A subset of COVID-19 patients exhibit Post-Acute Sequalae of COVID-19 (PASC), but little is known about the immune signatures associated with these syndromes. We investigated longitudinal peripheral blood samples in 50 individuals with previously confirmed SARS-CoV-2 infection, including 20 who experienced prolonged duration of COVID-19 symptoms (lasting more than 30 days; median=74 days) compared to 30 who had symptom resolution in 20 days or less.Individuals with prolonged symptom duration maintained antigen-specific T-cell response magnitudes to SARS-CoV-2 spike protein in CD4+ and cTfh populations during late convalescence while those without persistent symptoms demonstrated an expected decline. The prolonged group also displayed increased IgG avidity to SARS-CoV-2 S-protein. Significant correlations between symptom duration and both SARS-CoV-2-specific T cells and antibodies were observed.Activation and exhaustion markers were evaluated in multiple immune cell types, revealing few phenotypic differences between prolonged and recovered groups suggesting that prolonged symptom duration is not due to persistent systemic inflammation. These findings demonstrate that SARS-CoV-2-specific immune responses are maintained in patients suffering from prolonged post-COVID-19 symptom duration in contrast to those with resolved symptoms and may suggest the persistence of viral antigens as an underlying etiology.

Neutrophilic inflammation characterizes several respiratory viral infections including COVID-19-related ARDS, although its contribution to disease pathogenesis remains poorly understood. Here, we identified two neutrophil subpopulations (A1 and A2) in the airway compartment of 52 severe COVID-19 subjects, where loss of the A2 subset correlated with increased viral burden and reduced 30-days survival. A2 neutrophils showcased a discrete antiviral response with an increased interferon signature. Blockade of type I interferon attenuated viral clearance in A2 neutrophils and downregulated IFIT3 and key catabolic genes, demonstrating direct antiviral neutrophil function. Knockdown of IFIT3 in A2 neutrophils led to loss of IRF3 phosphorylation with consequent reduced viral catabolism, providing the first discrete mechanism of type I interferon signaling in neutrophils. The identification of this novel neutrophil phenotype and its association with severe COVID-19 outcomes emphasizes its likely importance in other respiratory viral infections and potential for new therapeutic approaches in viral illness.