COVID-19 Immunology: SARS-CoV-2 Modulates Dendritic Cell Maturation And Suppresses The Signaling Cascade Necessary For T Cell Activation!
: A new study led by researchers from University of Milano-Bicocca-Italy which included support from scientists from the National Institute of Molecular Genetics-Italy, Vita-Salute San Raffaele University-Italy, San Raffaele Hospital-Italy and the University of California, Los Angeles-USA has found that the SARS-CoV-2 coronavirus is able to modulate dendritic cell maturation and suppress the signaling cascade necessary for T cell activation.
According to the study abstract, “Emerging evidence suggests that conventional dendritic cells (cDCs) undergo aberrant maturation in COVID-19, and this adversely affects T cell activation. The study team found that cDC2 subtypes show similar infection-induced gene signatures with an increasing gradient of expression of interferon-stimulated genes from mild to severe patients and a down-regulation of major histocompatibility complex class II (MHC class II) molecules and some inflammatory cytokines compared to the baseline level of healthy donors. In vitro, the direct exposure of cDC2s to the virus recapitulates the type of activation observed in vivo. The study findings provide evidence that SARS-CoV-2 can directly interact with cDC2s and, by down-regulating crucial molecules required for T cell activation, implements an efficient immune escape mechanism.”
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.03.03.433597v1
The study team explored the maturation pattern of conventional dendritic cells (cDCs) during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections.
Their study findings reveal that the virus efficiently escapes host immune responses by directly interacting with cDCs and disrupting T cell activation.
To date since its emergence in December 2019 in China, SARS-CoV-2, the causative pathogen of coronavirus disease 2019 (COVID-19), has infected more than 117 million individuals and claimed almost 2.6 million lives globally.
So far in its milder form, COVID-19 is mainly associated with fever, dry cough, sore throat etc. However, a severe form of the disease often leads to serious health complications characterized by cardiovascular, pulmonary, and metabolic disorders. In general, COVID-19 patients with severe symptoms exhibit severe immune impairment characterized by aberrant production of proinflammatory mediators and alteration in dendritic cell populations in the peripheral blood.
The long terms effects of the disease known as long COVID is also just being studied and various medical conditions are seen to be emerging.
Typically in the context of any microbial infection, dendritic cells (DCs) are particularly important because of their significant involvement in T cell activation and antigen presentation. These cells directly sense pathogens and induce the production of proinflammatory mediators necessary for the initiation of adaptive immune responses.
Basically there are two subtypes of conventional DCs, namely cDC1 and cDC2. The cDC2 subtype is further divided into two subsets, namely DC2 and DC3.
s are specialized for antigen cross-presentation, cDC2s can induce a wide-range of immune responses by expressing different types of pattern recognition receptors (PRRs). There is evidence suggesting that SARS-CoV-2 infection causes a reduction in both the number and functionality of cDCs in the blood.
The study team explored the impact of SARS-CoV-2 infection on the maturation pattern of different cDC subtypes. The team has specifically analyzed the peripheral blood cDCs isolated from mild and severe COVID-19 patients and healthy individuals.
The study team observed a reduction in cDC subtypes (cDC1s, DC2s, and DC3s) in the peripheral blood of COVID-19 patients compared to that in healthy individuals.
Importantly, the findings revealed that although the total population of DC3s showed a decreasing trend, an increasing trend in the proportion of inflammatory DC3s was observed in COVID-19 patients.
In order to determine the transcriptional response of different cDC subtypes to SARS-CoV-2 infection, the study team thoroughly analyzed three different single-cell transcriptomics datasets. Their analysis revealed an upregulation of interferon-stimulated genes in all cDC subtypes isolated from COVID-19 patients.
The team also conducted a Principal Component Analysis using the single-cell dataset for an in-depth characterization of interferon-stimulated genes and inflammatory molecule-encoding genes in cDC subtypes.
The study findings revealed significantly increased and decreased expressions of interferon-stimulated genes in cDCs from severe and mild COVID-19 patients, respectively. In contrast, a progressive reduction in the expressions of inflammatory molecule-encoding genes was observed with disease severity.
Significantly these observations indicate an inverse correlation between the expression patterns of interferon-stimulated genes and inflammatory molecule-encoding genes. With further analysis, the scientists observed that type I interferon response stimulated by SARS-CoV-2 infection could equally affect the DC2 and DC3 subsets.
It was found that besides interferon signaling pathways, an induction in PI3K-AKT-mTOR signaling pathway and a reduction in expressions of genes encoding major histocompatibility complex (MHC) class II molecules were observed in COVID-19 patients.
In order to explore the mechanistic details of SARS-CoV-2-induced alteration in immune signatures of cDCs, the study team isolated cDC2s from healthy individuals and assessed their response to the virus. The findings revealed that SARS-CoV-2 significantly reduced the expression of MHC class II molecules and increased the expression of IL-6 in both DC2 and DC3 subsets.
Hence this indicates that the SARS-CoV-2 coronavirus directly modulates the maturation process of cDCs to escape host immune responses. With further analysis, the scientists identified a set of 52 genes that were differentially expressed in DC3s compared to DC2s in response to SARS-CoV-2. By conducting a separate set of experiments using transcriptomics data of patients with bacterial sepsis, they identified a set of 203 genes that were differentially expressed in DC3s in response to bacterial infection.
Just as important, these observations indicate that the prominent differences between DC2s and DC3s observed during bacterial infection are highly attenuated during SARS-CoV-2 infection. The similarity in responses of DC2s and DC3s in COVID-19 patients further indicates that a direct viral interaction rather than an exposure to infection-induced inflammatory mediators is responsible for the observed maturation patterns of these cells. Because of the variation in expressions of receptors like CD14 in DC2s and DC3, these two subsets could have responded differentially in response to exposure to inflammatory mediators.
In summary, the study findings reveal that SARS-CoV-2 directly interacts with conventional DCs and suppresses the signaling cascade necessary for T cell activation. Such modifications at the genetic and molecular level subsequently facilitate the SARS-CoV-2 virus to evade host immune responses.
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