Immune Response in Severe and Non-Severe Coronavirus Disease 2019 (COVID-19) Infection: A Mechanistic Landscape

Abstract

The mechanisms underlying the immune remodeling and severity response in coronavirus disease 2019 (COVID-19) are yet to be fully elucidated. Our comprehensive integrative analyses of single-cell RNA sequencing (scRNAseq) data from four published studies, in patients with mild/moderate and severe infections, indicate a robust expansion and mobilization of the innate immune response and highlight mechanisms by which low-density neutrophils and megakaryocytes play a crucial role in the cross talk between lymphoid and myeloid lineages. We also document a marked reduction of several lymphoid cell types, particularly natural killer cells, mucosal-associated invariant T (MAIT) cells, and gamma-delta T (γδT) cells, and a robust expansion and extensive heterogeneity within plasmablasts, especially in severe COVID-19 patients. We confirm the changes in cellular abundances for certain immune cell types within a new patient cohort. While the cellular heterogeneity in COVID-19 extends across cells in both lineages, we consistently observe certain subsets respond more potently to interferon type I (IFN-I) and display increased cellular abundances across the spectrum of severity, as compared with healthy subjects. However, we identify these expanded subsets to have a more muted response to IFN-I within severe disease compared to non-severe disease. Our analyses further highlight an increased aggregation potential of the myeloid subsets, particularly monocytes, in COVID-19. Finally, we provide detailed mechanistic insights into the interaction between lymphoid and myeloid lineages, which contributes to the multisystemic phenotype of COVID-19, distinguishing severe from non-severe responses.

Differential Functional Responses of Neutrophil Subsets in Severe COVID-19 Patients

“…Those LDN are present in BALF, as well as in the circulation ( 16 , 22 ). An altered functional status of those neutrophil clusters is inferred from their gene and protein signatures, leading to the hypothesis that dysregulated neutrophil host defense mechanisms and adaptive immune system suppression are major contributors to progression to severe COVID-19 ( 25 , 26 , 45 , 54 ). To characterize the dysregulated neutrophil functional responses associated with COVID-19 ARDS, the present study evaluated host defense functions and suppression of T cell activation of NDN and two populations of LDN from COVID-19 patients.…”

“…Patients with severe COVID-19 exhibit marked alterations in innate and adaptive immunity, including changes in neutrophil abundance, phenotype, and function ( 22 – 26 ). Neutrophil characterization by transcriptional and proteomic analysis in COVID-19 indicates significant heterogeneity among mature neutrophils and emergence of a large number of low density neutrophils (LDN) with multiple phenotypes ( 16 , 24 , 25 , 27 – 30 ).…”

“…Neutrophil characterization by transcriptional and proteomic analysis in COVID-19 indicates significant heterogeneity among mature neutrophils and emergence of a large number of low density neutrophils (LDN) with multiple phenotypes ( 16 , 24 , 25 , 27 – 30 ). The functional capability of these various neutrophil populations has been inferred from gene or protein expression profiles ( 22 – 26 ), however, previous direct functional studies either did not evaluate the various neutrophil populations or disparate results were reported ( 12 – 15 , 24 , 28 – 37 ). Thus, the functional heterogeneity among the various neutrophil populations remains to be defined.…”

The function of myeloid-derived suppressor cells in COVID-19 lymphopenia

“…MDSC-derived reactive oxygen species (ROS) and its downstream product peroxynitrate nitrate at the T-cell receptor [63] . Thus, T cells lose their capacity to attach to the phosphorylated major histocompatibility complex and are not able to react to particular antigens, leading to antigen-specific T-cell tolerance [64] .…”

Neutrophil Extracellular Traps in Severe SARS-CoV-2 Infection: A Possible Impact of LPS and (1→3)-β-D-glucan in Blood from Gut Translocation

“…Different from most respiratory viral infections, where the viral entry is limited only to specific cells in the oral–nasopharyngeal–respiratory epithelium, SARS-CoV-2 also infects several other organs (lung, stomach, small intestine, colon, skin, lymph node, thymus, bone marrow, spleen, liver, kidney, and brain) through angiotensin-converting enzyme 2 (ACE2) receptor [ 2 ]. Perhaps, the capability of COVID-19 in widespread infection into several cell types, including the immune cells, might—at least in part—result in the profound cytokine in the systemic circulation (cytokine storm) from cytokine production of different cell types in the host [ 3 ]. Additionally, COVID-19 not only induces cytokine storm but also causes neutrophilia [ 4 ], leading to the use of immunosuppressive treatment [ 5 ] that is not common in other viral infections [ 6 ].…”