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 ϩ T cells, CD8 ϩ T cells, or macrophages has no effect on MERS-CoV replication in the lungs of infected mice. However, we found that depletion of CD8 ϩ 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. In vitro analysis of MERS-CoV and immune cells has suggested that MERS-CoV interacts with and infects T cells and macrophages. The receptor for MERS-CoV was identified as dipeptidyl peptidase 4 (DPP4) (4). T cells express DPP4, and DPP4 activity

Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China

“…It is known that MERS-CoV is able to infect both CD4 + and CD8 + primary human T cells and, upon infection induces T cell apoptosis in vitro 7 . While the cell surface receptor for SARS-Cov-2 has now been identified as ACE2 8 , other receptors may also exist on immune cells to bind to coronavirus [9][10][11] . As there is no proven antiviral treatment yet available, strategies to enhance the immune system may be considered.…”

Development of a Mouse-Adapted MERS Coronavirus

“…Pascal et al reported a model in which all of the mouse Dpp4 exons had been humanized and also generated humanized monoclonal antibodies against the MERS-CoV S protein using a novel strategy [30]. MERS-CoV infection in this model caused pulmonary edema, vascular cuffing, and alveolar septal thickening with an associated~20% weight loss, necessitating euthanasia [31]. Another MERS mouse model was engineered by changing two amino acids in the mouse Dpp4 locus using CRISPR-Cas9 technology [32].…”

MERS coronavirus outbreak: Implications for emerging viral infections

“…Infection of common marmosets with MERS-CoV resulted in dissemination of virus to the spleen and infection of T cells in vivo . Results of a recent study on a transgenic mouse model expressing human DPP4 (hDPP4) suggested that depletion of CD8 T cells could actually protect from MERS-CoVinduced pathology and symptoms, whereas depletion of macrophages exacerbated the pathology and symptoms (Coleman et al, 2017). Meanwhile recent in vitro studies suggested that, in common with H5N1-VN1203 influenza virus, MERS-CoV can attempt to evade the adaptive immune response by down-regulation of antigen-presentation gene expression, mediated by epigenetic mechanisms (Menachery et al, 2018).…”