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The sst1 resistance locus regulates evasion of type I interferon signaling by Chlamydia pneumoniae as a disease tolerance mechanism.

He X, Berland R, Mekasha S, Christensen TG, Alroy J, Kramnik I, Ingalls RR - PLoS Pathog. (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Section of Infectious Diseases, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts, United States of America.

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.

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Cytokine production from the lung homogenates of C. pneumoniae infected mice.C57BL/6 (B6) or B6.C3H-sst1 congenic mice were infected with C. pneumoniae (Cp) as described in the Methods. At day 3 and day 6 post infection, mice were euthanized and lung homogenates prepared for detection of a panel of inflammatory cytokines and chemokines. Shown above are a subset of the cytokines assayed: (A) IL-6, (B) IL-1β, (C) IL-10, (D) IFN-β, (E) IFN-γ and (F) MCP-1. Each data point represents one mouse, and the horizontal bar represents the mean. Significance: *, p<0.05; **, p≤0.01; ***, p≤0.001 infected C57BL/6 vs. B6.C3H-sst1 mice. The result is representative of two independent experiments.
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ppat-1003569-g002: Cytokine production from the lung homogenates of C. pneumoniae infected mice.C57BL/6 (B6) or B6.C3H-sst1 congenic mice were infected with C. pneumoniae (Cp) as described in the Methods. At day 3 and day 6 post infection, mice were euthanized and lung homogenates prepared for detection of a panel of inflammatory cytokines and chemokines. Shown above are a subset of the cytokines assayed: (A) IL-6, (B) IL-1β, (C) IL-10, (D) IFN-β, (E) IFN-γ and (F) MCP-1. Each data point represents one mouse, and the horizontal bar represents the mean. Significance: *, p<0.05; **, p≤0.01; ***, p≤0.001 infected C57BL/6 vs. B6.C3H-sst1 mice. The result is representative of two independent experiments.

Mentions: When we examined lung homogenates for the presence of inflammatory mediators (Figure 2), we observed a bias towards an anti-inflammatory response in the B6.C3H-sst1 mice, with exaggerated IL-10, a classic anti-inflammatory cytokine, and IL-6, which can have both pro- and anti-inflammatory activity [24]. Although there was a trend towards higher IFN-β in the infected B6.C3H-sst1 mice, it did not reach statistical significance. The B6.C3H-sst1 mice also displayed higher levels of MCP-1 (also known as CCL-2) in the lungs, consistent with the exaggerated influx of monocytes, while the IFN-γ response was elevated but not significantly different between the two infected mouse strains. Together, these data demonstrate a dysregulated inflammatory and fibrogenic response in Cp-infected B6.C3H-sst1 mice, which carry the sst1 susceptible locus.


The sst1 resistance locus regulates evasion of type I interferon signaling by Chlamydia pneumoniae as a disease tolerance mechanism.

He X, Berland R, Mekasha S, Christensen TG, Alroy J, Kramnik I, Ingalls RR - PLoS Pathog. (2013)

Cytokine production from the lung homogenates of C. pneumoniae infected mice.C57BL/6 (B6) or B6.C3H-sst1 congenic mice were infected with C. pneumoniae (Cp) as described in the Methods. At day 3 and day 6 post infection, mice were euthanized and lung homogenates prepared for detection of a panel of inflammatory cytokines and chemokines. Shown above are a subset of the cytokines assayed: (A) IL-6, (B) IL-1β, (C) IL-10, (D) IFN-β, (E) IFN-γ and (F) MCP-1. Each data point represents one mouse, and the horizontal bar represents the mean. Significance: *, p<0.05; **, p≤0.01; ***, p≤0.001 infected C57BL/6 vs. B6.C3H-sst1 mice. The result is representative of two independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3757055&req=5

ppat-1003569-g002: Cytokine production from the lung homogenates of C. pneumoniae infected mice.C57BL/6 (B6) or B6.C3H-sst1 congenic mice were infected with C. pneumoniae (Cp) as described in the Methods. At day 3 and day 6 post infection, mice were euthanized and lung homogenates prepared for detection of a panel of inflammatory cytokines and chemokines. Shown above are a subset of the cytokines assayed: (A) IL-6, (B) IL-1β, (C) IL-10, (D) IFN-β, (E) IFN-γ and (F) MCP-1. Each data point represents one mouse, and the horizontal bar represents the mean. Significance: *, p<0.05; **, p≤0.01; ***, p≤0.001 infected C57BL/6 vs. B6.C3H-sst1 mice. The result is representative of two independent experiments.
Mentions: When we examined lung homogenates for the presence of inflammatory mediators (Figure 2), we observed a bias towards an anti-inflammatory response in the B6.C3H-sst1 mice, with exaggerated IL-10, a classic anti-inflammatory cytokine, and IL-6, which can have both pro- and anti-inflammatory activity [24]. Although there was a trend towards higher IFN-β in the infected B6.C3H-sst1 mice, it did not reach statistical significance. The B6.C3H-sst1 mice also displayed higher levels of MCP-1 (also known as CCL-2) in the lungs, consistent with the exaggerated influx of monocytes, while the IFN-γ response was elevated but not significantly different between the two infected mouse strains. Together, these data demonstrate a dysregulated inflammatory and fibrogenic response in Cp-infected B6.C3H-sst1 mice, which carry the sst1 susceptible locus.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Section of Infectious Diseases, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts, United States of America.

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.

Show MeSH
Related in: MedlinePlus