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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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PAR1 agonist or antagonist dose-dependent effect on hMPV infection during a 3-day treatment in mice.Groups of 12 mice were infected intranasally with hMPV (4-6 x105 TCID50) or mock infected and simultaneously treated for 3 days with a single daily dose of 50 or 500 µM of PAR1 agonist (TFLLR-NH2), PAR1 antagonist (SCH79797) or their respective vehicles. A) and B) Weight loss and mortality were monitored daily for 14 days for mice treated with the PAR1 agonist and antagonist, respectively. The horizontal bar underneath the graphic indicates the timing and duration of treatment. Arrows and numbers indicate the mice that reached the endpoint and were sacrificed (full line: mice treated with 50 µM of PAR1 agonist, dotted line: mice treated with 500 µM of PAR1 agonist). Significant differences in weight loss were observed between mice treated with 50 µM (†) or 500 µM (*) of compound compared to untreated mice based on a two-way ANOVA (* p<0.05, ** p<0.01, *** p<0.001, † p<0.05, † † p<0.01). C) Viral titers were determined by TCID50 in lung homogenates at day 5 pi. Significant differences were observed between treated or untreated mice as determined by one-way ANOVA. (* p<0.05, ** p<0.01) The bar indicates the lower limit of detection.
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pone-0072529-g001: PAR1 agonist or antagonist dose-dependent effect on hMPV infection during a 3-day treatment in mice.Groups of 12 mice were infected intranasally with hMPV (4-6 x105 TCID50) or mock infected and simultaneously treated for 3 days with a single daily dose of 50 or 500 µM of PAR1 agonist (TFLLR-NH2), PAR1 antagonist (SCH79797) or their respective vehicles. A) and B) Weight loss and mortality were monitored daily for 14 days for mice treated with the PAR1 agonist and antagonist, respectively. The horizontal bar underneath the graphic indicates the timing and duration of treatment. Arrows and numbers indicate the mice that reached the endpoint and were sacrificed (full line: mice treated with 50 µM of PAR1 agonist, dotted line: mice treated with 500 µM of PAR1 agonist). Significant differences in weight loss were observed between mice treated with 50 µM (†) or 500 µM (*) of compound compared to untreated mice based on a two-way ANOVA (* p<0.05, ** p<0.01, *** p<0.001, † p<0.05, † † p<0.01). C) Viral titers were determined by TCID50 in lung homogenates at day 5 pi. Significant differences were observed between treated or untreated mice as determined by one-way ANOVA. (* p<0.05, ** p<0.01) The bar indicates the lower limit of detection.

Mentions: In a first in vivo experiment, BALB/c mice were infected intranasally with hMPV (4-6x105 TCID50) or mock infected and simultaneously treated intranasally, for a period of 3 days, with a single daily dose of 50 or 500 µM of PAR1 agonist (TFLLR-NH2) or PAR1 antagonist (SCH79797). PAR1 agonist- or PAR1 antagonist-treatment of uninfected mice did not induce weight loss, mortality or any signs of toxicity (data not shown). Mortality was only observed in PAR1-agonist treated mice (17% on day 6 post infection (pi) and 50% on day 7 pi for mice treated with 50 µM and 500 µM of PAR1 agonist, respectively). These groups also had a greater weight loss compared to infected, vehicle-treated mice (Figure 1A). Conversely, weight loss was significantly reduced in a dose-dependent manner in PAR1 antagonist-treated mice compared to the infected, vehicle-treated group (Figure 1B). No significant difference in pulmonary viral titers was observed between PAR1 agonist-treated mice and vehicle-treated controls. In contrast, viral titers in the lungs of PAR1 antagonist-treated mice were significantly lower than those of vehicle-treated mice by about 1 log (Figure 1C). Thus, we conclude that PAR1 plays a deleterious role in the pathogenesis of hMPV infections.


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)

PAR1 agonist or antagonist dose-dependent effect on hMPV infection during a 3-day treatment in mice.Groups of 12 mice were infected intranasally with hMPV (4-6 x105 TCID50) or mock infected and simultaneously treated for 3 days with a single daily dose of 50 or 500 µM of PAR1 agonist (TFLLR-NH2), PAR1 antagonist (SCH79797) or their respective vehicles. A) and B) Weight loss and mortality were monitored daily for 14 days for mice treated with the PAR1 agonist and antagonist, respectively. The horizontal bar underneath the graphic indicates the timing and duration of treatment. Arrows and numbers indicate the mice that reached the endpoint and were sacrificed (full line: mice treated with 50 µM of PAR1 agonist, dotted line: mice treated with 500 µM of PAR1 agonist). Significant differences in weight loss were observed between mice treated with 50 µM (†) or 500 µM (*) of compound compared to untreated mice based on a two-way ANOVA (* p<0.05, ** p<0.01, *** p<0.001, † p<0.05, † † p<0.01). C) Viral titers were determined by TCID50 in lung homogenates at day 5 pi. Significant differences were observed between treated or untreated mice as determined by one-way ANOVA. (* p<0.05, ** p<0.01) The bar indicates the lower limit of detection.
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pone-0072529-g001: PAR1 agonist or antagonist dose-dependent effect on hMPV infection during a 3-day treatment in mice.Groups of 12 mice were infected intranasally with hMPV (4-6 x105 TCID50) or mock infected and simultaneously treated for 3 days with a single daily dose of 50 or 500 µM of PAR1 agonist (TFLLR-NH2), PAR1 antagonist (SCH79797) or their respective vehicles. A) and B) Weight loss and mortality were monitored daily for 14 days for mice treated with the PAR1 agonist and antagonist, respectively. The horizontal bar underneath the graphic indicates the timing and duration of treatment. Arrows and numbers indicate the mice that reached the endpoint and were sacrificed (full line: mice treated with 50 µM of PAR1 agonist, dotted line: mice treated with 500 µM of PAR1 agonist). Significant differences in weight loss were observed between mice treated with 50 µM (†) or 500 µM (*) of compound compared to untreated mice based on a two-way ANOVA (* p<0.05, ** p<0.01, *** p<0.001, † p<0.05, † † p<0.01). C) Viral titers were determined by TCID50 in lung homogenates at day 5 pi. Significant differences were observed between treated or untreated mice as determined by one-way ANOVA. (* p<0.05, ** p<0.01) The bar indicates the lower limit of detection.
Mentions: In a first in vivo experiment, BALB/c mice were infected intranasally with hMPV (4-6x105 TCID50) or mock infected and simultaneously treated intranasally, for a period of 3 days, with a single daily dose of 50 or 500 µM of PAR1 agonist (TFLLR-NH2) or PAR1 antagonist (SCH79797). PAR1 agonist- or PAR1 antagonist-treatment of uninfected mice did not induce weight loss, mortality or any signs of toxicity (data not shown). Mortality was only observed in PAR1-agonist treated mice (17% on day 6 post infection (pi) and 50% on day 7 pi for mice treated with 50 µM and 500 µM of PAR1 agonist, respectively). These groups also had a greater weight loss compared to infected, vehicle-treated mice (Figure 1A). Conversely, weight loss was significantly reduced in a dose-dependent manner in PAR1 antagonist-treated mice compared to the infected, vehicle-treated group (Figure 1B). No significant difference in pulmonary viral titers was observed between PAR1 agonist-treated mice and vehicle-treated controls. In contrast, viral titers in the lungs of PAR1 antagonist-treated mice were significantly lower than those of vehicle-treated mice by about 1 log (Figure 1C). Thus, we conclude that PAR1 plays a deleterious role in the pathogenesis of hMPV infections.

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