The glycan switch may explain why SARS-CoV-2 causes such variable symptoms

Researchers in Portugal have provided evidence that could explain why infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes mild or even asymptomatic disease in some, but severe coronavirus 2019 (COVID-19) in others.

Salome Pinho of the University of Porto and colleagues showed that circulating T cells show a specific “glycan switch” after SARS-CoV-2 infection and that this reversal is more pronounced in asymptomatic versus symptomatic individuals.

The researchers say that this change in the T cell glycosylation profile appears to have been caused by serum inflammatory factor, the identification of which could lead to a potential new biomarker and therapeutic goal.

The team also showed that circulating monocytes in asymptomatic patients show regulated expression of a protein called Dendritic Cell-Specific Intercell Adhesion Molecule-3-Grabbing Non-integrin (DC-SIGN).

Furthermore, higher levels of DC-SIGN expression in monocytes correlated with better patient prognosis.

“These new findings pave the way for the identification of a new glycan-based response in T cells that can provide protection against SARS-CoV-2 infection in asymptomatic patients, highlighting a new prognostic biomarker and potential therapeutic goal,” the team writes.

A pre-print version of the research paper is available at medRxiv* server, while the article is being reviewed.

SARS-CoV-2 infection has very variable effects on humans

The course of the disease after SARS-CoV-2 infection is highly variable and ranges from mild or even asymptomatic to severe disease characterized by pneumonia, acute respiratory distress syndrome, and multiple organ failure.

Although critical illness usually develops in the elderly, some relatively young and healthy individuals also develop severe COVID-19.

Pinho and colleagues say there is an urgent need for a better understanding of patient-specific immune responses to help identify prognostic biomarkers and therapeutic targets and to improve patient stratification for vaccination.

The peripheral T cell glycoprofile changes after SARS-CoV-2 infection at diagnosis.  Levels (medium intensity fluorescence, MFI) of (A) L-PHA lectin binding, detection of branched N-glycans β1,6-GlcNAc and (B) SNA lectins, detection of sialylation a-2,6, in CD8 +, CD4 + and γδ T cell subsets of uninfected donors (Non-IF;

The peripheral T cell glycoprofile changes after SARS-CoV-2 infection at diagnosis. Levels (medium intensity fluorescence, MFI) of (A) L-PHA lectin binding, detection of branched N-glycans β1,6-GlcNAc and (B) SNA lectins, detection of sialylation a-2,6, in CD8 +, CD4 + and γδ T cell subsets of uninfected donors (Non-IF; n = 5) and infected (IF; n = 30) patients. Binding levels of (A) L-PHA and (B) SNA lectins for each disease severity group: asymptomatic (Asympt .; N = 5), mild (n = 18), moderate (Mod.; N = 6) and recovered (Rec ; n = 2) Each point represents one patient. The Mann-Whitney t-test was performed to assess statistically significant differences between each pair of groups. * p-value <0.05, ** <0.005.

Where do glycans go?

Glycosylation refers to the controlled, enzymatic addition of glycans (carbohydrates) to proteins or lipids present on cells. Glycans are important regulators of immune cell function and determine the activation and differentiation of T cells.

Pinho and his team have previously shown that glycans modulate thresholds for T cell activation associated with immunopathogenesis in autoimmune diseases and cancer.

As is the case with most viruses, the SARS-CoV-2 viral envelope is highly glycosylated with structures such as oligomannose and branched N-glycans.

These structures are particularly recognized for glycan-binding proteins> such as DC-SIGN, which promote virus recognition and removal.

However, “the glycosylation profiles of immune cells in individuals infected with SARS-CoV-2 and how they affect their effector functions remain completely unknown,” the team says.

What did the current research involve?

Pinho and colleagues analyzed blood samples taken from 32 infected patients hospitalized between May 2020 and July 2020 and compared them with samples taken from healthy, uninfected controls.

The researchers showed that SARS-CoV-2 infection induced a change in the glycosylation profile of circulating T cells.

Specifically, T cells of infected individuals showed a reduction in branched structures of N-glycans (especially on CD8 + and γδ T cells), compared to T cells of uninfected individuals.

This specific “glycan switch” was more pronounced in the T cells of asymptomatic patients than in those symptomatic patients.

The results suggest that this glycan change was triggered by the appearance of serum inflammatory factor shortly after infection.

“It is necessary to identify the critical serological factor (s) that indicate the glycoprogramming of this T cell as a potential new biomarker and therapeutic target,” said Pinho and colleagues.

The study also showed that patients with a good prognosis showed regulated expression of DC-SIGN in circulating monocytes.

“This study reveals the identification of a specific T cell glycosignature, as well as a prognostic biomarker in COVID-19,” the team writes.

What are the implications of the study?

“We suggest here that the immune response against SARS-CoV-2 infection appears to be affected by the glycosylation profile of circulating T cells, which defines their effective functions,” the researchers write.

Pinho and colleagues say the findings pave the way for the identification of a specific glycosignature in the blood that could be used to stratify patients in the diagnosis according to the risk of worsening the disease.

“This will certainly contribute to improving the vaccination strategy and stratification of patient risk, optimizing the efficient allocation and management of health resources such as ventilators and intensive care facilities,” the team concludes.

* Important notice

medRxiv publishes preliminary scientific reports that have not been reviewed and, therefore, should not be considered definitive, guide clinical practice / behavior related to health, or be treated as established information.

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