The differential immune responses to COVID-19 in peripheral and lung revealed by single-cell RNA sequencing

Abstract

Understanding the mechanism that leads to immune dysfunction in severe coronavirus disease 2019 (COVID-19) is crucial for the development of effective treatment. Here, using single-cell RNA sequencing, we characterized the peripheral blood mononuclear cells (PBMCs) from uninfected controls and COVID-19 patients and cells in paired broncho-alveolar lavage fluid (BALF). We found a close association of decreased dendritic cells (DCs) and increased monocytes resembling myeloid-derived suppressor cells (MDSCs), which correlated with lymphopenia and inflammation in the blood of severe COVID-19 patients. Those MDSC-like monocytes were immune-paralyzed. In contrast, monocyte-macrophages in BALFs of COVID-19 patients produced massive amounts of cytokines and chemokines, but secreted little interferons. The frequencies of peripheral T cells and NK cells were significantly decreased in severe COVID-19 patients, especially for innate-like T and various CD8+ T cell subsets, compared to healthy controls. In contrast, the proportions of various activated CD4+ T cell subsets among the T cell compartment, including Th1, Th2, and Th17-like cells were increased and more clonally expanded in severe COVID-19 patients. Patients’ peripheral T cells showed no sign of exhaustion or augmented cell death, whereas T cells in BALFs produced higher levels of IFNG, TNF, CCL4, CCL5, etc. Paired TCR tracking indicated abundant recruitment of peripheral T cells to the severe patients’ lung. Together, this study comprehensively depicts how the immune cell landscape is perturbed in severe COVID-19.

Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning

“…Additionally, increased IFN-γ promotes myeloid cell activation which is observed in the augmented percentage of inflammatory CD14+CD16+ monocytes in the LH group compared to healthy donors, supporting lymphopenia and virus persistence in these patients. This is supported by recent findings describing an increased gene expression in response to IFN-γ in mild and severe COVID-19 patients in peripheral myeloid cells (19) and the dysregulation in the balance of monocyte populations by the expansion of the monocyte subsets described in COVID-19 patients (22). Finally, we propose that long-lasting pulmonary damage observed in LH, is caused by a combination of factors including 1) longer virus persistence influenced by LH immune profile characterized by high IFN-γ and IL-2 levels inducing Th1 polarization which is ineffective with low CCL4-induced T cell recruitment, leading to an inflammatory myeloid cell activation; and 2) the immunopathological pulmonary effects consequence of this LH immune profile.…”

“…CCL4 signals through the receptor CCR5 to attract T cells to the site of inflammation and depending on the immune context, this molecule recruits differently activated T cells (17,18). Moreover, it was recently shown by single cell analysis a down regulation of CCL4 expression in peripheral myeloid cell compartments in patients with mild and severe COVID-19 (19). In LH, IFN-γ and IL-2 would create an immune context to induce Th1 polarization, but the low levels of CCL4 affect the recruitment of these cells impairing the antiviral response.…”

Immune responses to SARS-CoV-2 infection in Humans and ACE2 humanized mice

“…Even in recovery stages, early or late, COVID-19 patients were reported to have more CD14 ++ IL-1β + and IFN-activated monocytes in their peripheral blood than healthy controls 20 . Intriguingly, a population of myeloid-derived suppressor cells (MDSCs)-like monocytes, which correlated with lymphopenia and inflammation in the blood of severe COVID-19 patients, were found to be immune-paralyzed 21 . Besides, a study on the combination of COVID-19 and type II diabetes (T2D) 22 revealed that a morphological anomaly of increased monocyte size and monocytopenia restricted to classical CD14 high CD16 - monocytes was specifically associated with severe COVID-19 in patients with T2D requiring intensive care.…”

A single-cell atlas of lymphocyte adaptive immune repertoires and transcriptomes reveals age-related differences in convalescent COVID-19 patients

“…It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted February 12, 2021. ; https://doi.org/10.1101/2021.02.12.430907 doi: bioRxiv preprint within an individual cell enables phenotypic analyses of a clonal population of lymphocytes and their dynamics [34][35][36] . scSeq of transcriptomes and immune repertoires in COVID-19 patients with severe symptoms has shown a high level of clonal expansion in specific T cell subsets (Th1, Th2, and Th17) and preferential germline gene usage in clonally expanded B cells 28,34,37 ; while a more recent study found a positive correlation between clonal expansion of effector-like CD8+ T cells and disease severity 38 .…”