Immune responses in COVID-19 respiratory tract and blood reveal mechanisms of disease severity

Zhang, W.; Chua, B.; John Selva, K.; Kedzierski, L.; Ashhurst, T.; Heycraft, E.; Shoffner, S.; Hensen, L.; Boyd, D.; James, F.; Mouhtouris, E.; Kwong, J. C.; Chua, K.; Drewett, G.; Copaescu, A.; Dobson, J.; Rowntree, L.; Habe, J.; Allen, L.; Koay, H.-F.; Neil, J.; Gartner, M.; Lee, C.; Andersson, P.; Seemann, T.; Sherry, N.; Amanat, F.; Krammer, F. C.; Londrigan, S.; Wakim, L.; King, N.; Godfrey, D.; Mackay, L.; Thomas, P.; Nicholson, S. R.; Arnold, K.; Chung, A.; Holmes, N.; Smibert, O.; Trubiano, J. A.; Gordon, C.; Nguyen, T. H.; Kedzierska, K.

Although the respiratory tract is the primary site of SARS-CoV-2 infection and the ensuing immunopathology, respiratory immune responses are understudied and urgently needed to understand mechanisms underlying COVID-19 disease pathogenesis. We collected paired longitudinal blood and respiratory tract samples (endotracheal aspirate, sputum or pleural fluid) from hospitalized COVID-19 patients and non-COVID-19 controls. Cellular, humoral and cytokine responses were analysed and correlated with clinical data. SARS-CoV-2-specific IgM, IgG and IgA antibodies were detected using ELISA and multiplex assay in both the respiratory tract and blood of COVID-19 patients, although a higher receptor binding domain (RBD)-specific IgM and IgG seroconversion level was found in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples was detected only when high levels of RBD-specific antibodies were present. Strikingly, cytokine/chemokine levels and profiles greatly differed between respiratory samples and plasma, indicating that inflammation needs to be assessed in respiratory specimens for the accurate assessment of SARS-CoV-2 immunopathology. Diverse immune cell subsets were detected in respiratory samples, albeit dominated by neutrophils. Importantly, we also showed that dexamethasone and/or remdesivir treatment did not affect humoral responses in blood of COVID-19 patients. Overall, our study unveils stark differences in innate and adaptive immune responses between respiratory samples and blood and provides important insights into effect of drug therapy on immune responses in COVID-19 patients.