A persistent neutrophil-associated immune signature characterises post-COVID19 pulmonary sequelae

Abstract

Persistent interstitial lung changes with associated symptoms occur in a proportion of individuals that have recovered from severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) infection through unknown mechanisms. We studied individuals with severe COVID-19 longitudinally following recovery from acute illness. Subjects with interstitial lung changes at 3-6 months post-recovery had an upregulated neutrophil-associated immune signature including increased chemokines, proteases and markers of neutrophil extracellular traps detectable systemically. Similar pathways were enriched in the upper airway with a concomitant augmentation of antiviral type-I interferon signalling. Interaction analysis of the peripheral phosphoproteome identified enriched kinases critical for neutrophil inflammatory pathways. Repeat sampling indicated that full normalisation of radiological and functional changes has not yet been reached in many individuals by 12 months post-recovery. These data provide functional insight into mechanisms driving pulmonary sequelae of COVID-19 and provide a rational basis for development of future targeted approaches to prevent long-term complications.

COVID‐19 immunopathology: From acute diseases to chronic sequelae

“…Chronic elevation of circulating IL‐1β, along with IL‐6 and TNF in PASC patients indicates a self‐sustaining feed‐forward loop, likely contributing to the establishment of a proinflammatory environment 299 . Furthermore, PASC patients with persistent interstitial lung changes maintain an immune signature associated with sustained neutrophilic inflammation, indicating a potential role for neutrophils in driving chronic sequelae 300,301 . In addition to pulmonary sequelae, myeloid cells have been found to contribute to cognitive impairments associated with PASC—typically referred to as “brain fog.” Microglia undergo significant perturbations during acute COVID‐19, exhibiting enhanced reactivity which has previously been linked to loss of oligodendrocytes and myelinated axons 302 …”

Myeloperoxidase inhibition may protect against endothelial glycocalyx shedding induced by COVID-19 plasma

“…Interestingly, despite clinical recovery, MPO levels and MPO activities remained elevated in the severe COVID19 group, and upregulated neutrophils-associated immune signatures including MPO levels have also been observed (23). In the same study, higher MPO levels measured at 3-6 months post recovery was associated with a pulmonary sequelae of COVID-19 (23). Others also reported neutrophilia and higher proportion of low-density neutrophils at convalescent in severe COVID-19 survivors (24,25).…”

“…Note, only four samples from non-severe group were available for AZD5904 treatment [mean, n=4, syndecan-1: 1. 23 On the other hand, when HAECs were incubated with untreated plasma, higher glypican-1 shedding was observed in the non-severe group [5.93 (0.92) ng/ml] but not in the severe group [4.47 (0.74) ng/ml] compared to the control group [3.95 (0.05) ng/ml], p = 0.01 and p = 0.28, respectively. In contrast to observations with syndecan-1 shedding, inhibiting MPO-H 2 O 2 with MPO-IN-28 [5.17 (0.26) ng/ml, p = 0.01] appeared to enhanced glypican-1 shedding in the control group.…”