title: CD8+ T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome.
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: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Christopher M
authors: CM
authors: Coleman
authors: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Jeanne M
authors: JM
authors: Sisk
authors: Regeneron Pharmaceuticals, Tarrytown, New York, USA.
authors: Gabor
authors: G
authors: Halasz
authors: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Jixin
authors: J
authors: Zhong
authors: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Sarah E
authors: SE
authors: Beck
authors: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Krystal L
authors: KL
authors: Matthews
authors: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Thiagarajan
authors: T
authors: Venkataraman
authors: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Sanjay
authors: S
authors: Rajagopalan
authors: Regeneron Pharmaceuticals, Tarrytown, New York, USA.
authors: Christos A
authors: CA
authors: Kyratsous
authors: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA mfrieman@som.umaryland.edu.
authors: Matthew B
authors: MB
authors: Frieman
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D018352:Coronavirus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D008168:Lung / Q000276:immunology / Q000821:virology; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000276:immunology / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D065207:Middle East Respiratory Syndrome Coronavirus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D011401:Promoter Regions, Genetic; D011991:Receptors, Virus / Q000235:genetics* / Q000276:immunology; D059467:Transcriptome; D019076:Transgenes; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: D011991:Receptors, Virus; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse
keywords: DPP4; MERS; MERS-CoV; coronavirus; immune response; mouse model; pathogenesis; viral pathogenesis