Functional paralysis of GM-CSF-derived bone marrow cells productively infected with ectromelia virus

• Published in: PloS one Vol. 12; no. 6; p. e0179166
• Main Authors: Szulc-Dąbrowska, Lidia, Struzik, Justyna, Ostrowska, Agnieszka, Guzera, Maciej, Toka, Felix N, Bossowska-Nowicka, Magdalena, Gieryńska, Małgorzata M, Winnicka, Anna, Nowak, Zuzanna, Niemiałtowski, Marek G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.06.2017; Public Library of Science (PLoS)
• Subjects: Animals; Antigens; Antigens - immunology; Apoptosis; Apoptosis - drug effects; Biology and Life Sciences; Bone marrow; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Bone Marrow Cells - virology; CD4 antigen; Cell activation; Cell Line; Cell proliferation; Cells, Cultured; Chemokines; Colony-stimulating factor; Cytokines; Cytokines - metabolism; Dendritic cells; Disease; Ectromelia; Ectromelia virus - physiology; Endocytosis - drug effects; Endocytosis - immunology; Functional anatomy; Gene expression; Gene regulation; Genes; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Host range; Immune response; Immune system; Immunophenotyping; Immunosuppression; Infections; Inflammation; Inhibition; Interferon; Interferon regulatory factor 3; Interferon regulatory factor 7; Interferon Type I - metabolism; Leukocytes - immunology; Leukocytes - metabolism; Leukocytes - virology; Life sciences; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Macrophages; Male; Maturity; Medicine and Health Sciences; Mice; Mixed leukocyte reaction; Morphology; Mortality; Paralysis; Proteins; Signal Transduction; Smallpox; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Toll-Like Receptor 4 - agonists; Toll-Like Receptor 4 - metabolism; Transcription factors; Translocation; Tumor necrosis factor-TNF; Vaccines; Veterinary medicine; Viral infections; Virus Replication; Viruses; Zoonoses; Poland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0179166

Ectromelia virus (ECTV) is an orthopoxvirus responsible for mousepox, a lethal disease of certain strains of mice that is similar to smallpox in humans, caused by variola virus (VARV). ECTV, similar to VARV, exhibits a narrow host range and has co-evolved with its natural host. Consequently, ECTV employs sophisticated and host-specific strategies to control the immune cells that are important for induction of antiviral immune response. In the present study we investigated the influence of ECTV infection on immune functions of murine GM-CSF-derived bone marrow cells (GM-BM), comprised of conventional dendritic cells (cDCs) and macrophages. Our results showed for the first time that ECTV is able to replicate productively in GM-BM and severely impaired their innate and adaptive immune functions. Infected GM-BM exhibited dramatic changes in morphology and increased apoptosis during the late stages of infection. Moreover, GM-BM cells were unable to uptake and process antigen, reach full maturity and mount a proinflammatory response. Inhibition of cytokine/chemokine response may result from the alteration of nuclear translocation of NF-κB, IRF3 and IRF7 transcription factors and down-regulation of many genes involved in TLR, RLR, NLR and type I IFN signaling pathways. Consequently, GM-BM show inability to stimulate proliferation of purified allogeneic CD4+ T cells in a primary mixed leukocyte reaction (MLR). Taken together, our data clearly indicate that ECTV induces immunosuppressive mechanisms in GM-BM leading to their functional paralysis, thus compromising their ability to initiate downstream T-cell activation events.