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

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

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 an in-silico analyses to evaluate the expression pattern of 38 selected immunoinhibitory receptors (IRs) associated with different myeloid and lymphoid immune cells during COVID-19 infection. Our analyses revealed a pattern of overall upregulation of IRs mRNA during SARS-CoV-2 infection. A large number of IRs expressed on both lymphoid and myeloid cells were upregulated in nasopharyngeal swabs (NPs), 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 NPs and autopsies, were more expressed in autopsies and were directly correlated with viral levels. Single-cell data from blood and bronchioalveolar samples also reflected the observed association between IRs 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.