From the influenza pandemic of 1918–1919 to the most recent COVID-19 pandemic, respiratory infections remain a leading cause of mortality worldwide [1, 2]. Concurrently, the development of high-throughput omics technologies has revolutionised research about host responses to known and emerging respiratory pathogens [3], accelerating our understanding of highly prevalent pulmonary diseases [4]. Notably, omics technology-based characterisation of pathogens and host pathophysiology have critically supported diagnostic and therapeutic global health efforts during both the influenza A H1N1 and SARS-CoV-2 pandemics [5–7]. Nonetheless, elucidation of key immune response mechanisms and development of host-targeted therapeutics remain important unrealised research and clinical priorities in the global fight against lower respiratory tract infections (LTRIs) [8, 9].

In a report published in this issue of the European Respiratory Journal, Long et al. [10] characterised the baseline and longitudinal proteomic profiles of neutrophils in patients hospitalised with SARS-CoV-2 infection in a 29-day prospective observational study. Analysing circulating neutrophils from >200 hospitalised COVID-19, non-COVID-19 LTRI and non-infected patients, the authors identified a core COVID-19 neutrophil proteomic signature at baseline (hospital day 1) comprised of 171 type I interferon (IFN) response-related molecules. These core signature proteins were differentially expressed across COVID-19 severity classifications at baseline (World Health Organization (WHO) scale 3–6), then mostly normalising by day 7. This early, transient core proteomic signature supports accumulating evidence that patients with SARS-CoV-2 infection generate an initial, robust type I IFN response, contrary to reports published at the beginning of the COVID-19 pandemic [11]. From this list of core signature proteins, CXCR2 was the only neutrophil receptor that remained downregulated in the longitudinal profile of non-recovered patients (hospital day 29). The downregulation of CXCR2 in this cohort was also accompanied by dysregulations of multiple metabolic pathways in severe COVID-19 patients (WHO 5–6). Not surprisingly, recent evidence also reveals that systemic type I IFN dysregulations in COVID-19 patients are linked to metabolic changes that lead to immune reprogramming of circulating immune cells [12]. Furthermore, CXCR2 was previously reported as an immunomodulatory receptor associated with programmed proteomic disarming of neutrophils in multiple patients with severe community-acquired pneumonia [13].

Given the cell-specific resolution of untargeted proteomics from isolated neutrophils, the authors described how the expression of regulatory receptors alter both baseline and longitudinal immune and metabolic proteome profiles of hospitalised COVID-19 patients (figure 1). At baseline, the type I IFN response of critically ill COVID-19 patients was accompanied by increased expression of immunomodulatory molecules (arginase 1 (ARG1) and transforming growth factor beta 1 (TGFB1)) and receptors (Toll-like receptor 2 (TLR2), Fc γ receptor Ia (CD64-FCGR1A), C-type lectin domain family 4 member E (CLEC4E) and V-domain Ig suppressor of T cell activation (VISTA)). Interestingly, these neutrophil proteins were representative markers of the initial type I IFN baseline profiles during early hospitalisation stages (up to day 7) of severe patients along with changes in multiple metabolic regulators, which later predominated as representative metabolic proteins in the later stages of the non-recovered patients (at day 29). The non-recovered COVID-19 patients exhibited downregulation of key glycolytic proteins (hexokinase 3 (HK3) and glucose transporter 3 (SLC2A3)), though these normalised in recovered patients. Additionally, the longitudinal analysis revealed a sustained reduction in glycogen phosphorylases L (PYGL) and B (PYGB). These rate-limiting enzymes of glycogenolysis were downregulated at all timepoints in non-recovered COVID-19 patients and were accompanied by dysfunctional neutrophil proteomes. These proteomes included reduction of integrins and migratory receptors (poor neutrophil migration), and granule proteins and inhibitory receptors (high granule loss). Altogether, these findings support the recent discoveries of a neutrophil-specific proteomic disarming role of immunomodulatory receptors in respiratory infections [13] and exemplifies the immunosuppressive reprogramming of glycolytic and glycogenolytic metabolic pathways involved in systemic immune responses after COVID-19 infection [12, 14].

Proteomic profiling of neutrophil responses to SARS-CoV-2 from Long et al. [10].

Bulk and single-cell omics-based research studies that aim to characterise systemic immune responses to SARS-CoV-2 infection have identified neutrophils as key players of local and systemic responses in COVID-19 patients [15, 16]. There is extensive evidence supporting the importance of either sustained (hyperinflammation) or impaired type I IFN responses at the systemic level with a worse disease progression in patients with SARS-CoV-2 infection [11, 17]. However, Long et al. [10] further suggest concurrent immunomodulatory receptor disturbances with temporally divergent metabolic reprogramming of neutrophils. Their results expand the growing notion that circulating transcriptomic, metabolic and proteomic profiling can provide novel predictive biomarkers of acute and long-term outcomes of COVID-19 disease [14, 18–21]. In fact, several prospective studies in hospitalised infants with severe bronchiolitis have successfully identified omics-based epigenetic markers that link immune host response mechanisms with current disease severity and future development of respiratory comorbidities [22, 23]. One study reported a blood epigenomic DNA profile of 33 methylated CpG sites associated with bronchiolitis severity that is also differentially expressed in circulating immune cell responses of neutrophils, cytotoxic T cells and helper T cells [22]. Another study found a nasal profile of 23 micro RNAs (miRNAs) that targets messenger RNA (mRNA) of Toll-like receptor, Fc γ and Fc ε signalling pathways via direct miRNA–mRNA interactions and correlates with subsequent risk of asthma development [23]. These unanticipated and time-dependent changes in molecular profiles highlight the need for longitudinal omics-based clinical discoveries when analysing immune host response landscapes of respiratory infections.

Naturally, the associations presented by Long et al. [10] are primarily descriptive, and the authors are appropriately cautious about asserting potential metabolic reprogramming mechanisms of neutrophils or predictive biomarker functions of their proteome profiles. However, descriptive omics-based clinical research are valuable early steps in understanding host immune responses to respiratory pathogens in our global efforts to mitigate the impacts of severe respiratory infections with rapidly evolving technologies [20, 21, 24–27].