SARS-CoV-2 variants of concern elicit divergent early immune responses in hACE2 transgenic mice.

Knowledge about early immunity to SARS-CoV-2 variants of concern mainly comes from analysis of human blood. Such data provide limited information about host responses at the site of infection and largely miss initial events. To gain insights into compartmentalization and early dynamics of host responses to different SARS-CoV-2 variants, we utilized hACE2 transgenic mice and tracked immune changes during the first days after infection by RNAseq, multiplex assays and flow cytometry. Viral challenge infection led to divergent viral loads in the lungs, distinct inflammatory patterns and innate immune cell accumulation in response to ancestral SARS-CoV-2, Beta (B.1.351) and Delta (B.1.617.2) variant of concern (VOC). Compared to other SARS-CoV-2 variants, infection with Beta (B.1.351) VOC spread promptly to the lungs, leading to increased inflammatory responses. SARS-CoV-2-specific antibodies and T cells developed earliest 7 days post infection and were required to reduce viral spread and replication. Our studies show that VOCs differentially trigger transcriptional profiles and inflammation. This information contributes to the basic understanding of immune responses immediately post exposure to SARS-CoV-2 and is relevant for developing pan-VOC interventions, including prophylactic vaccines. This article is protected by copyright. All rights reserved.