SARS-CoV-2 (E)-protein induces rapid TLR2-mediated T cell activation in mouse lungs revealed by intravital lung microscopy

Extract The SARS-CoV-2 envelope (E)-protein is a conserved structural protein of the corona virus family with a key role in SARS-CoV2 pathogenicity [1]. Its sequence conservation among different SARS-CoV-2 viral variants and related coronaviruses makes it a promising candidate for preventive and therapeutic strategies [2]. (E)-protein acts as a viroporin that disrupts the host cell plasma membrane and triggers cell death [3]. It also mediates SARS-CoV2 sensing and inflammatory signalling via activation of the TLR2 receptor in macrophages [4, 5] driving innate immune cell activation and cytokine storm-induced mortality in patients with COVID-19. Cytokines and T cell receptor (TCR) cross-reactivity are described to cause TLR2-dependent activation of T cells, termed innate or bystander activation, challenging the dogma of exclusive adaptive antigen-specific T cell activation [6–8]. If SARS-CoV2 (E)-protein can activate innate T cell function and whether TLR2 signaling is involved is currently unknown.