The sst1 Resistance Locus Regulates Evasion of Type I Interferon Signaling by Chlamydia pneumoniae as a Disease Tolerance Mechanism

Abstract

The sst1, “supersusceptibility to tuberculosis,” locus has previously been shown to be a genetic determinant of host resistance to infection with the intracellular pathogen, Mycobacterium tuberculosis. Chlamydia pneumoniae is an obligate intracellular bacterium associated with community acquired pneumonia, and chronic infection with C. pneumoniae has been linked to asthma and atherosclerosis. C. pneumoniae is a highly adapted pathogen that can productively infect macrophages and inhibit host cell apoptosis. Here we examined the role of sst1 in regulating the host response to infection with C. pneumoniae. Although mice carrying the sst1 susceptible (sst1S) locus were not impaired in their ability to clear the acute infection, they were dramatically less tolerant of the induced immune response, displaying higher clinical scores, more severe lung inflammation, exaggerated macrophage and neutrophil influx, and the development of fibrosis compared to wild type mice. This correlated with increased activated caspase-3 in the lungs of infected sst1S mice. Infection of sst1S macrophages with C. pneumoniae resulted in a shift in the secreted cytokine profile towards enhanced production of interferon-β and interleukin-10, and induced apoptotic cell death, which was dependent on secretion of interferon-β. Intriguingly macrophages from the sst1S mice failed to support normal chlamydial growth, resulting in arrested development and failure of the organism to complete its infectious cycle. We conclude that the sst1 locus regulates a shared macrophage-mediated innate defense mechanism against diverse intracellular bacterial pathogens. Its susceptibility allele leads to upregulation of type I interferon pathway, which, in the context of C. pneumoniae, results in decreased tolerance, but not resistance, to the infection. Further dissection of the relationship between type I interferons and host tolerance during infection with intracellular pathogens may provide identification of biomarkers and novel therapeutic targets.

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

“…Both of the independent lines of Sp140 -/were similarly susceptible to M. tuberculosis ( Figure S2E). Previous reports have shown that in addition to M. tuberculosis, the Sst1 locus also controls responses against other intracellular bacterial pathogens such as L. monocytogenes and C. pneumoniae (Boyartchuk et al, 2004;He et al, 2013;Pichugin et al, 2009). Therefore we infected Sp140 -/and B6.Sst1 S mice with L. monocytogenes.…”

The integrated stress response mediates type I interferon driven necrosis in Mycobacterium tuberculosis granulomas

“…Previously we reported that B6-sst1S mice infected with Chlamydia pneumoniae, as well as their bone marrow-derived macrophages (BMDMs) infected with C.pneumoniae, produce higher levels of IFNb 16 . This was associated with increased death of infected macrophages in vitro, which could be reduced using IFN receptor (IFNAR1) blocking antibodies.…”

“…Subsequent experiments using the sst1 congenic mice revealed that the sst1 locus controlled macrophage interactions with Mtb and other intracellular bacterial pathogens -Listeria monocytogenes 15 and Chlamydia pneumonia 16 . Using positional cloning approach, we have identified a variant of the interferon-inducible nuclear protein Sp110 or Ipr1 (intracellular pathogen resistance 1), as a strong candidate gene, whose expression is completely abolished in sst1S macrophages 17 .…”

Increased susceptibility to intracellular bacteria and necrotic inflammation driven by a dysregulated macrophage response to TNF

“…Subsequent experiments using the sst1 congenic mice revealed that the sst1 locus controlled macrophage interactions with Mtb and other intracellular bacterial pathogens -Listeria monocytogenes [18] and Chlamydia pneumonia [19]. Using positional cloning approach, we have identified a variant of the interferon-inducible nuclear protein Sp110, Ipr1 (intracellular pathogen resistance 1), as a strong candidate gene, whose expression is completely abolished in sst1S macrophages [20].…”