The Vibrio cholerae O139 Calcutta Bacteriophage CTXφ Is Infectious and Encodes a Novel Repressor

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Abstract
CTXφ is a lysogenic, filamentous bacteriophage. Its genome includes the genes encoding cholera toxin ( ctxAB ), one of the principal virulence factors of Vibrio cholerae ; consequently, nonpathogenic strains of V. cholerae can be converted into toxigenic strains by CTXφ infection. O139 Calcutta strains of V. cholerae , which were linked to cholera outbreaks in Calcutta, India, in 1996, are novel pathogenic strains that carry two distinct CTX prophages integrated in tandem: CTX ET , the prophage previously characterized within El Tor strains, and a new CTX Calcutta prophage (CTX calc ). We found that the CTX calc prophage gives rise to infectious virions; thus, CTX ET φ is no longer the only known vector for transmission of ctxAB . The most functionally significant differences between the nucleotide sequences of CTX calc φ and CTX ET φ are located within the phages’ repressor genes ( rstR calc and rstR ET , respectively) and their RstR operators. RstR calc is a novel, allele-specific repressor that regulates replication of CTX calc φ by inhibiting the activity of the rstA calc promoter. RstR calc has no inhibitory effect upon the classical and El Tor rstA promoters, which are instead regulated by their cognate RstRs. Consequently, production of RstR calc renders a CTX calc lysogen immune to superinfection by CTX calc φ but susceptible (heteroimmune) to infection by CTX ET φ. Analysis of the prophage arrays generated by sequentially integrated CTX phages revealed that pathogenic V. cholerae O139 Calcutta probably arose via infection of an O139 CTX ET φ lysogen by CTX calc φ.