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Modulation of protease activated receptor 1 influences human metapneumovirus disease severity in a mouse model.

Aerts L, Hamelin MÈ, Rhéaume C, Lavigne S, Couture C, Kim W, Susan-Resiga D, Prat A, Seidah NG, Vergnolle N, Riteau B, Boivin G - PLoS ONE (2013)

Bottom Line: Conversely, the PAR1 antagonist was beneficial to hMPV infection by decreasing weight loss and clinical signs and by significantly reducing pulmonary inflammation, pro-inflammatory cytokine levels (including IL-6, KC and MCP-1) and recruitment of immune cells to the lungs.Despite no apparent direct effect on virus replication during in vitro experiments, an important role for PAR1 in the regulation of furin expression in the lungs was shown for the first time.Further experiments indicated that the hMPV fusion protein can be cleaved by furin thus suggesting that PAR1 could have an effect on viral infectivity in addition to its immunomodulatory properties.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche en Infectiologie du Centre Hospitalier Universitaire de Québec and Université Laval, Quebec, Canada.

ABSTRACT
Human metapneumovirus (hMPV) infection causes acute respiratory tract infections (RTI) which can result in hospitalization of both children and adults. To date, no antiviral or vaccine is available for this common viral infection. Immunomodulators could represent an interesting strategy for the treatment of severe viral infection. Recently, the role of protease-activated receptors (PAR) in inflammation, coagulation and infection processes has been of growing interest. Herein, the effects of a PAR1 agonist and a PAR1 antagonist on hMPV infection were investigated in BALB/c mice. Intranasal administration of the PAR1 agonist resulted in increased weight loss and mortality of infected mice. Conversely, the PAR1 antagonist was beneficial to hMPV infection by decreasing weight loss and clinical signs and by significantly reducing pulmonary inflammation, pro-inflammatory cytokine levels (including IL-6, KC and MCP-1) and recruitment of immune cells to the lungs. In addition, a significant reduction in pulmonary viral titers was also observed in the lungs of PAR1 antagonist-treated mice. Despite no apparent direct effect on virus replication during in vitro experiments, an important role for PAR1 in the regulation of furin expression in the lungs was shown for the first time. Further experiments indicated that the hMPV fusion protein can be cleaved by furin thus suggesting that PAR1 could have an effect on viral infectivity in addition to its immunomodulatory properties. Thus, inhibition of PAR1 by selected antagonists could represent an interesting strategy for decreasing the severity of paramyxovirus infections.

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Cell recruitment in the lungs of hMPV-infected mice treated with the PAR1 antagonist.Groups of 6 mice were infected intranasally with hMPV (7 x105 TCID50) or mock infected and simultaneously treated for 5 days with a single daily dose of 500 µM of PAR1 antagonist (SCH79797). Mice were sacrificed on day 5 pi, lungs were removed, homogenized in HBSS and analyzed by flow cytometry for the presence of (A) dendritic cells expressing the MHC II molecules I-A/I-E (CD11c+CD11bloLy6G loI-A/I-E+), (B) macrophages (CD11c+CD11b+F4/80hi), (C) T lymphocytes (CD3+CD4+ or CD3+CD4-) and (D) neutrophils (CD11c-CD11bhiLy6G+). Significant differences in recruited cells were observed between treated and untreated mice based on a one-way ANOVA. (* p<0.05, *** p<0.001).
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pone-0072529-g003: Cell recruitment in the lungs of hMPV-infected mice treated with the PAR1 antagonist.Groups of 6 mice were infected intranasally with hMPV (7 x105 TCID50) or mock infected and simultaneously treated for 5 days with a single daily dose of 500 µM of PAR1 antagonist (SCH79797). Mice were sacrificed on day 5 pi, lungs were removed, homogenized in HBSS and analyzed by flow cytometry for the presence of (A) dendritic cells expressing the MHC II molecules I-A/I-E (CD11c+CD11bloLy6G loI-A/I-E+), (B) macrophages (CD11c+CD11b+F4/80hi), (C) T lymphocytes (CD3+CD4+ or CD3+CD4-) and (D) neutrophils (CD11c-CD11bhiLy6G+). Significant differences in recruited cells were observed between treated and untreated mice based on a one-way ANOVA. (* p<0.05, *** p<0.001).

Mentions: Immune cell populations present in the lungs on day 5 pi were analyzed by flow cytometry in mice treated for 5 days starting at the time of infection with 500 µM of the PAR1 antagonist (Figure 3). The immune cell populations analyzed included activated dendritic cells (CD11c+CD11bloLy6g loI-A/I-E+), macrophages (CD11b+CD11c+F4/80hi), T lymphocytes (CD3+CD4+ or CD3+CD4-) and neutrophils (CD11c-CD11bhiLy6G+). Significantly reduced populations of activated dendritic cells, macrophages and CD4- T-lymphocytes were observed in the lungs of PAR1 antagonist-treated mice compared to hMPV-infected untreated mice. Although there appears to be a decrease in neutrophils in infected untreated mice, CD11c-CD11bhiLy6G+ events were extremely low. This population no longer followed a Gaussian distribution and we are therefore reluctant to draw any definite conclusion for this specific population. These results confirm that the PAR1 antagonist protects mice from potentially deleterious lung inflammation induced by hMPV infection.


Modulation of protease activated receptor 1 influences human metapneumovirus disease severity in a mouse model.

Aerts L, Hamelin MÈ, Rhéaume C, Lavigne S, Couture C, Kim W, Susan-Resiga D, Prat A, Seidah NG, Vergnolle N, Riteau B, Boivin G - PLoS ONE (2013)

Cell recruitment in the lungs of hMPV-infected mice treated with the PAR1 antagonist.Groups of 6 mice were infected intranasally with hMPV (7 x105 TCID50) or mock infected and simultaneously treated for 5 days with a single daily dose of 500 µM of PAR1 antagonist (SCH79797). Mice were sacrificed on day 5 pi, lungs were removed, homogenized in HBSS and analyzed by flow cytometry for the presence of (A) dendritic cells expressing the MHC II molecules I-A/I-E (CD11c+CD11bloLy6G loI-A/I-E+), (B) macrophages (CD11c+CD11b+F4/80hi), (C) T lymphocytes (CD3+CD4+ or CD3+CD4-) and (D) neutrophils (CD11c-CD11bhiLy6G+). Significant differences in recruited cells were observed between treated and untreated mice based on a one-way ANOVA. (* p<0.05, *** p<0.001).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3755973&req=5

pone-0072529-g003: Cell recruitment in the lungs of hMPV-infected mice treated with the PAR1 antagonist.Groups of 6 mice were infected intranasally with hMPV (7 x105 TCID50) or mock infected and simultaneously treated for 5 days with a single daily dose of 500 µM of PAR1 antagonist (SCH79797). Mice were sacrificed on day 5 pi, lungs were removed, homogenized in HBSS and analyzed by flow cytometry for the presence of (A) dendritic cells expressing the MHC II molecules I-A/I-E (CD11c+CD11bloLy6G loI-A/I-E+), (B) macrophages (CD11c+CD11b+F4/80hi), (C) T lymphocytes (CD3+CD4+ or CD3+CD4-) and (D) neutrophils (CD11c-CD11bhiLy6G+). Significant differences in recruited cells were observed between treated and untreated mice based on a one-way ANOVA. (* p<0.05, *** p<0.001).
Mentions: Immune cell populations present in the lungs on day 5 pi were analyzed by flow cytometry in mice treated for 5 days starting at the time of infection with 500 µM of the PAR1 antagonist (Figure 3). The immune cell populations analyzed included activated dendritic cells (CD11c+CD11bloLy6g loI-A/I-E+), macrophages (CD11b+CD11c+F4/80hi), T lymphocytes (CD3+CD4+ or CD3+CD4-) and neutrophils (CD11c-CD11bhiLy6G+). Significantly reduced populations of activated dendritic cells, macrophages and CD4- T-lymphocytes were observed in the lungs of PAR1 antagonist-treated mice compared to hMPV-infected untreated mice. Although there appears to be a decrease in neutrophils in infected untreated mice, CD11c-CD11bhiLy6G+ events were extremely low. This population no longer followed a Gaussian distribution and we are therefore reluctant to draw any definite conclusion for this specific population. These results confirm that the PAR1 antagonist protects mice from potentially deleterious lung inflammation induced by hMPV infection.

Bottom Line: Conversely, the PAR1 antagonist was beneficial to hMPV infection by decreasing weight loss and clinical signs and by significantly reducing pulmonary inflammation, pro-inflammatory cytokine levels (including IL-6, KC and MCP-1) and recruitment of immune cells to the lungs.Despite no apparent direct effect on virus replication during in vitro experiments, an important role for PAR1 in the regulation of furin expression in the lungs was shown for the first time.Further experiments indicated that the hMPV fusion protein can be cleaved by furin thus suggesting that PAR1 could have an effect on viral infectivity in addition to its immunomodulatory properties.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche en Infectiologie du Centre Hospitalier Universitaire de Québec and Université Laval, Quebec, Canada.

ABSTRACT
Human metapneumovirus (hMPV) infection causes acute respiratory tract infections (RTI) which can result in hospitalization of both children and adults. To date, no antiviral or vaccine is available for this common viral infection. Immunomodulators could represent an interesting strategy for the treatment of severe viral infection. Recently, the role of protease-activated receptors (PAR) in inflammation, coagulation and infection processes has been of growing interest. Herein, the effects of a PAR1 agonist and a PAR1 antagonist on hMPV infection were investigated in BALB/c mice. Intranasal administration of the PAR1 agonist resulted in increased weight loss and mortality of infected mice. Conversely, the PAR1 antagonist was beneficial to hMPV infection by decreasing weight loss and clinical signs and by significantly reducing pulmonary inflammation, pro-inflammatory cytokine levels (including IL-6, KC and MCP-1) and recruitment of immune cells to the lungs. In addition, a significant reduction in pulmonary viral titers was also observed in the lungs of PAR1 antagonist-treated mice. Despite no apparent direct effect on virus replication during in vitro experiments, an important role for PAR1 in the regulation of furin expression in the lungs was shown for the first time. Further experiments indicated that the hMPV fusion protein can be cleaved by furin thus suggesting that PAR1 could have an effect on viral infectivity in addition to its immunomodulatory properties. Thus, inhibition of PAR1 by selected antagonists could represent an interesting strategy for decreasing the severity of paramyxovirus infections.

Show MeSH
Related in: MedlinePlus