Type I IFN-mediated NET release promotes Mycobacterium tuberculosis replication and is associated with granuloma caseation.

Neutrophils are the most abundant cell type in the airways of tuberculosis patients. Mycobacterium tuberculosis (Mtb) infection induces the release of neutrophil extracellular traps (NETs); however, the molecular regulation and impact of NET release on Mtb pathogenesis are unknown. We find that during Mtb infection in neutrophils, PAD4 citrullinates histones to decondense chromatin that gets released as NETs in a manner that can maintain neutrophil viability and promote Mtb replication.

Type I IFN signaling in the absence of IRGM1 promotes M. tuberculosis replication in immune cells by suppressing T cell responses.

Polymorphisms in the IRGM gene are associated with susceptibility to tuberculosis in humans. A murine ortholog of Irgm, Irgm1, is also essential for controlling Mycobacterium tuberculosis (Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells.

Autophagy promotes efficient T cell responses to restrict high-dose Mycobacterium tuberculosis infection in mice.

Although autophagy sequesters Mycobacterium tuberculosis (Mtb) in in vitro cultured macrophages, loss of autophagy in macrophages in vivo does not result in susceptibility to a standard low-dose Mtb infection until late during infection, leaving open questions regarding the protective role of autophagy during Mtb infection. Here we report that loss of autophagy in lung macrophages and dendritic cells results in acute susceptibility of mice to high-dose Mtb infection, a model mimicking active tuberculosis. Rather than observing a role for autophagy in controlling Mtb replication in macrophages, we find that autophagy suppresses macrophage responses to Mtb that otherwise result in accumulation of myeloid-derived suppressor cells and subsequent defects in T cell responses.

Type I IFN signaling in the absence of IRGM1 promotes replication in immune cells by suppressing T cell responses.

Polymorphisms in the gene are associated with susceptibility to tuberculosis in humans. A murine ortholog of , , is also essential for controlling (Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells.

Autophagy prevents early proinflammatory responses and neutrophil recruitment during Mycobacterium tuberculosis infection without affecting pathogen burden in macrophages.

The immune response to Mycobacterium tuberculosis infection determines tuberculosis disease outcomes, yet we have an incomplete understanding of what immune factors contribute to a protective immune response. Neutrophilic inflammation has been associated with poor disease prognosis in humans and in animal models during M. tuberculosis infection and, therefore, must be tightly regulated.