Being a primary and prerequisite Post Translational Modification (PTM), protein phosphorylation mediates the defense mechanisms that presides host defense against a pathogen attack. Hence, the current study was intended to uncover the role of regulatory proteins and their PTMs with special attention to phosphorylation during pathogen attack, using C. elegans as a host and S. Typhi as an interacting pathogen. The study was initiated with the identification of differential regulation of the crucial immune regulatory kinases such as PMK-1, JNK-1 and SGK-1 through immunoblotting analysis, which revealed up-regulation of kinases during 48 h of S. Typhi infection. Subsequent the phosphoproteome profiling of S. Typhi infected C. elegans, using TiO2 Column Chromatography followed by MALDI-ToF-ToF-MS, uncovered the regulated phosphoprotein players resulting in the identification of 166 and 54 proteins from gel-free and gel-based analysis, respectively. HSP-90 was found to be a central player from the interactome analyses and its role during pathogenic defense was validated using immunoblotting. Furthermore, the protein disorders of the identified phosphoproteins have been extensively analysed in silico. This study suggests that S. Typhi interferes with the homeostasis of chaperone molecules by kinetically interfering with the phosphorylation of the downstream pathway players of MAPK and JNK.