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

Abstract

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

Neutrophils reprograms the bone marrow to impair T-cell immunity during tuberculosis

“…1j ) 32,33 . Consistent with previously published studies in mice and NHPs 34,35 , we found iBALT-like structures containing B220 + and CD3e + T-lymphocytes mainly in the wt-mouse lung with fewer Ly6G + neutrophils and F4/80 + macrophages. In contrast, Ly6G + myeloid clusters were seen throughout the lung of Il1r1 −/− mice.…”

A Blunted GPR183/Oxysterol Axis During Dysglycemia Results in Delayed Recruitment of Macrophages to the Lung During Mycobacterium tuberculosis Infection

“…Jia et al [ 25 ] showed in a mouse model of COPD that GPR183 is required for the formation of inducible bronchus-associated lymphoid tissue (iBALT), a secondary lymphoid-like structure within the lung. The iBALTs are also formed during Mtb infection and correlate with protection [ 33 ]. The initial host determinants that govern the induction of iBALT formation during Mtb infection remain to be elucidated, but it is possible that oxysterols and GPR183 play a major role in iBALT formation during TB by serving as recruitment and retention signals.…”

A blunted GPR183/oxysterol axis during dysglycemia results in delayed recruitment of macrophages to the lung during M. tuberculosis infection

“…Jia et al showed in a mouse model of COPD that GPR183 is required for the formation of inducible bronchus-associated lymphoid tissue (iBALT), a secondary lymphoid-like structure within the lung [25]. iBALTs are also formed during Mtb infection and correlate with protection [33]. The initial host determinants that govern the induction of iBALT formation during Mtb infection remain to be elucidated, but it is possible that oxysterols and GPR183 play a major role in iBALT formation during TB by serving as recruitment and retention signals.…”