Capsule and toxin are the major virulence factors of Bacillus anthracis. The B. 
anthracis pleiotropic regulator CodY activates toxin gene expression by 
post-translationally regulating the accumulation of the global regulator AtxA. 
However, the role of CodY on B. anthracis capsulation and virulence of 
encapsulated strains has been unknown. The role of CodY in B. anthracis 
virulence was studied in mouse and guinea pig models. Spore outgrowth and 
dissemination of the vegetative cells was followed in mice by bioluminescent 
imaging. We also determined the state of capsulation and the iron requirement 
for growth of the codY mutant. In all models tested, the codY mutant strain was 
strongly attenuated compared to the wild-type strain and, in mice, also compared 
to the atxA strain. The disruption of codY did not affect either ex vivo or in 
vivo capsulation, whereas atxA deletion affected ex vivo capsulation only. The 
disruption of codY led to a delayed initiation of dissemination but similar 
kinetics of subsequent spread of the bacilli. The codY mutant cannot grow on 
heme iron as sole iron source, whereas the parental and complemented strains 
can. The lack of CodY-mediated transcription weakens virulence by controlling 
iron acquisition and synthesis of toxin, but without modifying capsulation.