A Counterintuitive Neutrophil-Mediated Pattern in COVID-19 Patients Revealed through Transcriptomics Analysis

Abstract

The COVID-19 pandemic has persisted for almost three years. However, the mechanisms linked to the SARS-CoV-2 effect on tissues and disease severity have not been fully elucidated. Since the onset of the pandemic, a plethora of high-throughput data related to the host transcriptional response to SARS-CoV-2 infections has been generated. To this end, the aim of this study was to assess the effect of SARS-CoV-2 infections on circulating and organ tissue immune responses. We profited from the publicly accessible gene expression data of the blood and soft tissues by employing an integrated computational methodology, including bioinformatics, machine learning, and natural language processing in the relevant transcriptomics data. COVID-19 pathophysiology and severity have mainly been associated with macrophage-elicited responses and a characteristic “cytokine storm”. Our counterintuitive findings suggested that the COVID-19 pathogenesis could also be mediated through neutrophil abundance and an exacerbated suppression of the immune system, leading eventually to uncontrolled viral dissemination and host cytotoxicity. The findings of this study elucidated new physiological functions of neutrophils, as well as tentative pathways to be explored in asymptomatic-, ethnicity- and locality-, or staging-associated studies.

In silico investigation of potential COVID-19-associated microRNA signatures

“…Over-expression of the cytokine IL6 has been reported to be highly associated with the mortality risk of COVID-19; IL6 also acts as a perpetrator of the SARS-CoV-2-induced cytokine storm [65][66][67] . However, IL6 appears to be down-regulated in the blood of COVID-19 patients (Figure 3), consistent with the findings of a previous bioinformatics study by Özbek and colleagues (2023), wherein IL6 was not found to be significantly dysregulated in diverse SARS-CoV-2-infected tissues 55 . This is probably due to the dual role of IL6 as a pro-and antiinflammatory cytokine [68][69] , as well as the diverse immune response patterns observed in COVID-19 patients 55,70 .…”

“…However, IL6 appears to be down-regulated in the blood of COVID-19 patients (Figure 3), consistent with the findings of a previous bioinformatics study by Özbek and colleagues (2023), wherein IL6 was not found to be significantly dysregulated in diverse SARS-CoV-2-infected tissues 55 . This is probably due to the dual role of IL6 as a pro-and antiinflammatory cytokine [68][69] , as well as the diverse immune response patterns observed in COVID-19 patients 55,70 . The pleiotropic anti-inflammatory cytokine IL4 71 is also down-regulated in COVID-19 blood samples (Figure 3), in agreement with previous studies suggesting cytokine storm suppression during SARS-CoV-2 infection 55,56 .…”

“…In many COVID-19 cases, exacerbated inflammatory responses ("cytokine storm") are observed, which result from the acute increase in the levels of circulating pro-inflammatory cytokines and chemokines, and their uncontrolled release, both at local and systemic levels [52][53][54] . Several studies, though, suggest that the human host's immune system is rather compromised upon SARS-CoV-2 infection and it is not capable of eliciting a sufficient immune response 55,56 .…”

“…This is probably due to the dual role of IL6 as a pro-and antiinflammatory cytokine [68][69] , as well as the diverse immune response patterns observed in COVID-19 patients 55,70 . The pleiotropic anti-inflammatory cytokine IL4 71 is also down-regulated in COVID-19 blood samples (Figure 3), in agreement with previous studies suggesting cytokine storm suppression during SARS-CoV-2 infection 55,56 .…”