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

Lidia Szulc-Dąbrowska,Magdalena Bossowska-Nowicka,Agnieszka Ostrowska,Marek G Niemiałtowski,Zuzanna Nowak,Justyna Struzik,Maciej Guzera,Anna Winnicka,Felix N Toka,Małgorzata M Gieryńska,Pierre Roques

doi:10.1371/journal.pone.0179166

Lidia Szulc-Dąbrowska, Magdalena Bossowska-Nowicka + Show 9 more

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https://doi.org/10.1371/journal.pone.0179166

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Abstract

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.

Highlights

Ectromelia virus (ECTV) is a member of the Poxviridae family, genus Orthopoxvirus and is the causative agent of mousepox, a disease called “smallpox of mice”
Our results show for the first time that ECTV productively infects granulocyte-macrophage colony stimulating factor (GM-CSF)–cultured bone marrow (GM-BM) cells, comprised of conventional dendritic cells (cDCs) and macrophages, and leads to their functional paralysis
Our results demonstrate that a single virus may affect GMCSF–derived bone marrow cells (GM-BM) functions at multiple levels of their physiology leading to complete inability to fulfill their innate and acquired immune functions

Summary

Introduction

Ectromelia virus (ECTV) is a member of the Poxviridae family, genus Orthopoxvirus and is the causative agent of mousepox, a disease called “smallpox of mice”. ECTV is closely related to variola virus (VARV)–the causative agent of smallpox responsible for millions of death in the history of mankind. Another member of orthopoxviruses–monkeypox virus (MPXV), is a zoonotic agent that causes a human disease with high mortality and clinical signs very similar to smallpox. The monkeypox outbreak in the United States of America in 2003 demonstrated that MPXV is capable of spreading to new animal reservoirs outside central Africa In this case prairie dogs were infected by rodents imported from Ghana and served as amplification vectors, transmitting disease to humans [1]. Cessation of vaccination against smallpox has created a real threat since VARV and MPXV can be used as potential agents of bioterrorism [3]

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