Study Shows SARS-CoV-2 Reduces The Numbers And Functional Competence Of Dendritic Cells In Circulation And Affect Responses To Secondary Infections
: A new study by German researchers from the Ludwig Maximilian University of Munich (LMU), University of Bonn and the Technical University of Munich has found that SARS-CoV-2 reduces the numbers and functional competence of certain types of immune cells in the blood, ie dendritic cells and affect responses to secondary infections.
The study team analyzed circulating dendritic cells (DC) and monocyte subsets in 65 hospitalized COVID-19 patients with mild/moderate or severe disease from acute illness to recovery and in healthy controls. Persisting reduction of all dendritic cells (DC) subpopulations was accompanied by an expansion of proliferating Lineage−HLADR+ cells lacking dendritic cells (DC) markers. Increased frequency of CD163+ CD14+ cells within the recently discovered DC3 subpopulation in patients with more severe disease was associated with systemic inflammation, activated T follicular helper cells, and antibody-secreting cells. Persistent downregulation of CD86 and upregulation of programmed death-ligand 1 (PD-L1) in conventional DCs (cDC2 and DC3) and classical monocytes associated with a reduced capacity to stimulate naïve CD4+ T cells correlated with disease severity.
It should be noted that long-lasting depletion and functional impairment of dendritic cells (DCs) and monocytes may have consequences for susceptibility to secondary infections and therapy of COVID-19 patients.
The study findings were published in the peer reviewed journal: PLOS Pathogens. https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009742
To date, it has been found that the SARS-CoV-2 coronavirus causes moderate to severe disease in 3-10% of those infected. In such cases, the immune system overreacts to the virus, triggering an aberrant innate immune response that is characterized by systemic inflammation, intravascular blood clotting and damage to the cardiovascular system.
study team led by immunology professor Dr Anne Krug at LMU's Biomedical Center (BMC), which included many scientists and researchers based at the BMC and the LMU Medical Center, had carried out a comprehensive study of this phenomenon, and uncovered hitherto unknown effects of the virus on the immune system.
The study team report that, following infection with SARS-CoV-2, the numbers of immune cells called dendritic cells in the circulation decline, while the functionality of the remaining fraction is impaired.
The study team believe that this could make patients more susceptible to secondary infections during, and immediately after recovery from a bout of COVID-19.
The dendritic cells (DCs) are responsible for initiating immune responses against invasive pathogens. They do so by activating helper T cells, which in turn stimulate B cells to secrete antibodies directed against the invader. Krug and her colleagues set out to determine the effects of moderate to severe coronavirus infection on this process.
The study team analyzed blood samples obtained from 65 COVID-19 patients who had been treated at the LMU Medical Center. The team found that there were fewer DCs in these samples than in the blood of healthy controls.
Alarmingly, DCs isol
ated from the blood of patients showed a reduced ability to activate T cells.
Dr Krug told Thailand Medical
News, "We had actually expected that DCs isolated from patients infected with SARS-CoV-2 would activate T cells more potently than DCs obtained from healthy donors. However, we discovered that, in the course of the disease, the proteins present on the surface of the DCs in patients' blood were altered in a way that made them more likely to inhibit T cell responses."
She further added, “ In spite of this, by 15 days after diagnosis 90% of these patients had generated antibodies directed against the SARS-CoV-2 spike protein, and many of them had also activated a T cell response. These responses are the hallmarks of a robust immune reaction against the virus.
So, the drop in the numbers and reduced functionality of DCs does not seem to have a negative impact on the immune response to the coronavirus itself."
But the study team is convinced that the reduced number and altered function of DCs is significant. It is conceivable that this might cause the immune system to react less strongly than expected to bacterial or other viral infections following recovery from COVID-19, but this possibility will require further clinical investigation.
Dr Krug has several hypotheses to offer as to what might account for the depletion of DCs in the blood and the decrease in their capacity to stimulate T cells ie it could in fact represent an appropriate regulatory process, she suggests. COVID-19 is often associated with vigorous inflammation reactions – so the phenomenon might be part of an attempt to downregulate inflammatory processes. Dendritic cells might migrate from the blood into inflamed tissues, such as the lung, which could explain the fall in the numbers of DCs in the circulation.
She added, "However, we also found that the regeneration of dendritic cells is delayed.”
The study team believes that this phenomenon could weaken the ability of patients to mount effective immune responses to other pathogens during, and in the immediate aftermath of a symptomatic COVID-19 infection. The study team will now explore this issue further in an effort to determine whether the effects of SARS-CoV-2 on DCs play a role in long-term COVID.
In summary the study team concluded, “Dendritic cells (DCs) recognize viral infections and trigger innate and adaptive antiviral immunity. COVID-19 severity is greatly influenced by the host immune response and modulation of DC generation and function after SARS-CoV-2 infection could play an important role in this disease. This study identifies a long-lasting reduction of DCs in the blood of COVID-19 patients and a functional impairment of these cells. Downregulation of costimulatory molecule CD86 and upregulation of inhibitory molecule PD-L1 in conventional DCs correlated with disease severity and were accompanied by a reduced ability to stimulate T cells. A higher frequency of CD163+ CD14+ cells in the DC3 subpopulation correlated with systemic inflammation suggesting that these cells may play a role in inflammatory responses of COVID-19 patients. Depletion and functional impairment of DCs beyond the acute phase of the disease may have consequences for susceptibility to secondary infections and clinical management of COVID-19 patients.”
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