A persistent neutrophil-associated immune signature characterizes post–COVID-19 pulmonary sequelae

Abstract

Interstitial lung disease and associated fibrosis occur in a proportion of individuals who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through unknown mechanisms. We studied individuals with severe coronavirus disease 2019 (COVID-19) after recovery from acute illness. Individuals with evidence of interstitial lung changes at 3 to 6 months after recovery had an up-regulated neutrophil-associated immune signature including increased chemokines, proteases, and markers of neutrophil extracellular traps that were detectable in the blood. Similar pathways were enriched in the upper airway with a concomitant increase in antiviral type I interferon signaling. Interaction analysis of the peripheral phosphoproteome identified enriched kinases critical for neutrophil inflammatory pathways. Evaluation of these individuals at 12 months after recovery indicated that a subset of the individuals had not yet achieved full normalization of radiological and functional changes. These data provide insight into mechanisms driving development of pulmonary sequelae during and after COVID-19 and provide a rational basis for development of targeted approaches to prevent long-term complications.

Down-regulation of KLF2 in lung fibroblasts is linked with COVID-19 immunofibrosis and restored by combined inhibition of NETs, JAK-1/2 and IL-6 signaling

“…Taken together, these findings support the involvement of multiple inflammatory signals in the expression of KLF2 in LFs during an aberrant immunofibrotic response in severe COVID-19. Indeed, recent data demonstrated an association of inflammatory responses and persistent NETosis with fibrotic processes and impaired lung function in patients that had been severely affected by SARS-CoV-2 [ 65 , 66 ].…”

Phenotypic alteration of low-density granulocytes in people with pulmonary post-acute sequelae of SARS-CoV-2 infection

“…Further analysis showed that mature neutrophils, but not T cell or B cell subsets, were strongly inversely correlated with recovery pseudotime, suggesting that severe COVID-19 patients who have persistent elevation in mature neutrophil levels over time is predictive for unfavorable disease outcomes. In line with this finding, George et al., 2022 observed increases in systemic neutrophil counts and MPO expression, primarily in severe COVID-19 survivors diagnosed interstitial lung disease in comparison with resolved individuals ( 30 ). Furthermore, MPO levels were positively correlated with disease extent visualized by CT scan and negatively associated with TLCO%.…”

Emergence and antibody evasion of BQ, BA.2.75 and SARS-CoV-2 recombinant sublineages in the face of maturing antibody breadth at the population level

“…Culture and infection of pBEC and alveolar epithelial cultures at air-liquid interface (ALI) was performed as previously described 24,25 . Briefly, prior to infection, cells were washed once with PBS and inoculated with equal number of virus particles for Delta, Omicron BA.2 and BA.5.…”