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.