Abstract
SARS-CoV-2 infection induces interferon (IFN) response by plasmacytoid dendritic cells (pDCs), but the underlying mechanisms are poorly defined. Here, we show that the bulk of the IFN-I release comes from pDC sensing of infected cells and not cell-free virions. Physical contact (or conjugates) between pDCs and infected cells is mediated through CD54-CD11a engagement, and such conjugate formation is required for efficient IFN-I production. Interestingly, CD11a is inducible on infected epithelial cells when they are co-cultured with PBMCs, thus allowing for potentially bidirectional cross-talks between CD54 and CD11a, which further amplify the sensing. SARS-CoV-2 variants of concern (VOCs) are sensed less efficiently than the Wuhan ancestral strain (LSPQ1), but the mechanisms driving the defect are different among the VOCs. CD11a induction on infected cells is correlated with their ability to form cell conjugates with pDCs. Impaired sensing of the Alpha variant is linked to reduced CD11a induction on infected cells and to fewer conjugates formed with pDCs. Collectively, our findings provide new insights into how SARS-CoV-2-infected cells are sensed by pDCs and reveal that this process is targeted by some VOCs to limit IFN-I production. IMPORTANCE: Type I interferons (IFN-I) represent an important component of the host's innate defense against initial SARS-CoV-2 infections. Plasmacytoid dendritic cells (pDCs) produce large quantities of IFN-I upon recognition of viral particles or infected cells. This study shows that pDCs sense infected cells more efficiently than viral particles, leading to a higher production of IFN-I. Physical contact between a pDC and an infected cell is critical to this process; the interaction is mediated via CD11a and ICAM-1 complex and potentially is bidirectional. SARS-CoV-2 variants of concern (VOCs) have evolved to limit the IFN response through different mechanisms. For the Alpha variant, reduced level of CD11a on infected cells is linked to less contact with pDCs and decreased IFN-I release. Overall, our study characterizes some of the early steps involved in pDC-mediated response against SARS-CoV-2 infection and shows that these processes are targeted by VOCs to likely limit IFN-I response and enhance viral spread.