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Type 1 interferon gene transfer enhances host defense against pulmonary Streptococcus pneumoniae infection via activating innate leukocytes.

Damjanovic D, Khera A, Medina MF, Ennis J, Turner JD, Gauldie J, Xing Z - Mol Ther Methods Clin Dev (2014)

Bottom Line: We found that in control animals, Streptococcus pneumoniae infection caused severe weight loss and excessive lung inflammation, associated with rapid bacterial outgrowth.In contrast, the animals that received a single dose of an adenoviral vector expressing IFN-α prior to pneumococcal infection demonstrated rapid and effective control of bacterial replication and lung inflammation and improved clinical outcome.Furthermore, we found that raised levels of IFN-α in the lung remained immune protective even when the gene transfer vector was given at a time postpneumococcal infection.

View Article: PubMed Central - PubMed

Affiliation: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University , Hamilton, Ontario, Canada ; M.G. DeGroote Institute for Infectious Disease Research, McMaster University , Hamilton, Ontario, Canada.

ABSTRACT
Pneumococcal infections are the leading cause of community-acquired pneumonia. Although the type 1 interferon-α (IFN-α) is a well-known antiviral cytokine, the role of IFN-α in antipneumococcal host defense and its therapeutic potential remain poorly understood. We have investigated these issues by using a murine transgene expression model. We found that in control animals, Streptococcus pneumoniae infection caused severe weight loss and excessive lung inflammation, associated with rapid bacterial outgrowth. In contrast, the animals that received a single dose of an adenoviral vector expressing IFN-α prior to pneumococcal infection demonstrated rapid and effective control of bacterial replication and lung inflammation and improved clinical outcome. Enhanced protection by IFN-α was due to increased activation of neutrophils and macrophages with increased release of reactive oxygen and nitrogen species and bacterial killing. Furthermore, we found that raised levels of IFN-α in the lung remained immune protective even when the gene transfer vector was given at a time postpneumococcal infection. Our study thus shows that the classically antiviral type 1 IFN can be exploited for enhancing immunity against pneumococcal infection via its activating effects on innate immune cells. Our findings hold implications for the therapeutic use of IFN-α gene transfer strategies to combat pneumococcal infections.

No MeSH data available.


Related in: MedlinePlus

Transgenic expression of interferon (IFN)-α leads to enhanced release of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Female C57BL/6 mice were infected with 107 plaque-forming units AdIFN-α or Addl and 48 hours later with 104 colony-forming unit of S. pneumoniae. Lung homogenates at various time points were measured for concentration of total ROS/RNS. Data are expressed as mean ± SEM of n = 3–4/group/time point, representative of two independent experiments. **P < 0.01; ***P < 0.005.
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fig4: Transgenic expression of interferon (IFN)-α leads to enhanced release of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Female C57BL/6 mice were infected with 107 plaque-forming units AdIFN-α or Addl and 48 hours later with 104 colony-forming unit of S. pneumoniae. Lung homogenates at various time points were measured for concentration of total ROS/RNS. Data are expressed as mean ± SEM of n = 3–4/group/time point, representative of two independent experiments. **P < 0.01; ***P < 0.005.

Mentions: To further assess the mechanisms of increased bacterial control by raised IFN-α levels, we measured reactive oxygen species (ROS) and reactive nitrogen species (RNS) (hydrogen peroxide, peroxyl radical, nitric oxide, and peroxynitrite anion) in lung homogenates collected at various time points post-Strep infection, given their critical antibacterial activities and association with activated neutrophils and macrophages. Significantly increased levels of ROS/RNS were induced by IFN-α at 8, 20, and 48 hours with equalized levels with the control mice at 72-hour postinfection (Figure 4). The largest difference in ROS/RNS between the two groups was seen at 20-hour postinfection (Figure 4), corresponding with high neutrophil influx in the lung of the mice with raised IFN-α levels at this time point (Figure 2a).


Type 1 interferon gene transfer enhances host defense against pulmonary Streptococcus pneumoniae infection via activating innate leukocytes.

Damjanovic D, Khera A, Medina MF, Ennis J, Turner JD, Gauldie J, Xing Z - Mol Ther Methods Clin Dev (2014)

Transgenic expression of interferon (IFN)-α leads to enhanced release of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Female C57BL/6 mice were infected with 107 plaque-forming units AdIFN-α or Addl and 48 hours later with 104 colony-forming unit of S. pneumoniae. Lung homogenates at various time points were measured for concentration of total ROS/RNS. Data are expressed as mean ± SEM of n = 3–4/group/time point, representative of two independent experiments. **P < 0.01; ***P < 0.005.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4378291&req=5

fig4: Transgenic expression of interferon (IFN)-α leads to enhanced release of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Female C57BL/6 mice were infected with 107 plaque-forming units AdIFN-α or Addl and 48 hours later with 104 colony-forming unit of S. pneumoniae. Lung homogenates at various time points were measured for concentration of total ROS/RNS. Data are expressed as mean ± SEM of n = 3–4/group/time point, representative of two independent experiments. **P < 0.01; ***P < 0.005.
Mentions: To further assess the mechanisms of increased bacterial control by raised IFN-α levels, we measured reactive oxygen species (ROS) and reactive nitrogen species (RNS) (hydrogen peroxide, peroxyl radical, nitric oxide, and peroxynitrite anion) in lung homogenates collected at various time points post-Strep infection, given their critical antibacterial activities and association with activated neutrophils and macrophages. Significantly increased levels of ROS/RNS were induced by IFN-α at 8, 20, and 48 hours with equalized levels with the control mice at 72-hour postinfection (Figure 4). The largest difference in ROS/RNS between the two groups was seen at 20-hour postinfection (Figure 4), corresponding with high neutrophil influx in the lung of the mice with raised IFN-α levels at this time point (Figure 2a).

Bottom Line: We found that in control animals, Streptococcus pneumoniae infection caused severe weight loss and excessive lung inflammation, associated with rapid bacterial outgrowth.In contrast, the animals that received a single dose of an adenoviral vector expressing IFN-α prior to pneumococcal infection demonstrated rapid and effective control of bacterial replication and lung inflammation and improved clinical outcome.Furthermore, we found that raised levels of IFN-α in the lung remained immune protective even when the gene transfer vector was given at a time postpneumococcal infection.

View Article: PubMed Central - PubMed

Affiliation: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University , Hamilton, Ontario, Canada ; M.G. DeGroote Institute for Infectious Disease Research, McMaster University , Hamilton, Ontario, Canada.

ABSTRACT
Pneumococcal infections are the leading cause of community-acquired pneumonia. Although the type 1 interferon-α (IFN-α) is a well-known antiviral cytokine, the role of IFN-α in antipneumococcal host defense and its therapeutic potential remain poorly understood. We have investigated these issues by using a murine transgene expression model. We found that in control animals, Streptococcus pneumoniae infection caused severe weight loss and excessive lung inflammation, associated with rapid bacterial outgrowth. In contrast, the animals that received a single dose of an adenoviral vector expressing IFN-α prior to pneumococcal infection demonstrated rapid and effective control of bacterial replication and lung inflammation and improved clinical outcome. Enhanced protection by IFN-α was due to increased activation of neutrophils and macrophages with increased release of reactive oxygen and nitrogen species and bacterial killing. Furthermore, we found that raised levels of IFN-α in the lung remained immune protective even when the gene transfer vector was given at a time postpneumococcal infection. Our study thus shows that the classically antiviral type 1 IFN can be exploited for enhancing immunity against pneumococcal infection via its activating effects on innate immune cells. Our findings hold implications for the therapeutic use of IFN-α gene transfer strategies to combat pneumococcal infections.

No MeSH data available.


Related in: MedlinePlus