Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons

Abstract

Type I interferons (IFNs) are essential for anti-viral immunity, but often impair protective immune responses during bacterial infections. How type I IFNs are strongly induced during viral infections, and yet are appropriately restrained during bacterial infections, remains poorly understood. The Super susceptibility to tuberculosis 1 (Sst1) locus in mice confers resistance to many bacterial infections. Here we provide evidence that Sp140 is a gene encoded within the Sst1 locus that functions to repress the expression of type I IFNs during bacterial infections. We generated Sp140 -/mice and find they are susceptible to infection by diverse bacteria, including Listeria monocytogenes, Legionella pneumophila, and Mycobacterium tuberculosis. Susceptibility of Sp140-/mice to bacterial infection was rescued by crosses to mice lacking the type I IFN receptor (Ifnar -/-). Our results implicate Sp140 as an important repressor of type I IFNs that is essential for resistance to bacterial infections.

The integrated stress response mediates necrosis in murine Mycobacterium tuberculosis granulomas

“…Real-time PCR was performed with the GoTaq qPCR Mastermix (Promega) using the CFX-90 real-time PCR System (Bio-Rad).Oligonucleotide primers were designed using Primer 3 software ( Supplementary Table S1) and specificity was confirmed by melting curve analysis. Thermal cycling parameters involved 40 hrs. Images were acquired using Leica SP5 confocal microscope.…”

“…(SERP1) which interacts with target proteins during their translocation into the lumen of the endoplasmic reticulum and protects unfolded target proteins against degradation during ER stress(39). Only the TNF-stimulated B6wt cells upregulated the Sp110/Ipr1 and Sp140 proteins encoded within the sst1 locus and implicated in TB susceptibility in vivo(15,40). We extended…”

Maladaptive oxidative stress cascade drives type I interferon hyperactivity in TNF activated macrophages promoting necrosis in murine tuberculosis granulomas

“…Overexpression of Sp110 in the sst1 susceptible macrophages and mice increased their resistance to Mtb (13). More recently, using CRISPR knockout, Vance and colleagues have shown that the Sp140 gene may play a bigger role in the sst1-mediated phenotype in mice (14).…”

“…Surprisingly, a single locus on chromosome 1, sst1 (supersusceptibility to tuberculosis 1), was responsible for the control of the necrotization of TB lesions (12). This locus contains strong candidate genes Sp110b (13) and Sp140 (14), whose expression is greatly diminished in mice that carry the sst1 susceptibility allele. To study mechanisms of necrosis controlled by the sst1 locus at cellular, tissue and whole organism levels, we made a congenic mouse strain B6J.C3-Sst1 C3HeB/Fej Krmn (B6.Sst1S) that carries the C3HeB/FeJ-derived susceptibility allele of the sst1 locus on the resistant B6 genetic background (15).…”

Type I interferon signaling mediates Mycobacterium tuberculosis–induced macrophage death

“…In mouse models of TB, host genetic background affects the impact of type I IFN signaling. Necrotic pulmonary lesions are prominent in mice bearing a hypomorphic allele of Sp140 in the “ Super susceptibility to tuberculosis 1 ( Sst1 )” locus ( Kramnik et al, 2000 ) that impairs the ability of Sp140 to suppress the type I IFN response during intracellular bacterial infections ( Ji et al, 2020 Preprint ). In C57BL/6 (B6) congenic mice carrying the “susceptible” allele of the Sst1 locus, heightened tissue damage has been related to increased production of IL-1 receptor antagonist ( Ji et al, 2019 ).…”