Identification of Bhlhe40 and Irg1 as Essential Regulators of the Inflammatory Response to Mycobacterium tuberculosi

Protective immune responses to Mycobacterium tuberculosis (Mtb) must induce bactericidal functions while minimizing damage to the lung. Such responses require precise control of pro- and anti-inflammatory factors to regulate the recruitment and function of protective immune cells but the mechanisms by which this control is exerted remain incompletely defined. Basic helix-loop-helix family, member e40 (Bhlhe40) is a transcription factor known to regulate production of pro- and anti-inflammatory cytokines that affect protective immunity to Mtb. Immune-responsive Gene 1 (Irg1) is an enzyme that generates itaconate, a metabolite with potential anti-inflammatory and antibacterial roles during Mtb infection. The impact of Bhlhe40 and Irg1 on protective immunity to Mtb was unknown prior to the studies detailed in this dissertation.;We utilized genetically deficient mice to assess the roles of Bhlhe40 and Irg1 expression on control of in vivo Mtb infection. We found that Bhlhe40 enables protective immune responses to Mtb by restricting expression of the anti-inflammatory cytokine IL-10 and is required in T cells and CD11c+ cells. Bhlhe40 does so by repressing Il10 transcription, likely by direct binding to the Il10 locus. Additionally, we discovered that Irg1 functions in LysM + and CD11c+ cells to prevent neutrophil-mediated immunopathology. Irg1 expression restricts inflammatory responses in myeloid cells at a transcriptional level, likely through production of the metabolite itaconate. Thus, Bhlhe40 and Irg1 directly and indirectly tune the inflammatory response to Mtb at a transcriptional level. These findings advance our understanding of protective immunity to Mtb by revealing novel mechanisms used by specific immune cell types to promote bacterial killing and restrict pathologic inflammation.