A number of antiviral immune defenses are compromised among people who develop severe COVID-19, a new single-cell RNA sequencing analysis has found.

Some people infected with SARS-CoV-2 develop severe disease marked by acute respiratory failure and possibly sepsis and death. While studies have highlighted the possible role of systemic inflammatory responses in severe COVID-19, the cellular mechanisms behind this response remain largely unclear.

Analyzing blood samples collected from individuals with severe disease, moderate disease, and health controls, researchers from the University of Paris focused in on how dendritic cells, which are involved in antiviral defense, are affected by COVID-19. As they reported in Nature Cell Biology, they uncovered defects in the various roles dendritic cells typically fill in immune defense within patients with severe COVID-19.

“These novel mechanisms may explain patient aggravation and suggest strategies to restore the defective immune defense,” senior author Vassili Soumelis, a researcher at the University of Paris, and his colleagues wrote in their paper.

To analyze the effect of COVID-19 on antigen-presenting cells — which include dendritic cells — the researchers collected blood samples from five patients with moderate disease, 10 patients with severe disease, and four elderly, healthy controls for single-cell RNA sequencing.

Examining dendritic cells can be tricky, as they are present in low numbers, lack defining markers, and have a number of subsets. For their study, the researchers added a pre-enrichment step in their analysis for some of their samples to capture additional dendritic cells, which they then compared to the remaining samples that did not undergo that step. This approach, they found, enabled them to identify all antigen-presenting cell populations, including rare ones. In all, they generated a dataset of more than 81,000 antigen-presenting cells.

Dendritic cells have a number of roles in immune defense — such as sensing pathogens, producing antimicrobial and antiviral effector molecules, and presenting antigens to T cells — and the researchers uncovered defects in all of those processes that were associated with severe COVID-19.

For instance, plasmacytoid dendritic cells, which typically produce type I interferon, from patients with severe disease showed higher expression of genes involved in apoptosis. This, the researchers noted, could potentially account for why plasmacytoid dendritic cells are present in lower numbers among severely ill patients.

Additionally, the researchers uncovered changes to the expression of major histocompatibility class II-related genes and major histocompatibility class II transactivator activity in another dendritic cell subset, cDC1c⁺ DCs, which suggests that their ability to present antigens might be affected in severe disease.

In all, the researchers said that their analysis “provides the first detailed molecular map of [dendritic cell] subsets and underlying molecular pathways in COVID-19.”

The findings also hint at possible clinical applications. The researchers noted that molecular markers of defective subsets of antigen-presenting cells could potentially serve as prognostic or stratification biomarkers for patients. Additionally, innate adjuvants that target particular subsets of dendritic cells could potentially be used as personalized immunotherapies based on patients’ specific dendritic cell dysfunction. They further noted that dendritic cells are being considered in the development of preventative vaccines.

“Ultimately, our study may form the ground for novel therapies to restore defective [antigen-presenting cell] functions in patients with COVID-19,” they added.

In the same paper a commentary has been published.