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

Zhang, Wuji; Chua, Brendon; Selva, Kevin; Kedzierski, Lukasz; Ashhurst, Thomas; Haycroft, Ebene; Shoffner, Suzanne; Hensen, Luca; Boyd, David; James, Fiona; Mouhtouris, Effie; Kwong, Jason; Chua, Kyra; Drewett, George; Copaescu, Ana; Dobson, Julie; Rowntree, Louise; Habel, Jennifer; Allen, Lilith; Koay, Hui-Fern; Neil, Jessica; Gartner, Matthew; Lee, Christina; Andersson, Patiyan; Seemann, Torsten; Sherry, Norelle; Amanat, Fatima; Krammer, Florian; Londrigan, Sarah; Wakim, Linda; King, Nicholas; Godfrey, Dale; Mackay, Laura; Thomas, Paul; Nicholson, Suellen; Arnold, Kelly; Chung, Amy; Holmes, Natasha; Smibert, Olivia; Trubiano, Jason; Gordon, Claire; Nguyen, Thi; Kedzierska, Katherine

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.