Host acid signal controls <i>Salmonella</i> flagella biogenesis through CadC-YdiV axis

Abstract

Upon entering host cells, <i>Salmonella</i> quickly turns off flagella biogenesis to avoid recognition by the host immune system. However, it is not clear which host signal(s) <i>Salmonella</i> senses to initiate flagellum control. Here, we demonstrate that the acid signal can suppress flagella synthesis and motility of <i>Salmonella</i>, and this occurs after the transcription of master flagellar gene <i>flhDC</i> and depends on the anti-FlhDC factor YdiV. YdiV expression is activated after acid treatment. A global screen with <i>ydiV</i> promoter DNA and total protein from acid-treated <i>Salmonella</i> revealed a novel regulator of YdiV, the acid-related transcription factor CadC. Further studies showed that CadC_C, the DNA binding domain of CadC, directly binds to a 33 nt region of the <i>ydiV</i> promoter with a 0.2 μM K_D affinity. Furthermore, CadC could separate H-NS-<i>ydiV</i> promoter DNA complex to form CadC-DNA complex at a low concentration. Structural simulation and mutagenesis assays revealed that H43 and W106 of CadC are essential for <i>ydiV</i> promoter binding. No acid-induced flagellum control phenotype was observed in <i>cadC</i> mutant or <i>ydiV</i> mutant strains, suggesting that flagellum control during acid adaption is dependent on CadC and YdiV. The intracellular survival ability of <i>cadC</i> mutant strain decreased significantly compared with WT strain while the flagellin expression could not be effectively controlled in the <i>cadC</i> mutant strain when surviving within host cells. Together, our results demonstrated that acid stress acts as an important host signal to trigger <i>Salmonella</i> flagellum control through the CadC-YdiV-FlhDC axis, allowing <i>Salmonella</i> to sense a hostile environment and regulate flagellar synthesis during infection.