Formation of Lung Inducible Bronchus Associated Lymphoid Tissue Is Regulated by Expressed Determinants.

() is the causative agent of the infectious disease tuberculosis (TB), which is a leading cause of death worldwide. Approximately one fourth of the world's population is infected with . A major unresolved question is delineating the inducers of protective long-lasting immune response without inducing overt, lung inflammation. Previous studies have shown that the presence of inducible Bronchus-Associated Lymphoid Tissue (iBALT) correlate with protection from infection. In this study, we hypothesized that specific factors could influence the formation of iBALT, thus skewing the outcome of TB disease. We infected non-human primates (NHPs) with a transposon mutant library of , and identified specific mutants that were over-represented within iBALT-containing granulomas. A major pathway reflected in these mutants was cell wall lipid transport and metabolism. We mechanistically addressed the function of one such mutant lacking mycobacteria membrane protein large 7 (), which transports phthiocerol dimycocerosate (PDIM) to the mycobacterial outer membrane (MOM). Accordingly, murine aerosol infection with the mutant Δ correlated with increased iBALT-containing granulomas. Our studies showed that the Δ mutant lacking PDIMs on the surface overexpressed diacyl trehaloses (DATs) in the cell wall, which altered the cytokine/chemokine production of epithelial and myeloid cells, thus leading to a dampened inflammatory response. Thus, this study describes an specific factor that participates in the induction of iBALT formation during TB by directly modulating cytokine and chemokine production in host cells.