Type I interferon signaling mediates Mycobacterium tuberculosis–induced macrophage death

Abstract

Macrophages help defend the host against Mycobacterium tuberculosis (Mtb), the major cause of tuberculosis (TB). Once phagocytized, Mtb resists killing by macrophages, replicates inside them, and leads to their death, releasing Mtb that can infect other cells. We found that the death of Mtb-infected mouse macrophages in vitro does not appear to proceed by a currently known pathway. Through genome-wide CRISPR-Cas9 screening, we identified a critical role for autocrine or paracrine signaling by macrophage-derived type I IFNs in the death of Mtb-infected macrophages in vitro, and blockade of type I IFN signaling augmented the effect of rifampin, a first-line TB drug, in Mtb-infected mice. Further definition of the pathway of type I IFN–mediated macrophage death may allow for host-directed therapy of TB that is more selective than systemic blockade of type I IFN signaling.

Breaching the phagosome, the case of the tuberculosis agent

“…These observations are in agreement with previous data that showed substantially increased cell death caused by ESX-1 proficient Mtb strains, compared to Mtb strains secreting truncated ESX-1 protein(s) (Simeone et al, 2012). Finally, it should also be mentioned that a recent paper reported that type I IFN signalling mediates Mtb-induced macrophage death (Zhang, Jiang, Pfau, Ling, & Nathan, 2021), which adds additional possibilities to other reported virulence-enhancing consequences of type I IFN release (Moreira-Teixeira et al, 2020;Moreira-Teixeira, Mayer-Barber, Sher, & O'Garra, 2018).…”

Viral coinfection promotes tuberculosis immunopathogenesis by type I IFN signaling-dependent impediment of Th1 pulmonary influx

“…In mice infected rst with in uenza virus, a major in vivo inducer of type I IFN production, and then Mtb infection, the pulmonary pathology deteriorated in a type I IFN-dependent manner 31 . Moreover, type I IFNs derived from macrophages have been shown to contribute to Mtbinduced macrophage cell death, and blockade of type I IFN signaling has been shown to enhance the activity of rifampin 32 . Furthermore, the magnitude of Mtb-induced type I IFN production in mice has been reported to differ according to the Mtb strain.…”

Type I interferon signaling and macrophages: a double-edged sword?

“…Barbara Adler 1 and Heiko Adler 2 Cellular & Molecular Immunology _#####################_ ; https://doi.org/10.1038/s41423-020-00609-0…”

“…In a recent issue of the Journal of Experimental Medicine, Zhang et al reported that type I interferon (type I IFN) signaling mediates Mycobacterium tuberculosis (Mtb)-induced macrophage (MΦ) death, most likely by a new, currently unknown cell death pathway. 1 Type I IFNs are a major host defense against viral and bacterial infections. They are produced by a variety of cell types, including MΦs.…”

“…Considering that the principal lesions of mucosal disease, the lethal form of infection with cytopathic BVDV, are located in regions with high concentrations of endotoxin (the oral cavity and gastrointestinal tract), our findings strongly suggested a role of this pathway in the pathogenesis of mucosal disease. 8 By showing a key role for type I IFN signaling in Mtb-induced MΦ cell death, Zhang et al 1 uncovered a new mechanism for the adverse effects of pathogen-induced type I IFN on disease outcome. Furthermore, they suggest that MΦ cell death occurs via a new, yet unknown, cell death pathway.…”