Modulation of protease activated receptor 1 influences human metapneumovirus disease severity in a mouse model
Laetitia Aerts1, Marie-Ève Hamelin, Chantal Rhéaume
1Centre 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.
Insights
Inhibition of protease-activated receptor 1 (PAR1) with an antagonist reduced severity of human metapneumovirus (hMPV) infection in mice. This approach decreased inflammation and viral load, offering a potential treatment strategy for this common respiratory virus.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- Human metapneumovirus (hMPV) causes acute respiratory tract infections (RTI) with no available antiviral treatments or vaccines.
- Protease-activated receptors (PARs) are increasingly recognized for their roles in inflammation and infection.
- PAR1, a specific type of PAR, is a potential target for modulating immune responses during viral infections.
Purpose of the Study:
- To investigate the therapeutic potential of targeting PAR1 in hMPV infection.
- To evaluate the effects of a PAR1 agonist and antagonist on hMPV-induced disease in a mouse model.
Main Methods:
- BALB/c mice were infected with hMPV and treated with either a PAR1 agonist or antagonist via intranasal administration.
- Clinical outcomes, including weight loss and mortality, were monitored.
- Pulmonary inflammation, cytokine levels (IL-6, KC, MCP-1), immune cell infiltration, and viral titers were assessed.
Main Results:
- PAR1 agonist treatment exacerbated hMPV infection, leading to increased weight loss and mortality.
- PAR1 antagonist treatment significantly reduced weight loss, clinical signs, pulmonary inflammation, and pro-inflammatory cytokine production.
- PAR1 antagonist administration also decreased pulmonary viral titers and modulated furin expression, impacting viral infectivity.
Conclusions:
- PAR1 plays a significant role in regulating the immune response and potentially viral infectivity during hMPV infection.
- Inhibition of PAR1 by antagonists demonstrates a promising therapeutic strategy for mitigating the severity of hMPV and potentially other paramyxovirus infections.
- Targeting PAR1 offers a novel immunomodulatory approach for managing severe viral respiratory diseases.
