Project 2: Systems biology analyses of RHCMV/SIV and IL-15 mechanisms of immune programming

Project 2 brings a systems biology approach, “systems vaccinology”, to investigate immune response programing by IL-15 and RhCMV/SIV vaccine. Our goal is to define the molecular response by which IL-15 and RhCMV/SIV vaccine program the protection-predictive immune phenotype in whole blood to vaccination, what we term as the “whole blood protection-predictive transcriptomic signature” [wbPPTS] that predicts and underlies vaccine protection from SIV infection. We will conduct three Aims including i) Determine the response to IL-15 in monocytes and T cells; ii) Define the tissue and cell-specific transcriptome correlates of IL-15 signaling linked with RhCMV/SIV vaccination phenotype to program the wbPPTS, and iii) Validate RhCMV/SIV vaccination tissue and wbPPTS signature linkage with protection against SIV challenge. Our research design features in vitro and ex vivo models for analyses of cell signaling/responses to IL-15, and in vivo analyses of cell and tissue application of three "omics" platforms including single cell RNA sequencing (scRNAseq and CITEseq), bulk RNAseq, and tissue spatial profiling. Our bioinformatics/computational analyses will integrate functional genomics data sets with immune response and protection phenotypes to determine the molecular and cellular features directing the wbPPTS and vaccine protection. We will conduct bioinformatics of RhCMV/SIV transcriptomic responses in an independent vaccination/SIV challenge cohort to ascertain specific tissue signature of protection and the wbPPTS. This work will be conducted in a collaborative framework conjunction with Cores A-C and Project 1.