Alveolar Macrophages Are a Prominent but Nonessential Target for Murine Cytomegalovirus Infecting the Lungs
| Autor: | Clara Lawler, Nicholas Davis-Poynter, Helen E. Farrell, Philip G. Stevenson, Martha Oliveira |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Muromegalovirus Rhadinovirus Chemokine viruses 030106 microbiology Immunology Herpesvirus 1 Human medicine.disease_cause Microbiology 03 medical and health sciences Virology Macrophages Alveolar medicine Animals Macrophage Lung Mice Inbred BALB C biology Murid herpesvirus 4 virus diseases Epithelial Cells Cytomegalovirus respiratory system biology.organism_classification 3. Good health Mice Inbred C57BL 030104 developmental biology Herpes simplex virus medicine.anatomical_structure Insect Science biology.protein Pathogenesis and Immunity |
| Zdroj: | Journal of Virology. 90:2756-2766 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.02856-15 |
| Popis: | 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 alveolar epithelial cells (AEC1s). In contrast, herpes simplex virus 1 infected AEC1s and murid herpesvirus 4 (MuHV-4) infected AEC1s via AMs. MCMV-infected AMs prominently expressed viral reporter genes from a human CMV IE1 promoter; but most IE1-positive cells were AEC2s, and CD11c-cre mice, which express cre in AMs, switched the fluorochrome expression of 90% of floxed MuHV-4 in the lungs and 50% of floxed MCMV in the blood. AM depletion increased MCMV titers in the lung during the acute phase of infection. Thus, the influence of AMs was more restrictive than permissive. Circulating monocytes entered infected lungs in large numbers and became infected, but not directly; infection occurred mainly via AEC2s. Mice infected with an MCMV mutant lacking its m131/m129 chemokine homolog, which promotes macrophage infection, showed levels of lung infection equivalent to those of wild-type MCMV-infected mice. The level of lung infiltration by Gr-1-positive cells infected with the MCMV m131/m129-null mutant was modestly different from that for wild-type MCMV-infected lungs. These results are consistent with myeloid cells mainly disseminating MCMV from the lungs, whereas AEC2s provide local amplification. IMPORTANCE 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 analyze, studies with 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 epithelial cells. Macrophages had an important defensive role, as their removal increased the level of infection. These results establish the dual nature of lung infection, with local virus replication occurring in epithelial cells and spread occurring via quiescently infected macrophages. Distinct therapies may be needed to target these contrasting events. |
| Databáze: | OpenAIRE |
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