Phosphoproteomic analysis of interleukin 15 stimulated monocytes reveals signaling pathway induction associated with vaccine protection 4609

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Abstract Description A cytomegalovirus (CMV) vector-based vaccine platform has emerged as a promising HIV vaccine candidate, with profound protection in preclinical animal models. Vaccine protection is highly correlated with the persistent induction of a whole-blood transcriptional signature (wbPPTS) involving immune cell, toll-like receptor (TLR), and inflammasome/death receptor signaling pathways. IL-15 was identified as the primary upstream signaling intermediate, while monocytes were identified as a major contributor of the wbPPTS. Phosphoproteomic analysis was conducted on IL-15 stimulated human monocytes over a time series (6, 12, 24, & 48hrs) to evaluate signal transduction pathway recruitment. Significant differences in phosphite abundance for key wbPPTS signaling intermediates were present in IL-15 stimulated monocytes relative to untreated controls, including MAP kinases, STAT, and IRF transcription factors. Functional enrichment analysis revealed enriched pathways linked to canonical IL-15 signaling, including AKT, mTOR, and MAPK/ERK signaling. Additionally, we observed enrichment in TLR and immune cell signaling pathways, consistent with the predicted transcriptomic signaling pathways associated with vaccine protection. These results demonstrate the diverse physiologic effects IL-15 signaling has on monocytes, with recruitment of novel signaling pathways, and have important implications for understanding the underlying protective mechanisms of the CMV vector vaccine platform. Funding Sources Studies supported by NIH/NIAID P01AI177688. IBA is supported by internal funds from the UW Department of Comparative Medicine. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)

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