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CD8+ T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome.
J Virol. 2017 Jan 01; 91(1)JV

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) is an important emerging pathogen that was first described in 2012. While the cell surface receptor for MERS-CoV has been identified as dipeptidyl peptidase 4 (DPP4), the mouse DPP4 homologue does not allow virus entry into cells. Therefore, development of mouse models of MERS-CoV has been hampered by the fact that MERS-CoV does not replicate in commonly available mouse strains. We have previously described a mouse model in which mDPP4 was replaced with hDPP4 such that hDPP4 is expressed under the endogenous mDPP4 promoter. In this study, we used this mouse model to analyze the host response to MERS-CoV infection using immunological assays and transcriptome analysis. Depletion of CD4+ T cells, CD8+ T cells, or macrophages has no effect on MERS-CoV replication in the lungs of infected mice. However, we found that depletion of CD8+ T cells protects and depletion of macrophages exacerbates MERS-CoV-induced pathology and clinical symptoms of disease. Overall, we demonstrate an important role for the inflammatory response in regulating MERS-CoV pathogenesis in vivo IMPORTANCE: The Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic respiratory virus that emerged from zoonotic sources in 2012. Human infections are still occurring throughout Saudi Arabia at a 38% case fatality rate, with the potential for worldwide spread via air travel. In this work, we identify the host response to the virus and identify inflammatory pathways and cell populations that are critical for protection from severe lung disease. By understanding the immune response to MERS-CoV we can develop targeted therapies to inhibit pathogenesis in the future.

Authors+Show Affiliations

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.Regeneron Pharmaceuticals, Tarrytown, New York, USA.Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.Regeneron Pharmaceuticals, Tarrytown, New York, USA.Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA mfrieman@som.umaryland.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27795435

Citation

Coleman, Christopher M., et al. "CD8+ T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome." Journal of Virology, vol. 91, no. 1, 2017.
Coleman CM, Sisk JM, Halasz G, et al. CD8+ T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome. J Virol. 2017;91(1).
Coleman, C. M., Sisk, J. M., Halasz, G., Zhong, J., Beck, S. E., Matthews, K. L., Venkataraman, T., Rajagopalan, S., Kyratsous, C. A., & Frieman, M. B. (2017). CD8+ T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome. Journal of Virology, 91(1). https://doi.org/10.1128/JVI.01825-16
Coleman CM, et al. CD8+ T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome. J Virol. 2017 Jan 1;91(1) PubMed PMID: 27795435.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CD8+ T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome. AU - Coleman,Christopher M, AU - Sisk,Jeanne M, AU - Halasz,Gabor, AU - Zhong,Jixin, AU - Beck,Sarah E, AU - Matthews,Krystal L, AU - Venkataraman,Thiagarajan, AU - Rajagopalan,Sanjay, AU - Kyratsous,Christos A, AU - Frieman,Matthew B, Y1 - 2016/12/16/ PY - 2016/09/13/received PY - 2016/10/18/accepted PY - 2016/11/1/pubmed PY - 2017/5/16/medline PY - 2016/11/1/entrez KW - DPP4 KW - MERS KW - MERS-CoV KW - coronavirus KW - immune response KW - mouse model KW - pathogenesis KW - viral pathogenesis JF - Journal of virology JO - J Virol VL - 91 IS - 1 N2 - Middle East respiratory syndrome coronavirus (MERS-CoV) is an important emerging pathogen that was first described in 2012. While the cell surface receptor for MERS-CoV has been identified as dipeptidyl peptidase 4 (DPP4), the mouse DPP4 homologue does not allow virus entry into cells. Therefore, development of mouse models of MERS-CoV has been hampered by the fact that MERS-CoV does not replicate in commonly available mouse strains. We have previously described a mouse model in which mDPP4 was replaced with hDPP4 such that hDPP4 is expressed under the endogenous mDPP4 promoter. In this study, we used this mouse model to analyze the host response to MERS-CoV infection using immunological assays and transcriptome analysis. Depletion of CD4+ T cells, CD8+ T cells, or macrophages has no effect on MERS-CoV replication in the lungs of infected mice. However, we found that depletion of CD8+ T cells protects and depletion of macrophages exacerbates MERS-CoV-induced pathology and clinical symptoms of disease. Overall, we demonstrate an important role for the inflammatory response in regulating MERS-CoV pathogenesis in vivo IMPORTANCE: The Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic respiratory virus that emerged from zoonotic sources in 2012. Human infections are still occurring throughout Saudi Arabia at a 38% case fatality rate, with the potential for worldwide spread via air travel. In this work, we identify the host response to the virus and identify inflammatory pathways and cell populations that are critical for protection from severe lung disease. By understanding the immune response to MERS-CoV we can develop targeted therapies to inhibit pathogenesis in the future. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/27795435/CD8+_T_Cells_and_Macrophages_Regulate_Pathogenesis_in_a_Mouse_Model_of_Middle_East_Respiratory_Syndrome_ L2 - https://journals.asm.org/doi/10.1128/JVI.01825-16?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -