Granzyme A- and B-cluster deficiency delays acute lung injury in pneumovirus-infected mice
Reinout A Bem1, Job B M van Woensel, Rene Lutter
1Pediatric Intensive Care Unit, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands. r.a.bem@amc.uva.nl
Insights
Granzyme A and B deficiency in mice delays acute lung injury from pneumovirus infection. This suggests granzymes contribute to severe respiratory illness by increasing inflammation and cell damage.
Area of Science:
- Immunology
- Virology
- Pathology
Background:
- Human pneumovirus respiratory syncytial virus causes acute lung injury in children.
- Severe disease involves granzyme pathway activation by effector lymphocytes, potentially increasing apoptosis and inflammation.
- The role of granzymes in pneumovirus-induced acute lung injury is not fully understood.
Purpose of the Study:
- To investigate the contribution of granzymes to acute lung injury in a mouse model of pneumovirus infection.
Main Methods:
- Mice expressing granzymes and knockout mice for granzyme A and B clusters were infected with pneumonia virus of mice.
- Lung inflammation and injury markers were assessed.
- Virus titers, clinical response, neutrophil recruitment, caspase-3 activation, and lung permeability were analyzed.
Main Results:
- Granzyme A and B expression was detected in mouse lungs post-infection.
- Mice lacking granzyme A and B clusters showed no change in lung virus titers.
- These mice exhibited a delayed clinical response to infection, with reduced neutrophil influx, diminished caspase-3 activation, and lower lung permeability.
Conclusions:
- Granzyme A and B deficiency delays the acute progression of pneumovirus disease.
- This delay is attributed to reduced alveolar injury.
- Granzymes play a significant role in the pathogenesis of pneumovirus-induced lung injury.
Abstract:
Lower respiratory tract infection by the human pneumovirus respiratory syncytial virus is a frequent cause of acute lung injury in children. Severe pneumovirus disease in humans is associated with activation of the granzyme pathway by effector lymphocytes, which may promote pathology by exaggerating proapoptotic caspase activity and proinflammatory activity. The main goal of this study was to determine whether granzymes contribute to the development of acute lung injury in pneumovirus-infected mice. Granzyme-expressing mice and granzyme A- and B-cluster single- and double-knockout mice were inoculated with the rodent pneumovirus pneumonia virus of mice strain J3666, and were studied for markers of lung inflammation and injury. Expression of granzyme A and B is detected in effector lymphocytes in mouse lungs in response to pneumovirus infection. Mice deficient for granzyme A and the granzyme B cluster have unchanged virus titers in the lungs but show a significantly delayed clinical response to fatal pneumovirus infection, a feature that is associated with delayed neutrophil recruitment, diminished activation of caspase-3, and reduced lung permeability. We conclude that granzyme A- and B-cluster deficiency delays the acute progression of pneumovirus disease by reducing alveolar injury.
Related Concept Videos
01:29Pneumonia II: Pathophysiology
01:29Respiratory Syncytial Virus Disease