis of Bacillus anthracis by subverting the host defenses. However, besides toxins, B. anthracis expresses effector proteins, whose role in pathogenesis are yet to be investigated. Here we present that suppressor-of-variegation, enhancer-of-zeste, trithorax protein from B. anthracis (BaSET) methylates human histone H1, resulting in repression of NF-κB functions. Notably, BaSET is secreted and undergoes nuclear translocation to enhance H1 methylation in B. anthracis-infected macrophages. Compared with wild type Sterne, delayed growth kinetics and altered septum formation were observed in the BaSET knock-out (BaΔSET) bacilli. Uncontrolled BaSET expression during complementation of the BaSET gene in BaΔSET partially restored growth during stationary phase but resulted in substantially shorter bacilli throughout the growth cycle. Importantly, in contrast to Sterne, the BaΔSET B. anthracis is avirulent in a lethal murine bacteremia model of infection. Collectively, BaSET is required for repression of host transcription as well as proper B. anthracis growth, making it a potentially unique virulence determinant.