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Respiratory syncytial virus-like nanoparticle vaccination induces long-term protection without pulmonary disease by modulating cytokines and T-cells partially through alveolar macrophages.

Lee YT, Ko EJ, Hwang HS, Lee JS, Kim KH, Kwon YM, Kang SM - Int J Nanomedicine (2015)

Bottom Line: The mechanisms of protection against respiratory syncytial virus (RSV) are poorly understood.Virus-like nanoparticles expressing RSV glycoproteins (eg, a combination of fusion and glycoprotein virus-like nanoparticles [FG VLPs]) have been suggested to be a promising RSV vaccine candidate.The results in this study suggest that FG nanoparticle vaccination induces long-term protection against RSV and that AMs play a role in the RSV protection by modulating eosinophilia, mucus production, inflammatory cytokines, and T-cell infiltration.

View Article: PubMed Central - PubMed

Affiliation: Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.

ABSTRACT
The mechanisms of protection against respiratory syncytial virus (RSV) are poorly understood. Virus-like nanoparticles expressing RSV glycoproteins (eg, a combination of fusion and glycoprotein virus-like nanoparticles [FG VLPs]) have been suggested to be a promising RSV vaccine candidate. To understand the roles of alveolar macrophages (AMs) in inducing long-term protection, mice that were 12 months earlier vaccinated with formalin-inactivated RSV (FI-RSV) or FG VLPs were treated with clodronate liposome prior to RSV infection. FI-RSV immune mice with clodronate liposome treatment showed increases in eosinophils, plasmacytoid dendritic cells, interleukin (IL)-4(+) T-cell infiltration, proinflammatory cytokines, chemokines, and, in particular, mucus production upon RSV infection. In contrast to FI-RSV immune mice with severe pulmonary histopathology, FG VLP immune mice showed no overt sign of histopathology and significantly lower levels of eosinophils, T-cell infiltration, and inflammatory cytokines, but higher levels of interferon-γ, which are correlated with protection against RSV disease. FG VLP immune mice with depletion of AMs showed increases in inflammatory cytokines and chemokines, as well as eosinophils. The results in this study suggest that FG nanoparticle vaccination induces long-term protection against RSV and that AMs play a role in the RSV protection by modulating eosinophilia, mucus production, inflammatory cytokines, and T-cell infiltration.

No MeSH data available.


Related in: MedlinePlus

CL-mediated depletion of alveolar macrophages increases eosinophil recruitments and chemokine expression.Notes: (A and B) Flow cytometry analysis of immune cells from BAL and lungs was used to investigate the pattern of eosinophil infiltration. (A) The surface markers such as CD11c, CD11b, and Siglec F were used to characterize eosinophil infiltration. For flow cytometric gating of eosinophils (the circled areas), CD11b+ population was first gated and further analyzed into Siglec F and CD11c in BAL and lung samples. PBS panel: mock (PBS)-treated groups. CL panel: CL-treated groups. (B) The numbers of eosinophils in BAL and lung samples. (C and D) BAL and lung lysates were also used to determine chemokine levels 5 days post-RSV challenge. (C) Eotaxin in BAL and lung extract. (D) MIP-1β in BAL and lung extract. The eosinophil chemoattractants (eotaxin, MIP-1β) were determined in the airways and lungs. The results are representative out of two independent experiments. Statistical significance was determined using an unpaired two-tailed Student’s t-test. Error bars indicate means ± standard error of the mean of concentration or ratios from individual animals (n=5). *P<0.05; **P<0.01; ***P<0.001.Abbreviations: BAL, bronchoalveolar lavage; CL, clodronate liposome; FG VLP, a combination of fusion and glycoprotein virus-like nanoparticles; FI-RSV, formalin-inactivated RSV; MIP-1β, macrophage inflammatory protein-1 beta; PBS, phosphate-buffered saline; RSV, respiratory syncytial virus.
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f3-ijn-10-4491: CL-mediated depletion of alveolar macrophages increases eosinophil recruitments and chemokine expression.Notes: (A and B) Flow cytometry analysis of immune cells from BAL and lungs was used to investigate the pattern of eosinophil infiltration. (A) The surface markers such as CD11c, CD11b, and Siglec F were used to characterize eosinophil infiltration. For flow cytometric gating of eosinophils (the circled areas), CD11b+ population was first gated and further analyzed into Siglec F and CD11c in BAL and lung samples. PBS panel: mock (PBS)-treated groups. CL panel: CL-treated groups. (B) The numbers of eosinophils in BAL and lung samples. (C and D) BAL and lung lysates were also used to determine chemokine levels 5 days post-RSV challenge. (C) Eotaxin in BAL and lung extract. (D) MIP-1β in BAL and lung extract. The eosinophil chemoattractants (eotaxin, MIP-1β) were determined in the airways and lungs. The results are representative out of two independent experiments. Statistical significance was determined using an unpaired two-tailed Student’s t-test. Error bars indicate means ± standard error of the mean of concentration or ratios from individual animals (n=5). *P<0.05; **P<0.01; ***P<0.001.Abbreviations: BAL, bronchoalveolar lavage; CL, clodronate liposome; FG VLP, a combination of fusion and glycoprotein virus-like nanoparticles; FI-RSV, formalin-inactivated RSV; MIP-1β, macrophage inflammatory protein-1 beta; PBS, phosphate-buffered saline; RSV, respiratory syncytial virus.

Mentions: To understand whether CL treatment influenced eosinophilia in the lungs during RSV infection, eosinophil infiltration was analyzed by using the surface markers (CD11b+Siglec F+CD11c−). Approximately 10- to 50-fold higher numbers of eosinophils were detected in the BAL and lungs of FI-RSV immune mice than those in naïve or FG VLP immune mice day 5 post-RSV challenge (Figure 3A and B). Interestingly, CL treatment resulted in increases in numbers of eosinophils in the BAL and lungs of FI-RSV immune mice (Figure 3A and B). Eosinophils were increased to a moderate level in the BAL of naïve and FG VLP mice with CL treatment (Figure 3A). Importantly, we found that CL treatment resulted in significant increases in the levels of eotaxin and MIP-1β from the lungs and BAL samples of all groups of mice except the BAL eotaxin from the FG group (Figure 3C and D). These results suggest that AMs may contribute to modulating the production of chemoattractants and eosinophil recruitment in FI-RSV immune mice, although chemokine levels alone do not explain the enormous infiltration of eosinophils into the lungs of FI-RSV immune mice.


Respiratory syncytial virus-like nanoparticle vaccination induces long-term protection without pulmonary disease by modulating cytokines and T-cells partially through alveolar macrophages.

Lee YT, Ko EJ, Hwang HS, Lee JS, Kim KH, Kwon YM, Kang SM - Int J Nanomedicine (2015)

CL-mediated depletion of alveolar macrophages increases eosinophil recruitments and chemokine expression.Notes: (A and B) Flow cytometry analysis of immune cells from BAL and lungs was used to investigate the pattern of eosinophil infiltration. (A) The surface markers such as CD11c, CD11b, and Siglec F were used to characterize eosinophil infiltration. For flow cytometric gating of eosinophils (the circled areas), CD11b+ population was first gated and further analyzed into Siglec F and CD11c in BAL and lung samples. PBS panel: mock (PBS)-treated groups. CL panel: CL-treated groups. (B) The numbers of eosinophils in BAL and lung samples. (C and D) BAL and lung lysates were also used to determine chemokine levels 5 days post-RSV challenge. (C) Eotaxin in BAL and lung extract. (D) MIP-1β in BAL and lung extract. The eosinophil chemoattractants (eotaxin, MIP-1β) were determined in the airways and lungs. The results are representative out of two independent experiments. Statistical significance was determined using an unpaired two-tailed Student’s t-test. Error bars indicate means ± standard error of the mean of concentration or ratios from individual animals (n=5). *P<0.05; **P<0.01; ***P<0.001.Abbreviations: BAL, bronchoalveolar lavage; CL, clodronate liposome; FG VLP, a combination of fusion and glycoprotein virus-like nanoparticles; FI-RSV, formalin-inactivated RSV; MIP-1β, macrophage inflammatory protein-1 beta; PBS, phosphate-buffered saline; RSV, respiratory syncytial virus.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4508085&req=5

f3-ijn-10-4491: CL-mediated depletion of alveolar macrophages increases eosinophil recruitments and chemokine expression.Notes: (A and B) Flow cytometry analysis of immune cells from BAL and lungs was used to investigate the pattern of eosinophil infiltration. (A) The surface markers such as CD11c, CD11b, and Siglec F were used to characterize eosinophil infiltration. For flow cytometric gating of eosinophils (the circled areas), CD11b+ population was first gated and further analyzed into Siglec F and CD11c in BAL and lung samples. PBS panel: mock (PBS)-treated groups. CL panel: CL-treated groups. (B) The numbers of eosinophils in BAL and lung samples. (C and D) BAL and lung lysates were also used to determine chemokine levels 5 days post-RSV challenge. (C) Eotaxin in BAL and lung extract. (D) MIP-1β in BAL and lung extract. The eosinophil chemoattractants (eotaxin, MIP-1β) were determined in the airways and lungs. The results are representative out of two independent experiments. Statistical significance was determined using an unpaired two-tailed Student’s t-test. Error bars indicate means ± standard error of the mean of concentration or ratios from individual animals (n=5). *P<0.05; **P<0.01; ***P<0.001.Abbreviations: BAL, bronchoalveolar lavage; CL, clodronate liposome; FG VLP, a combination of fusion and glycoprotein virus-like nanoparticles; FI-RSV, formalin-inactivated RSV; MIP-1β, macrophage inflammatory protein-1 beta; PBS, phosphate-buffered saline; RSV, respiratory syncytial virus.
Mentions: To understand whether CL treatment influenced eosinophilia in the lungs during RSV infection, eosinophil infiltration was analyzed by using the surface markers (CD11b+Siglec F+CD11c−). Approximately 10- to 50-fold higher numbers of eosinophils were detected in the BAL and lungs of FI-RSV immune mice than those in naïve or FG VLP immune mice day 5 post-RSV challenge (Figure 3A and B). Interestingly, CL treatment resulted in increases in numbers of eosinophils in the BAL and lungs of FI-RSV immune mice (Figure 3A and B). Eosinophils were increased to a moderate level in the BAL of naïve and FG VLP mice with CL treatment (Figure 3A). Importantly, we found that CL treatment resulted in significant increases in the levels of eotaxin and MIP-1β from the lungs and BAL samples of all groups of mice except the BAL eotaxin from the FG group (Figure 3C and D). These results suggest that AMs may contribute to modulating the production of chemoattractants and eosinophil recruitment in FI-RSV immune mice, although chemokine levels alone do not explain the enormous infiltration of eosinophils into the lungs of FI-RSV immune mice.

Bottom Line: The mechanisms of protection against respiratory syncytial virus (RSV) are poorly understood.Virus-like nanoparticles expressing RSV glycoproteins (eg, a combination of fusion and glycoprotein virus-like nanoparticles [FG VLPs]) have been suggested to be a promising RSV vaccine candidate.The results in this study suggest that FG nanoparticle vaccination induces long-term protection against RSV and that AMs play a role in the RSV protection by modulating eosinophilia, mucus production, inflammatory cytokines, and T-cell infiltration.

View Article: PubMed Central - PubMed

Affiliation: Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.

ABSTRACT
The mechanisms of protection against respiratory syncytial virus (RSV) are poorly understood. Virus-like nanoparticles expressing RSV glycoproteins (eg, a combination of fusion and glycoprotein virus-like nanoparticles [FG VLPs]) have been suggested to be a promising RSV vaccine candidate. To understand the roles of alveolar macrophages (AMs) in inducing long-term protection, mice that were 12 months earlier vaccinated with formalin-inactivated RSV (FI-RSV) or FG VLPs were treated with clodronate liposome prior to RSV infection. FI-RSV immune mice with clodronate liposome treatment showed increases in eosinophils, plasmacytoid dendritic cells, interleukin (IL)-4(+) T-cell infiltration, proinflammatory cytokines, chemokines, and, in particular, mucus production upon RSV infection. In contrast to FI-RSV immune mice with severe pulmonary histopathology, FG VLP immune mice showed no overt sign of histopathology and significantly lower levels of eosinophils, T-cell infiltration, and inflammatory cytokines, but higher levels of interferon-γ, which are correlated with protection against RSV disease. FG VLP immune mice with depletion of AMs showed increases in inflammatory cytokines and chemokines, as well as eosinophils. The results in this study suggest that FG nanoparticle vaccination induces long-term protection against RSV and that AMs play a role in the RSV protection by modulating eosinophilia, mucus production, inflammatory cytokines, and T-cell infiltration.

No MeSH data available.


Related in: MedlinePlus