Unique signatures of airway and systemic immunity in severe COVID-19 patients infected with alpha to Omicron SARS-CoV-2 variants of concern.

In this study, systemic and localized immunity induced by SARS-CoV-2 variants of concern or interest (VOC/VOI) was investigated. For that, serum and tracheal aspirate soluble chemokines, pro-inflammatory/regulatory cytokines, and growth factors were measured in severe COVID-19 patients under mechanical ventilation upon infection with different SARS-CoV-2 variants, namely Alpha, Gamma, Zeta, Delta and Omicron. Increased levels of soluble mediators were observed in serum from severe COVID-19 patients regardless of the variant. In tracheal aspirate samples, the patients infected with the Gamma, Zeta, Delta, and Omicron variants exhibited reduced levels of inflammatory cytokines when compared to those infected with the Alpha variant. The trend of lower cytokine levels was also observed in the serum of patients across these variants, except for the Delta variant. By using network analysis and cytokine storm signatures, the data confirmed that severe COVID-19 induced by different variants have a completely divergent pattern of connectivity in serum samples as well as tracheal aspirates. Patients infected with variants at later time points in the pandemic such as Omicron exhibited networks of weak central architecture in serum samples as compared to tracheal aspirates, with lower number of neighborhood connections and clusters of pro-inflammatory and regulatory cytokines. By and large, this study points out to important systemic and local divergences and to loss of airway localized immunity in severe COVID-19 patients infected with SARS-CoV-2 variants, which brings insight into understanding host responses and viral escape vis-à-vis the virus mutations and evolution.