Influenza-induced alveolar macrophages protect against death by malaria-associated acute lung injury.

Lower respiratory tract infections are common in malaria-endemic areas, and there is some evidence that co-infections between various bacteria/viruses and may affect disease prognosis. In this study, we report the novel finding that co-infection with influenza/A/X31 protects mice from death by NK65-Edinburgh, a model of severe malarial pulmonary leak which underpins malaria-associated acute lung injury (MA-ALI) and malaria-associated acute respiratory distress (MA-ARDS). Co-infected mice exhibit equivalent parasitemia as mice with malaria only, suggesting that the survival phenotype is due to differences in immune kinetics. We demonstrated that the pulmonary leak typical of E is attenuated in co-infected mice without alteration in CD8 T cell activation and recruitment to the lung. Upon further examination of the immune response to influenza/A/X31 we identified a population of arginase 1-expressing alveolar macrophages that traffic to the lungs early during infection. In vitro these macrophages inhibit CD8 T cell activation and proliferation better than non-arginase expressing cells. Removal of arginase-1 expressing alveolar macrophages via administration of the antimetabolite gemcitabine removed the protective effects of influenza/A/X31co-infection on MA-ALI. This study opens a route to better understanding of how to modulate the immunopathology observed in pulmonary leak associated with severe malaria, which must be achieved to rationally design therapeutic interventions for MA-ARDS / MA-ALI.