Translation terminates at UAG (amber), UGA (opal), and UAA (ochre) stop codons. In nature, readthrough of stop codons can be substantially enhanced by suppressor tRNAs. Stop-codon suppression also provides powerful tools in synthetic biology and disease treatment. How stop-codon suppression affects bacterial pathogenesis is poorly understood. Here, we show that suppression of UAG codons, but not UGA or UAA codons, attenuates expression of Salmonella Pathogenicity Island 1 (SPI-1) genes, which are required for virulence. Consistently, amber suppression abolishes Salmonella infection of macrophages. Systematic genetic and biochemical analyses further show that amber suppression decreases the activity, but not the level, of the master SPI-1 regulator HilD. Our work thus demonstrates an unexpected selectivity of stop codons in regulating Salmonella virulence.
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