NEW YORK – A new study of the immune landscape of COVID-19 has found that type I interferons (IFN) exacerbate inflammation in severe cases of the disease.
In a paper published in Science Immunology on Friday, South Korean researchers said they used the 10x Genomics scRNA-seq platform to perform single-cell RNA sequencing on peripheral blood mononuclear cells (PBMCs) from four healthy donors, eight patients with mild or severe COVID-19, and five patients with severe influenza, in order to identify factors that drive severe progression of COVID-19.
They found that patients with COVID-19 exhibited hyper-inflammatory signatures across all cell types among PBMCs, particularly an up-regulation of the TNF/IL-1β-driven inflammatory response, as compared to patients with severe influenza. They also observed that type I IFN response co-existed with the TNF/IL-1β-driven inflammation in classical monocytes from patients with severe COVID-19, but didn't observe this in patients with milder COVID-19. Interestingly, the researchers also observed type I IFN-driven inflammatory features in patients with severe influenza.
As a feature of immunological changes, the researchers investigated the relative proportions of immune cells among PBMCs in the disease groups compared to the healthy donor group. Unlike the limited changes in mild COVID-19, they saw significant changes in both influenza and severe COVID-19 across multiple cell types among PBMCs. In severe COVID-19, they found that the proportion of classical monocytes significantly increased, whereas those of dendritic cells (DC), non-classical monocytes, intermediate monocytes, natural killer (NK) cells, effector memory (EM)-like CD8+ T cells, and EM-like CD4+ T cells significantly decreased. In severe influenza, the investigators found that the proportion of classical monocytes significantly increased whereas those of DCs, non-EM-like CD4+ T cells, EM-like CD4+ T cells, IgG+ B cells, and IgG- B cells significantly decreased.
In order to compare the effect of infection between diseases, the researchers then performed hierarchical clustering based on relative gene expression changes compared to the healthy donor group. Unexpectedly, they found that all cell types among PBMCs were clustered together by disease group instead of by cell type. Further analysis indicated that, in COVID-19, peripheral blood immune cells may be influenced by common inflammatory mediators regardless of cell type. Further, despite COVID-19 and influenza having their own distinct transcriptional signatures, severe COVID-19 and influenza shared transcriptional signatures in all types of monocytes and DCs, possibly reflecting common mechanisms underlying the innate immune responses in severe influenza and severe COVID-19.
The investigators next analyzed the three types of monocyte clusters to find COVID-19-specific sub-clusters. They specifically focused on classical monocytes, considering their crucial roles for inflammatory responses, and investigated differentially expressed genes between influenza and COVID-19 in order to find COVID-19-specific transcriptional signatures in classical monocytes.
They found that COVID-19-specific genes were enriched by TNF/IL-1β-responsive genes whereas influenza-specific genes were enriched by IFN-I-responsive genes in addition to TNF/IL-1β-responsive genes, indicating that the IFN-I response is dominant in influenza compared to COVID-19. Unexpectedly, they also observed that severe COVID-19 acquires IFN-I-responsive features in addition to TNF/IL-1β-inflammatory features.
Finally, the researchers validated IFN-I response and inflammatory features using bulk RNA-seq data obtained from the post-mortem lung tissues of patients with lethal COVID-19. Although the analysis was limited to only two patients, they prominently exhibited both the IFN-I response and TNF/IL-1β-inflammatory response.
"In the current study, we demonstrated that severe COVID-19 is characterized by TNF/IL-1β-inflammatory features combined with the IFN-I response. In a murine model of SARS-CoV infection, timing of the IFN-I response is a critical factor determining outcomes of infection," the authors concluded. "Delayed IFN-I response contributes to pathological inflammation whereas early IFN-I response controls viral replication. Therefore, we propose that anti-inflammatory strategies targeting not only inflammatory cytokines, including TNF, IL-1β, and IL-6, but also pathological IFN-I response needs to be investigated for the treatment of patients with severe COVID-19."