Biochemical and mutational analyses demonstrated that CRP binds directly and specifically to upstream regions in the PrtxA regulatory region, which results in repression of rtxA. Interestingly, CRP also represses both lrp and hlyU by directly binding to their upstream regions, forming coherent feed-forward loops with Lrp and HlyU to regulate rtxA. Taken together, this study suggests that rtxA expression is elaborately regulated by host environmental signals, including leucine and glucose, through the CRP-coordinated regulatory network for the overall success of V. vulnificus during infection. The gene discussed is CRP; the disease is infection.