SARS-CoV-2 infection induces polyfunctional antibodies

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Drawing on epidemiological field studies and the FrenchCOVID hospital cohort coordinated by Inserm, teams from the Institut Pasteur, the CNRS and the Vaccine Research Institute (VRI, Inserm/University Paris-Est Créteil) studied the antibodies induced in individuals with asymptomatic or symptomatic SARS-CoV-2 infection.

The scientists demonstrated that infection induces polyfunctional antibodies. Beyond neutralization, these antibodies can activate NK (natural killer) cells or the complement system, leading to the destruction of infected cells.

Antibody levels are slightly lower in asymptomatic as opposed to symptomatic individuals, but polyfunctional antibodies were found in all individuals. These findings show that infection induces antibodies capable of killing infected cells regardless of the severity of the disease. The research was published in the journal Cell Reports Medicine on April 21, 2021.

Nearly half of those infected with SARS-CoV-2 do not develop symptoms. Yet, the immune response induced by asymptomatic forms of COVID-19 remains poorly characterized.

The extent of the antiviral functions of SARS-CoV-2 antibodies is also poorly characterized. Antibodies are capable of both neutralizing the virus and activating “non-neutralizing” functions. The latter include antibody-dependent cellular cytotoxicity (ADCC) and complement activation, which are major components of the immune response and play a key role in the efficacy of some vaccines.

ADCC is a two-stage process in which infected cells are first recognized by antibodies, then destroyed by NK cells. The complement system consists of a series of plasma proteins that also enable the elimination of cells targeted by antibodies. The ability of antibodies to activate these non-neutralizing functions has been little described for SARS-CoV-2 infection so far.

The teams from the Institut Pasteur, the CNRS and the VRI (Inserm/University Paris-Est Créteil) initially developed new assays to measure the various antibody functions. They produced assays to study cell death induced by NK cells or by complement in the presence of antibodies.

By analyzing cultures in real time using video microscopy, the scientists showed that NK cells kill infected cells in the presence of antibodies, demonstrating new antiviral activity employed by SARS-CoV-2 antibodies.

The scientists then examined the serum of patients with symptomatic or asymptomatic forms of COVID-19 with their new assays. They also used methods previously developed at the Institut Pasteur, such as the S-Flow assay, to detect SARS-CoV-2 anti-spike antibodies, and the S-Fuse assay, to measure the neutralization capacity of these antibodies.

“This study demonstrated that individuals infected with SARS-CoV-2 have antibodies that are capable of attacking the virus in different ways, by preventing it from entering cells (neutralization) or by activating NK cells to kill infected cells (via ADCC).

We therefore use the term polyfunctional antibodies,” explains Timothée Bruel, co-last author of the study and a scientist in the Institut Pasteur’s Virus & Immunity Unit and at the VRI.

By comparing different groups of patients, the scientists then showed that asymptomatic individuals also have polyfunctional antibodies and that their response is slightly weaker than those of patients with moderate forms of COVID-19.

The study reveals new mechanisms of action of SARS-CoV-2 antibodies and suggests that the protection induced by an asymptomatic infection is very close to that observed after a symptomatic infection,” concludes Olivier Schwartz, co-last author of the study, head of the Virus & Immunity Unit and at the VRI.


The new strain of the large betacoronavirus family (severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2) that is spreading as a global pathogen causing coronavirus-19 disease (COVID-19) [1, 2]] has caused an ongoing global pandemic with over 23 million infections (Worldometers [http://www.worldometers.info] The Real Time Statistics Project) [3].

SARS-CoV-2 is the seventh known strain of enveloped positive-strand RNA coronaviruses, which causes a range of diseases in humans [4], ranging from asymptomatic or mild non-respiratory disease in 80–90% of cases [5–7] to a severe disease requiring hospitalization and intensive oxygen support in 10–20% of cases.

The severity and mortality of COVID-19 is increased by age and by many comorbidities, including diabetes, obesity, and cardiovascular and pulmonary disease [8, 9]. It is, however, still largely unclear whether or to what extent disease severity is associated with virus replication and with derangements in the host response. There is an urgent need to focus on the immune dysregulation underlying early COVID-19 [10].

NK cells help clear virus-infected cells through multiple mechanisms, including direct contact, cytokine or chemokine secretion, and indirectly influencing lateral and downstream adaptive immune responses via their crosstalk with dendritic cells and T cells [11–13].

They are markedly activated during ongoing viral infection [14, 15] and contribute to viral control [16, 17], for example by memory-like responses [12], both directly and by regulating dendritic cell maturation and adaptive responses [11, 12]. Their derangement may thus be deranging not only direct virus control, but also the efficient organization of downstream T and B cell adaptive responses.

Profiling of innate immune responses to SARS-CoV-2 so has far shown that during COVID-19, there is a significant decrease in total peripheral blood lymphocytes of T and natural killer cells, which is associated with disease severity [18, 19]. The features of immune response dysregulation include unusually high cytokine plasma concentrations (TNFa, IL-6, IL-8, IL-10) and decreased T regulatory cells, with apparently unchanged T cell and NK production of IFN-gamma [20].

More recently, multiple derangements have been reported in COVID-19 patients, including T cell activation and oligoclonal plasmablast expansion with some Fc receptor dysregulation in innate cells (NK cells, monocytes) [21].

None of the immune parameters studied, however, correlate with disease trajectories beyond neutrophil to lymphocyte ratio [21]. Additional antiviral dysregulation has also been associated with increased expression of the inhibitory HLA-E-specific NKG2A+ receptor on T cells and NK cells that may decrease their antiviral function [22].

Overall, there has been limited research on the extent and type of NK cell derangement during SARS-CoV-2 infection, particularly with regard to the expression of the full array of the cells’ activating receptors (e.g., natural cytotoxicity receptors, NKG2D, DNAM-1, etc.), inhibitory receptors (e.g., NKG2A/CD94, CD85j, killer immunoglobulin-like receptors, KIRs), and circulating subsets, including CD56dimCD16+ effectors, less developmentally advanced CD56brightCD16+/- regulatory NK cells [23, 24], and CD56-CD16+ “exhausted” NK cells with dysfunctional properties [25, 26].

In addition, although decreases in peripheral NK cells are consistently associated with severe SARS-CoV-2 infection [19, 22], it is unclear whether this is due to NK cell trafficking to infected tissues, to cell leakage from involved tissues, or to cell death and turnover. It is also unclear whether or to what extent increased inhibitory signaling may favor virus replication and pathology.

In order to contribute to the ongoing work on innate immune landscape profiling, and to support immune intervention strategies, we have performed an in-depth analysis of NK cells, focusing on their peripheral distribution, function, trafficking, and turnover in hospitalized COVID-19 patients with different disease trajectories.

The results indicate that an intense derangement of NK cell trafficking, activation, function, and turnover occurs early on, and is associated with the subsequent disease trajectory in hospitalized patients.

reference link: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009448


More information: Jérémy Dufloo et al, Asymptomatic and symptomatic SARS-CoV-2 infections elicit polyfunctional antibodies., Cell Reports Medicine (2021). DOI: 10.1016/j.xcrm.2021.100275

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