AUTHOR=Dunlap Micah D. , Prince Oliver A. , Rangel-Moreno Javier , Thomas Kimberly A. , Scordo Julia M. , Torrelles Jordi B. , Cox Jeffery , Steyn Adrie J. C. , Zúñiga Joaquín , Kaushal Deepak , Khader Shabaana A. 

TITLE=Formation of Lung Inducible Bronchus Associated Lymphoid Tissue Is Regulated by Mycobacterium tuberculosis Expressed Determinants

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.01325

DOI=10.3389/fimmu.2020.01325

ISSN=1664-3224

ABSTRACT=<p><italic>Mycobacterium tuberculosis</italic> (<italic>Mtb</italic>) 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 <italic>Mtb</italic>. 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 <italic>Mtb</italic> infection. In this study, we hypothesized that specific <italic>Mtb</italic> 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 <italic>Mtb</italic>, and identified specific <italic>Mtb</italic> mutants that were over-represented within iBALT-containing granulomas. A major pathway reflected in these mutants was <italic>Mtb</italic> cell wall lipid transport and metabolism. We mechanistically addressed the function of one such <italic>Mtb</italic> mutant lacking mycobacteria membrane protein large 7 (<italic>MmpL7</italic>), which transports phthiocerol dimycocerosate (PDIM) to the mycobacterial outer membrane (MOM). Accordingly, murine aerosol infection with the <italic>Mtb</italic> mutant Δ<italic>mmpl7</italic> correlated with increased iBALT-containing granulomas. Our studies showed that the Δ<italic>mmpl7</italic> 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 <italic>Mtb</italic> specific factor that participates in the induction of iBALT formation during TB by directly modulating cytokine and chemokine production in host cells.</p>