Mafb loss weakens immune defense against tuberculosis in mice

Tuberculosis remains a major global concern because the bacteria that cause it, Mycobacterium tuberculosis (Mtb), can evade and resist the immune system. Genetic factors that influence whether people develop disease early or late after exposure are a focus of current research. One candidate identified by a genome-wide association study is v-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog B ( MAFB ). Shintaro Seto and colleagues set out to learn what role this gene plays in defending against Mtb. To do this, they used mice engineered to lack Mafb specifically in myeloid cells (Mafb -cKO) and studied both isolated immune cells and whole animals. The team infected bone marrow-derived macrophages (BMMs) and mice with Mycobacterium tuberculosis (Mtb) to compare how cells and tissues with and without Mafb respond to infection. By focusing on a myeloid-specific knockout, their work isolates the contribution of Mafb in the cells that first encounter and try to control Mtb, connecting genetic evidence from human studies to mechanisms that might explain susceptibility in living animals.

The researchers examined infected cells and organs using multiple laboratory tools. They infected bone marrow-derived macrophages (BMMs) from Mafb -cKO mice with Mycobacterium tuberculosis (Mtb) and tracked bacterial growth; the absence of Mafb promoted Mtb proliferation in BMMs. To understand changes in gene activity, they performed RNA sequencing (RNA-seq). In Mtb-infected BMMs from Mafb -cKO mice, RNA-seq showed activation of the metabolic process and an impairment of the response to type Ⅰ interferons (IFNs). These patterns matched previous findings in Mtb-infected human macrophages with MAFB knockdown. In whole animals, Mafb deficiency increased mortality and bacterial burden in the lungs and spleens during Mtb infection. RNA-seq of infected mouse lungs revealed weakened leukocyte or lymphocyte chemotaxis in Mtb-infected Mafb -cKO mouse lungs, and flow cytometry demonstrated an alteration in the proportion of immune cells in Mtb-infected mouse lungs due to Mafb deficiency. Together, these methods linked cellular defects to worsened disease in mice.

Taken together, the results indicate that Mafb in myeloid cells supports two important parts of the host defense against Mtb. First, Mafb helps macrophages carry out antibacterial processes that limit Mtb proliferation; without it, bacteria multiply more readily in bone marrow-derived macrophages. Second, Mafb contributes to the recruitment and balance of immune cells in the lung during infection: Mafb deficiency weakened signals for leukocyte or lymphocyte chemotaxis and altered immune cell proportions, coinciding with higher bacterial loads and mortality. Because MAFB had been nominated as a candidate gene for early tuberculosis onset in a genome-wide association study, these findings by Shintaro Seto and colleagues provide a mechanistic link between that genetic signal and altered immune function. The study suggests that disturbances in Mafb-dependent pathways can make hosts more vulnerable to tuberculosis by undermining both cell-intrinsic antibacterial defenses and the coordinated immune response in the lung.