Streptococcus suis serotype 2 (SS2) is a major swine pathogen of significant commercial importance worldwide and an emerging zoonotic agent of human streptococcal toxic shock-like syndrome. We previously reported that the Chinese highly pathogenic SS2 strains specifically harbor an 89K pathogenicity island, and the SalK/SalR two-component system encoded within this island mediates a piglet-lethal phenotype. However, its regulatory mechanism remains obscure. In the present study, we performed a proteome analysis to identify the target proteins regulated by the SalK/SalR system. This expression profiling analysis reveals 14 down-regulated proteins and 1 up-regulated protein. In partial accord with our previous microarray analysis, 9 out of the 14 down-regulated genes are also repressed at the transcriptional level. From the 9 matched genes, 5 were selected and further subjected to gene knockout and experimental infection of mice. The results show that the selected 5 genes are potential virulence factors and participate to various extents in the pathogenesis of SS2 infection, and may contribute to the attenuation of virulence mediated by the SalK/SalR system.