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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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C. pneumoniae infected B6.C3H-sst1 mice develop diffuse lung inflammation compared to B6 mice.C57BL/6 (B6) or B6.C3H-sst1 congenic mice were infected with C. pneumoniae as described in the Methods. At day 3 and day 6 post infection, mice were euthanized and lungs removed for histologic analysis. A–D: routine H & E staining for day 3 (A–B) and day 6 (C–D). Black arrow heads indicate areas of patchy inflammatory infiltrate. E–F: CAE staining for detection of neutrophils, indicated by red arrow heads. G–H: immunohistochemistry for the macrophage marker CD68, shown by brown staining. Graphs at the bottom represent quantified data from (I) neutrophil images E–F and (J) macrophage images G–H. Original magnification: A–D, 40×; E–F, 400×; G–H, 100×. Shown above are images from one of four infected mice from each genetic background. The result is a representative of two independent experiments. ***, p≤0.001.
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ppat-1003569-g001: C. pneumoniae infected B6.C3H-sst1 mice develop diffuse lung inflammation compared to B6 mice.C57BL/6 (B6) or B6.C3H-sst1 congenic mice were infected with C. pneumoniae as described in the Methods. At day 3 and day 6 post infection, mice were euthanized and lungs removed for histologic analysis. A–D: routine H & E staining for day 3 (A–B) and day 6 (C–D). Black arrow heads indicate areas of patchy inflammatory infiltrate. E–F: CAE staining for detection of neutrophils, indicated by red arrow heads. G–H: immunohistochemistry for the macrophage marker CD68, shown by brown staining. Graphs at the bottom represent quantified data from (I) neutrophil images E–F and (J) macrophage images G–H. Original magnification: A–D, 40×; E–F, 400×; G–H, 100×. Shown above are images from one of four infected mice from each genetic background. The result is a representative of two independent experiments. ***, p≤0.001.

Mentions: When histological sections of the lung were examined from infected mice, we observed qualitative differences in the inflammatory response. Infected B6 mice displayed patchy, focal areas of inflammation, while the B6.C3H-sst1 mice developed more diffuse, extensive inflammation. This was true on both day 3 (Figure 1 A–B) and day 6 (Figure 1 C–D) post-infection, suggesting a defective ability of the B6.C3H-sst1 mice to regulate inflammation in the lungs during the period of bacterial replication. We also observed an exaggerated influx of both PMNs (Figure 1 E–F) and macrophages (Figure 1 G–H) in the lungs of B6.C3H-sst1 mice compared to B6 mice histologically, which was confirmed when the images were quantified (Figure 1 I–J). Furthermore, we observed increased immunostaining for vimentin in the lung parenchyma of the B6.C3H-sst1 mice as early as day 3, along with enhanced collagen deposition consistent with fibrosis, as detected by Masson's trichrome staining, and increased staining for thyroid transcription factor-1 (TTF-1), a nuclear protein expressed in type II pneumocytes (Figure S2). These data are consistent with increased tissue damage and repair in response to infection in the B6.C3H-sst1 mice.


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)

C. pneumoniae infected B6.C3H-sst1 mice develop diffuse lung inflammation compared to B6 mice.C57BL/6 (B6) or B6.C3H-sst1 congenic mice were infected with C. pneumoniae as described in the Methods. At day 3 and day 6 post infection, mice were euthanized and lungs removed for histologic analysis. A–D: routine H & E staining for day 3 (A–B) and day 6 (C–D). Black arrow heads indicate areas of patchy inflammatory infiltrate. E–F: CAE staining for detection of neutrophils, indicated by red arrow heads. G–H: immunohistochemistry for the macrophage marker CD68, shown by brown staining. Graphs at the bottom represent quantified data from (I) neutrophil images E–F and (J) macrophage images G–H. Original magnification: A–D, 40×; E–F, 400×; G–H, 100×. Shown above are images from one of four infected mice from each genetic background. The result is a representative of two independent experiments. ***, p≤0.001.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3757055&req=5

ppat-1003569-g001: C. pneumoniae infected B6.C3H-sst1 mice develop diffuse lung inflammation compared to B6 mice.C57BL/6 (B6) or B6.C3H-sst1 congenic mice were infected with C. pneumoniae as described in the Methods. At day 3 and day 6 post infection, mice were euthanized and lungs removed for histologic analysis. A–D: routine H & E staining for day 3 (A–B) and day 6 (C–D). Black arrow heads indicate areas of patchy inflammatory infiltrate. E–F: CAE staining for detection of neutrophils, indicated by red arrow heads. G–H: immunohistochemistry for the macrophage marker CD68, shown by brown staining. Graphs at the bottom represent quantified data from (I) neutrophil images E–F and (J) macrophage images G–H. Original magnification: A–D, 40×; E–F, 400×; G–H, 100×. Shown above are images from one of four infected mice from each genetic background. The result is a representative of two independent experiments. ***, p≤0.001.
Mentions: When histological sections of the lung were examined from infected mice, we observed qualitative differences in the inflammatory response. Infected B6 mice displayed patchy, focal areas of inflammation, while the B6.C3H-sst1 mice developed more diffuse, extensive inflammation. This was true on both day 3 (Figure 1 A–B) and day 6 (Figure 1 C–D) post-infection, suggesting a defective ability of the B6.C3H-sst1 mice to regulate inflammation in the lungs during the period of bacterial replication. We also observed an exaggerated influx of both PMNs (Figure 1 E–F) and macrophages (Figure 1 G–H) in the lungs of B6.C3H-sst1 mice compared to B6 mice histologically, which was confirmed when the images were quantified (Figure 1 I–J). Furthermore, we observed increased immunostaining for vimentin in the lung parenchyma of the B6.C3H-sst1 mice as early as day 3, along with enhanced collagen deposition consistent with fibrosis, as detected by Masson's trichrome staining, and increased staining for thyroid transcription factor-1 (TTF-1), a nuclear protein expressed in type II pneumocytes (Figure S2). These data are consistent with increased tissue damage and repair in response to infection in the B6.C3H-sst1 mice.

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