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Cited by 119Air Quality and Health ImpactsInfluenza Virus Research StudiesImmunotoxicology and immune responses

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Exposure to combustion generated environmentally persistent free radicals enhances severity of influenza virus infection

Open access
Lee, Greg I, Saravia, Jordy, You, Dahui, Shrestha, Bishwas, Jaligama, Sridhar, Hebert, Valerie Y, Dugas, Tammy R, Cormier, Stephania A·2014·Particle and Fibre Toxicology
DOI 10.1186/s12989-014-0057-1PMC PMC4222384
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Abstract

BACKGROUND: Exposures to elevated levels of particulate matter (PM) enhance severity of influenza virus infection in infants. The biological mechanism responsible for this phenomenon is unknown. The recent identification of environmentally persistent free radicals (EPFRs) associated with PM from a variety of combustion sources suggests its role in the enhancement of influenza disease severity. METHODS: Neonatal mice (< seven days of age) were exposed to DCB230 (combustion derived PM with a chemisorbed EPFR), DCB50 (non-EPFR PM sample), or air for 30 minutes/day for seven consecutive days. Four days post-exposure, neonates were infected with influenza intranasally at 1.25 TCID50/neonate. Neonates were assessed for morbidity (% weight gain, peak pulmonary viral load, and viral clearance) and percent survival. Lungs were isolated and assessed for oxidative stress (8-isoprostanes and glutathione levels), adaptive immune response to influenza, and regulatory T cells (Tregs). The role of the EPFR was also assessed by use of transgenic mice expressing human superoxide dismutase 2. RESULTS: Neonates exposed to EPFRs had significantly enhanced morbidity and decreased survival following influenza infection. Increased oxidative stress was also observed in EPFR exposed neonates. This correlated with increased pulmonary Tregs and dampened protective T cell responses to influenza infection. Reduction of EPFR-induced oxidative stress attenuated these effects. CONCLUSIONS: Neonatal exposure to EPFR containing PM resulted in pulmonary oxidative stress and enhanced influenza disease severity. EPFR-induced oxidative stress resulted in increased presence of Tregs in the lungs and subsequent suppression of adaptive immune response to influenza.

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Figure 1 Effect of EPFR exposure on oxidative stress burden in neonates. A) Neonatal exposure and influenza infection model. Three day old mice were exposed to 200 μg/m3 of DCB230, DCB50, or air for seven consecutive days (0-7 dpe) for 30 min/day (black arrow head) and infected with influenza at 1.25 TCID50/neonate on the fourth dpe (red arrow head). Non-infected lungs were isolated at four dpe for analysis of oxidative stress and regulatory T cells (Tregs). Infected lungs were isolated for pulmonary viral load, flow cytometry, and pulmonary viral clearance on four, six, and eight days post-infection (dpi; asterisks). Pulmonary oxidative stress, determined by levels of (B) 8-isoprostance (IP) and (C) GSH/GSSG ratio in lungs of wild-type C57BL/6 after five days of exposure to air, DCB50 (D50), or DCB230 (D230) and in lungs of hSOD2 transgenic neonates exposed to DCB230 (D230(hSOD+)). Data plotted as mean ± standard error of mean (SEM). *p <0.05 D230 vs Air, D50, and D230(hSOD+); # p <0.05 D230(hSOD+) vs Air, D50, and D230; Brackets indicate p <0.05 D230 vs Air and D230(hSOD+); one-way analysis of variance (ANOVA) with Tukey’s multiple comparisons test. N =4-10/group.
Figure 1 Effect of EPFR exposure on oxidative stress burden in neonates. A) Neonatal exposure and influenza infection model. Three day old mice were exposed to 200 μg/m3 of DCB230, DCB50, or air for seven consecutive days (0-7 dpe) for 30 min/day (black arrow head) and infected with influenza at 1.25 TCID50/neonate on the fourth dpe (red arrow head). Non-infected lungs were isolated at four dpe for analysis of oxidative stress and regulatory T cells (Tregs). Infected lungs were isolated for pulmonary viral load, flow cytometry, and pulmonary viral clearance on four, six, and eight days post-infection (dpi; asterisks). Pulmonary oxidative stress, determined by levels of (B) 8-isoprostance (IP) and (C) GSH/GSSG ratio in lungs of wild-type C57BL/6 after five days of exposure to air, DCB50 (D50), or DCB230 (D230) and in lungs of hSOD2 transgenic neonates exposed to DCB230 (D230(hSOD+)). Data plotted as mean ± standard error of mean (SEM). *p <0.05 D230 vs Air, D50, and D230(hSOD+); # p <0.05 D230(hSOD+) vs Air, D50, and D230; Brackets indicate p <0.05 D230 vs Air and D230(hSOD+); one-way analysis of variance (ANOVA) with Tukey’s multiple comparisons test. N =4-10/group.CC BY · PubMed Central
Figure 2 Effect of EPFR exposure on influenza morbidity and viral load in neonates. Neonatal mice were exposed to air, DCB50, or DCB230 and infected i.n. with influenza (AirF, D50F, D230F, D230F(hSOD+)) at 1.25 TCID50/neonate or sham infected with DPBS (Air). (A) Average percent change in weight plotted against dpi. N =16-35/group. (B) Peak pulmonary viral load assessed at four dpi. N =10-22/group. (C) Pulmonary viral clearance assessed at eight dpi. Dotted line indicates limit of detection (35 TCID50/mL) of assay. (D) Effect of EPFR exposure on influenza infection associated drop in survival in neonates. Survival was recorded daily until 14 dpi. N =8-18/group. Data plotted as mean ± SEM. *p <0.05 D230F vs Air, AirF, D50F, and D230F(hSOD+). (A) Multiple t tests with Holm-Sidak correction for multiple comparisons. (B and C) One-way ANOVA with Tukey’s multiple comparisons test. (D) Gehan-Breslow Wilcoxon test with Bonferroni correction for multiple comparisons; *p <0.014 between D230F vs AirF and D230F(hSOD+). N =17-47/group.
Figure 2 Effect of EPFR exposure on influenza morbidity and viral load in neonates. Neonatal mice were exposed to air, DCB50, or DCB230 and infected i.n. with influenza (AirF, D50F, D230F, D230F(hSOD+)) at 1.25 TCID50/neonate or sham infected with DPBS (Air). (A) Average percent change in weight plotted against dpi. N =16-35/group. (B) Peak pulmonary viral load assessed at four dpi. N =10-22/group. (C) Pulmonary viral clearance assessed at eight dpi. Dotted line indicates limit of detection (35 TCID50/mL) of assay. (D) Effect of EPFR exposure on influenza infection associated drop in survival in neonates. Survival was recorded daily until 14 dpi. N =8-18/group. Data plotted as mean ± SEM. *p <0.05 D230F vs Air, AirF, D50F, and D230F(hSOD+). (A) Multiple t tests with Holm-Sidak correction for multiple comparisons. (B and C) One-way ANOVA with Tukey’s multiple comparisons test. (D) Gehan-Breslow Wilcoxon test with Bonferroni correction for multiple comparisons; *p <0.014 between D230F vs AirF and D230F(hSOD+). N =17-47/group.CC BY · PubMed Central
Figure 3 Effect of EPFR exposure on adaptive immune response (Tc1 and Th1) to influenza infection in neonates. Neonatal mice were exposed to air, DCB50, or DCB230 and infected i.n. with influenza (AirF, D50F, D230F, D230F(hSOD+)) or sham infected with DPBS (Air). Lung effector T cell profiles were determined by flow cytometry at six dpi. (A) Percentage of CD8+ cells expressing IFNγ (Tc1) with representative flow contour plots demonstrating outliers. N = 3-12/group. (B) Percentage of CD4+ cells expressing IFNγ (Th1) with representative flow contour plots demonstrating outliers. N = 3-12/group. Data plotted as mean ± SEM. *p <0.05 D230F vs AirF, D50F, and D230F(hSOD+); multiple t tests with Holm-Sidak correction for multiple comparisons.
Figure 3 Effect of EPFR exposure on adaptive immune response (Tc1 and Th1) to influenza infection in neonates. Neonatal mice were exposed to air, DCB50, or DCB230 and infected i.n. with influenza (AirF, D50F, D230F, D230F(hSOD+)) or sham infected with DPBS (Air). Lung effector T cell profiles were determined by flow cytometry at six dpi. (A) Percentage of CD8+ cells expressing IFNγ (Tc1) with representative flow contour plots demonstrating outliers. N = 3-12/group. (B) Percentage of CD4+ cells expressing IFNγ (Th1) with representative flow contour plots demonstrating outliers. N = 3-12/group. Data plotted as mean ± SEM. *p <0.05 D230F vs AirF, D50F, and D230F(hSOD+); multiple t tests with Holm-Sidak correction for multiple comparisons.CC BY · PubMed Central
Figure 4 Effect of EPFR exposure on pulmonary regulatory T cells (Tregs). Neonatal mice were exposed to air or DCB230 (Air, D230, D230(hSOD+)) for five consecutive days and lungs were isolated four dpe (at the time infection would have occurred). Pulmonary Tregs were identified and quantified by flow cytometry. N =6-8/group. Data plotted as mean ± SEM with representative flow contour plots with outliers. *p <0.05 D230 vs Air and D230(hSOD+), # p <0.05 D230(hSOD+) vs Air and D230; one-way ANOVA with Tukey’s multiple comparisons test.
Figure 4 Effect of EPFR exposure on pulmonary regulatory T cells (Tregs). Neonatal mice were exposed to air or DCB230 (Air, D230, D230(hSOD+)) for five consecutive days and lungs were isolated four dpe (at the time infection would have occurred). Pulmonary Tregs were identified and quantified by flow cytometry. N =6-8/group. Data plotted as mean ± SEM with representative flow contour plots with outliers. *p <0.05 D230 vs Air and D230(hSOD+), # p <0.05 D230(hSOD+) vs Air and D230; one-way ANOVA with Tukey’s multiple comparisons test.CC BY · PubMed Central

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Metadata

Authors
Lee, G. I., Saravia, J., You, D., Shrestha, B., Jaligama, S., Hebert, V. Y., Dugas, T. R., & Cormier, S. A.
Affiliations
  • University of Tennessee Health Science Center (US)
  • Louisiana State University Health Sciences Center Shreveport (US)
Corresponding author
Cormier, Stephania A
ORCID
Venue
Particle and Fibre Toxicology
Publisher
Springer Science and Business Media LLC
Published
2014-10-30
Volume
11
Issue
1
Pages
57-57
ISSN
1743-8977 (ISSN-L)
DOI
10.1186/s12989-014-0057-1
PMC
PMC4222384
OpenAlex
W2102366014
Cited by
119
References
47
Citations by year
2026: 1 · 2025: 7 · 2024: 14 · 2023: 17 · 2022: 16 · 2021: 23 · 2020: 13 · 2019: 8 · 2018: 6 · 2017: 4 · 2016: 5 · 2015: 5
FWCI
3.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Particle and Fibre Toxicology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Civil War Book Review (submittedVersion)
Funders
  • National Institute of Allergy and Infectious Diseases (R01AI090059)
  • National Institute of Environmental Health Sciences (P42ES013648, R01ES015050)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Air Quality and Health Impacts
  • Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
Keywords
environmentally persistent free radicals, particulate matter, influenza, disease severity, neonatal mice, oxidative stress, regulatory T cells, adaptive immune response, manganese superoxide dismutase, air pollution
MeSH terms
Superoxide Dismutase 2, Animals, Animals, Newborn, Free Radicals, Glutathione, Humans, Lung, Mice, Inbred C57BL, Mice, Transgenic, Orthomyxoviridae Infections, Superoxide Dismutase, Time Factors, Dinoprost, Oxidative Stress, Risk Assessment, Viral Load, Inhalation Exposure, T-Lymphocytes, Regulatory, Mice, Particulate Matter, Influenza A Virus, H1N1 Subtype, Adaptive Immunity

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