Enhanced expression of immune checkpoint receptors during SARS-CoV-2 viral infection

Narjes Saheb Sharif-Askari; Fatemeh Saheb Sharif-Askari; Bushra Mdkhana; Saba Al Heialy; Habiba S Alsafar; Rifat Hamoudi; Qutayba Hamid; Rabih Halwani

doi:10.1016/j.omtm.2020.11.002

Enhanced expression of immune checkpoint receptors during SARS-CoV-2 viral infection

Mol Ther Methods Clin Dev. 2021 Mar 12:20:109-121. doi: 10.1016/j.omtm.2020.11.002. Epub 2020 Nov 12.

Authors

Narjes Saheb Sharif-Askari¹, Fatemeh Saheb Sharif-Askari¹, Bushra Mdkhana¹, Saba Al Heialy^{2

3}, Habiba S Alsafar^{4

5

6}, Rifat Hamoudi^{1

7}, Qutayba Hamid^{1

3

7}, Rabih Halwani^{1

7

8}

Affiliations

¹ Sharjah Institute of Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
² College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates.
³ Meakins-Christie Laboratories, Research Institute of the McGill University Healthy Center, McGill University, Montreal, QC, Canada.
⁴ Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.
⁵ Department of Biomedical Engineering, College of Engineering, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.
⁶ Department of Genetics and Molecular Biology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.
⁷ Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
⁸ Prince Abdullah Ben Khaled Celiac Disease Research Chair, Department of Pediatrics, Faculty of Medicine, King Saud University, Saudi Arabia.

Abstract

The immune system is tightly regulated by the activity of stimulatory and inhibitory immune receptors. This immune homeostasis is usually disturbed during chronic viral infection. Using publicly available transcriptomic datasets, we conducted in silico analyses to evaluate the expression pattern of 38 selected immune inhibitory receptors (IRs) associated with different myeloid and lymphoid immune cells during coronavirus disease 2019 (COVID-19) infection. Our analyses revealed a pattern of overall upregulation of IR mRNA during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A large number of IRs expressed on both lymphoid and myeloid cells were upregulated in nasopharyngeal swabs (NPSs), while lymphoid-associated IRs were specifically upregulated in autopsies, reflecting severe, terminal stage COVID-19 disease. Eight genes (BTLA, LAG3, FCGR2B, PDCD1, CEACAM1, CTLA4, CD72, and SIGLEC7), shared by NPSs and autopsies, were more expressed in autopsies and were directly correlated with viral levels. Single-cell data from blood and bronchoalveolar samples also reflected the observed association between IR upregulation and disease severity. Moreover, compared to SARS-CoV-1, influenza, and respiratory syncytial virus infections, the number and intensities of upregulated IRs were higher in SARS-CoV-2 infections. In conclusion, the immunopathology and severity of COVID-19 could be attributed to dysregulation of different immune inhibitors. Targeting one or more of these immune inhibitors could represent an effective therapeutic approach for the treatment of COVID-19 early and late immune dysregulations.

Keywords: CEACAM1; COVID-19; SARS-CoV-2; SIGLEC10; immune checkpoint inhibitors; immune inhibitory receptors; influenza A virus; lung autopsies; respiratory viral infection; sialic acid.