Highly functional immune response in asymptomatic SARS-CoV-2 infection

Singapore researchers conducted a study showing that asymptomatic individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent that causes coronavirus disease 2019 (COVID-19) – trigger a response efficient, balanced and coordinated cellular immune system that protects the host without giving the impression of triggering pathological processes.

Compared to symptomatic disease, asymptomatic infection activated virus-specific T cells that produced higher levels of the cytokines interferon-γ (IFN-γ) and interleukin-2 (IL-2) and triggered a more proportional secretion of cytokines inflammatory and regulatory.

Clarence Tam of the National University of Singapore and colleagues suggest that the ability of asymptomatic individuals to induce proportionate secretion of the cytokine IL-10 may help reduce inflammatory events while clearing the virus.

A pre-printed version of the document is available on bioRxiv * server while the article is peer reviewed.

Characterization of adaptive immunity is essential

Characterization of the adaptive immune response following SARS-CoV-2 infection is essential to understand how it contributes to protective or pathological processes.

Antibodies specific to SARS-CoV-2 and T cells work together to reduce viral spread and eliminate the pathogen from infected cells. However, this protective immune response can also induce pathological processes such as inflammation and tissue damage following the lysis of infected cells or their release of inflammatory mediators.

Studies have shown that in severe cases of COVID-19, high levels of inflammatory cytokines and the presence of activated monocytes in the lung coexist with T cells and antibodies specific to the virus.

“Therefore, the question of whether virus-specific antibodies or T cells are preferentially mediating protection or damage remains open,” Tam and colleagues said.

Antibodies to a surface viral protein called spike, which SARS-CoV-2 uses to enter host cells, have been shown to exhibit protective activity in vitro, but titers of these antibodies have also been associated with disease severity in COVID-19 patients.

Studies in SARS-CoV-2 specific T cells have also shown an association between the frequencies of these cells and disease severity in COVID-19 patients.

Frequency of specific T cells for different SARS-CoV-2 proteins in asymptomatic donors with distinct serological profiles. The frequency of IFN-γ stain-forming cells (SFCs) reactive to individual peptide pools is shown for asymptomatic donors with distinct serological profiles (line = midline). IFN-γ-SFC ≥10 / 106 PBMC were considered positive (the gray area is below the limit of detection). The circles below represent the percentage of a positive (red) response to individual peptide pools.

Asymptomatic infection has been proposed to reduce antiviral adaptive immunity

Although infection is efficiently controlled in asymptomatic infection, asymptomatic individuals have been proposed to activate a reduced antiviral adaptive immune response.

Studies reported a lower magnitude of antibody and T-cell responses in asymptomatic than symptomatic individuals, which was interpreted as indicative of a normal innate immune response, but a weak adaptive immune response.

However, current knowledge about antiviral immunity in asymptomatic individuals is limited, Tam and the team say.

Researchers propose that asymptomatic individuals may be the key to understanding how the immune response controls SARS-CoV-2 infection without causing disease.

“SARS-CoV-2-specific T cells in individuals who clear SARS-CoV-2 infection without symptoms or disease could reveal non-pathological but protective features,” they write.

What did the researchers do?

The team compared the quantity and function of SARS-CoV-2-specific T cells between asymptomatic individuals and symptomatic COVID-19 patients.

Researchers quantified the secretion of a number of cytokines in whole blood following activation of SARS-CoV-2 peptide pooled T cells.

“This experimental system not only measures the amount of T lymphocyte cytokines (IL-2, IL-4, IFN-γ) secreted directly by SARS-CoV-2 specific T lymphocytes, but can provide a direct assessment of the lymphocyte capacity T to activate inflammatory or regulatory pathways in other circulating immune cells, “the team says.

What did they find?

The overall magnitude of T-cell responses against viral proteins during the early stages of recovery was similar between asymptomatic individuals and COVID-19 patients.

However, T cells induced by asymptomatic infection secreted higher amounts of IFN-γ and IL-2 than those induced by symptomatic infection.

Only in asymptomatic individuals, the team observed proportional and coordinated secretion of the pro-inflammatory cytokines IL-6, TNF-α and IL-1β and the anti-inflammatory cytokine IL-10.

By contrast, the secretion of inflammatory cytokines in symptomatic individuals was disproportionate, Tam and colleagues say.

“Our results provide experimental evidence that asymptomatic individuals mount a virus-specific T-cell response that is indistinguishable from symptomatic patients in amplitude but is functionally more suitable,” they write.

Asymptomatic SARS-CoV-2 infection is therefore not characterized by weak antiviral immunity; but rather a highly functional virus-specific cellular immune response, they add.

What are the implications of the study?

‘The ability to induce proportionate production of IL-10 could help reduce inflammatory events during viral clearance,’ the team suggests.

The researchers state that preclinical studies have already indicated that the simultaneous secretion of IFN-γ and IL-10 by T lymphocytes leads to effective viral control without inducing pathological processes.

They suggest that this may be the functional signature of virus-specific protective cellular immune responses in cases of asymptomatic SARS-CoV-2 infection.

“Detailed single-cell-level analysis of the functional profile of SARS-CoV-2 specific T cells in symptomatically and asymptomatically infected individuals will be required to formally demonstrate this hypothesis,” Tam and colleagues conclude.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice / health-related behaviors, or treated as consolidated information.