Studies on the virulence properties and regulation of the CorA magnesium channel

CorA is the primary Mg2+ channel in Salmonella enterica serovar Typhimurium. A strain lacking corA is attenuated in mice after infection either by oral gavage or intraperitoneal injection. Microarray studies show that several virulence effectors in Salmonella pathogenicity island 1 and Salmonella pathogenicity island 2 are repressed in the corA strain compared to wild type. While these results could be sufficient to explain the virulence deficit, the microarray data suggest additional defects that could also contribute. Motility is significantly reduced in a corA strain whereas enterochelin-dependent iron uptake and curli are upregulated. A corA strain is defective for invasion of and replication within Caco-2 epithelial cells. However, a corA strain does not have a significant survival defect in J774A.1 macrophages. Thus, despite the presence of two other Mg2+ transporters, loss of CorA affects multiple systems which manifests ultimately as a decrease in virulence. We further examined Salmonella interaction with Caco-2 epithelial cells. Inhibiting CorA acutely or chronically with a high concentration of a selective inhibitor, cobalt (III) hexaammine, had no effect on S. Typhimurium invasion of and replication within Caco-2 epithelial cells. Complementing the corA mutation with a corA from various species rescued the invasion defect only if the complementing allele was functional and if it was evolutionarily similar to S. Typhimurium CorA. One explanation for these results could be that regulation of CorA function is needed for optimal virulence. Further experiments examining corA transcription, CorA protein content, CorA transport, and Mg2+ content indicated that both CorA expression and CorA function are differentially regulated. Moreover the rates of Mg2+ influx via CorA are not strictly correlated with either protein levels or Mg2+ content. We conclude that loss of the CorA protein disrupts a regulatory network(s) with the ultimate phenotype of decreased virulence. This conclusion is compatible with the microarray results which showed that loss of corA resulted in changes in transcription in multiple metabolic pathways. Further study of the regulation of CorA expression and function provides an opportunity to dissect the complexity of Mg2+ homeostasis and its ties to virulence within the bacterium.