Tuberculosis (TB) is a leading global infectious killer responsible for > 1 million deaths per year, the majority of which occur in resource-constrained settings. While an effective TB vaccine is therefore an urgent global health priority, progress has been disappointing, with the last major landmark being the development of BCG a century ago. Recently, the tools of genomics have offered new, systems-level views of anti-TB immunity that have the potential to illuminate more rational approaches to vaccine development.
To that end, we are working to generate systems-level analyses of the CD4 T cell response to TB in 2-dimensions:
(i) The first dimension is the TB genome, where we will combine TGen’s expertise in pathogen genomics with novel, multiplexed technologies to survey T cell antigenicity across the pathogen’s ~4000 genes. Phylogenetic evidence already provides clues that T cell reactivity to different regions of the TB genome may have differential effects, and we expect this genome-wide analysis to provide new insights into host-pathogen adaptation and highlight TB genes that may be priority targets for protective immunity.
(ii) The second dimension is the human genome. Using high-dimensional probesets developed in the TB genome-wide analysis, we plan to apply single cell methods to study the transcriptional landscape of TB-specific T cells in different disease settings. A simultaneous view of T cell states and specifities has the potential to define new T cell correlates of disease and protection.