Alveolar Macrophages Are a Prominent but Nonessential Target for Murine Cytomegalovirus Infecting the Lungs

Helen E. Farrell, Clara Lawler, Martha T. Oliveira, Nick Davis-Poynter, Philip G. Stevenson

Cytomegaloviruses (CMVs) infect the lungs and cause pathological damage there in immunocompromised hosts. How lung infection starts is unknown. Inhaled murine CMV (MCMV) directly infected alveolar macrophages (AMs) and type 2 alveolar epithelial cells (AEC2s), but not type 1 AECs (AEC1s). By contrast Herpes simplex virus type 1 infected AEC1s, and Murid Herpesvirus-4 (MuHV-4) infected AEC1s via AMs. MCMV-infected AMs prominently expressed viral reporter genes from an HCMV IE1 promoter; but most IE1(+) cells were AEC2s, and CD11c-cre mice, which express cre in AMs, switched <5% of floxed MCMV in the lungs. By contrast they switched >90% of floxed MuHV-4 in the lungs and 50% of floxed MCMV in the blood. AM depletion also increased acute MCMV lung titers. Thus, their influence was more restrictive than permissive. Circulating monocytes entered infected lungs in large numbers and became infected, but not directly - this occurred mainly via AEC2s. MCMV lacking its m131/m129 chemokine homolog, which promotes macrophage infection, showed a modest difference in lung infiltration by Gr-1(+) cells and no defect in lung infection. These results were consistent with myeloid cells mainly disseminating MCMV from the lungs, whereas AEC2s provided local amplification. Cytomegaloviruses (CMVs) chronically and systemically infect most mammals. Human CMV infection is usually asymptomatic, but causes lung disease in people with poor immune function. As human infection is hard to analyse, related animal viruses provide important insights. We show that Murine CMV has two targets in the lungs: macrophages and surfactant-secreting epithelial cells. Acute virus replication occurred largely in the epithelial cells. Macrophages had an important defensive role, as removing them increased infection. These results establish the dual nature of lung infection, with local virus replication in epithelial cells, and spread via quiescently infected macrophages. Distinct therapies may be needed to target these contrasting events.