Streptococcus agalactiae(GBS) is a seriously threat to the farmed tilapia, and oral vaccination was considered to be the most desirable means which requires deep understanding of virulence mechanism of the fish-derived GBS. Our previous genome study of the fish-derived attenuated strain YM001 showed that there were two large deletions in YM001 compared to its parental virulent strain HN016. In this study, a combined transcriptomic and proteomic analysis was performed on YM001 and HN016 strains, and the important genes were verified by RT-qPCR in bacteria strains and infected-tilapia tissues. Overall, we have shown that a total of 958 genes and 331 proteins were significantly differential expressed between YM001 and HN016. By functional annotation of these DEGs and DEPs, genes that were enriched in pentose phosphate pathway(pgm, ptsG, pgi pfkA, fbaA and FBP3) and pyruvate metabolism pathway(pdhA, pdhB, pdhC and pdhD) were identifed as important candidate genes for leads low growth ability in attenuated strain, which may be an important reasons leading virulence attenuation in the end. The expression levels the candidate genes in pentose phosphate pathway and pyruvate metabolism pathway were significant differential expressed in tilapia' brain and spleen when infected with YM001 and HN016. Our study indicated that the pentose phosphate pathway and pyruvate metabolism pathway that affecting the growth of the strain may be one of the important reasons for the virulence attenuation in HN016.