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 (sst1^S) 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 sst1^S mice. Infection of sst1^S 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 sst1^S 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. Chlamydia pneumoniae is a highly adapted intracellular pathogen and a common cause of atypical, community acquired pneumonia. It has also been suggested as a trigger or promoter of asthma and atherosclerosis. In this study, we examined the role of a genetic locus on mouse chromosome 1 that has been associated with susceptibility to another intracellular pathogen, Mycobacterium tuberculosis, in the pathogenesis of respiratory infections secondary to Chlamydia pneumoniae. We have determined that a variant at this locus, known as sst1 and associated with destructive pulmonary tuberculosis, makes mice dramatically more sensitive in vivo to the inflammatory changes following respiratory infection with C. pneumoniae. This appears to arise from activation of type I interferons and apoptotic cell death, two signaling pathways that are normally silent during productive C. pneumoniae infection. Despite a noted inability of sst1 susceptible macrophages to support chlamydial development, exuberant lung tissue damage resulted in overall more severe disease in vivo. We conclude the sst1-mediated control of lung tissue damage is an important determinant of the genetic susceptibility of a given host to a number of diverse intracellular bacterial pathogens, which may provide predictors of outcomes to infectious diseases as well as possible target for novel therapeutics.