Is non-severe SARS-CoV-2 infection characterized by early T cell proliferation?

The extent of severity of the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), varies from asymptomatic, mild to severe. Scientists found that during the first wave of the pandemic, individuals infected with non-severe SARS-CoV-2, before the onset of the vaccination program, induced effective host-defense mechanisms in naive populations.

To date, little evidence has been documented regarding the immune responses after the onset of the symptoms or virus detection. Further, no cross-sectional studies have been conducted that define the time of infection. Thereby, no report is available that explains the relationship between the earliest immune responses to COVID-19 and temporal kinetics. Scientists believe that understanding the early immune response regarding the asymptomatic or mildly infected population may help determine the factors associated with immune protection in naive populations. This may also provide perceptions about the variants that do not react to the developed vaccines. New research published on the medRxiv* preprint server deals with this research gap using blood transcriptomics, multiparameter flow cytometry, and T cell receptor (TCR) sequencing methods.

Study: Non-severe SARS-CoV-2 infection is characterised by very early T cell proliferation independent of type 1 interferon responses and distinct from other acute respiratory viruses. Image Credit: Kateryna Kon / Shutterstock

Scientists of the current study carried out weekly transcriptional profiling of the entire genome of the blood samples obtained from individuals before, during, and after SARS-CoV-2 infections. This experiment was conducted during the first epidemic wave in London, and the results were compared with the publicly available data on human experiments, which deals with the immune responses to other acute respiratory viruses. The researchers claim that the current research is the first report dealing with the in vivo immune responses to COVID-19 infection. They conducted a systematic serial sampling of individuals who were at risk of SARS-CoV-2 infection during the peak of the first epidemic wave in London.

Typically, after the onset of viral infection, the early host defense mechanism is governed by the induction of type 1 Interferons (IFNs). Previous studies have reported that in severe cases of the disease, a decrease in immune response occurred because (a) production of autoantibodies to type 1 IFNs, (b) genetic polymorphisms in regards to lowering of the expression of a type 1 IFN receptor subunit, and (c) genetic polymorphisms that decrease the expression of the IFN-inducible oligoadenylate synthetase (OAS) gene cluster. Thereby, in other words, type 1 IFN responses are extremely important in providing effective protection against SARS-CoV-2 infection.

The current research has shown that type 1 IFN may provide early protection to individuals against COVID-19. The presence of IFNs was detected, by the PCR method, before infection, independent of symptoms. This early detection of IFN-inducible genes in the blood transcriptome could be due to the emergence of localized immune responses at the site of infection, or as a result of leukocyte trafficking through lymphoid tissues.

An earlier study revealed the importance of using IFN-inducible transcripts in blood as a diagnostic biomarker for the detection of early viral infection. Additionally, early T cell proliferation response in the blood transcriptome showed the dominance of CD8 and CD4 to a lesser extent. This study was conducted using cell-type-specific transcriptional modules. These results were validated using flow cytometry which showed a significant increase in Ki67 positive CD8 T cells. Further, an increase in the T cell clones was found with the help of T Cell Receptor (TCR) sequencing.

The earlier modeling experiments using humans showed the presence of type 1 IFN responses in a range of acute respiratory viruses other than SARS-CoV-2. On the contrary, the current research reports a significant early T cell response to SARS-CoV-2. A comparative study based on data obtained from emerging databases of SARS-CoV-2 specific TCRs revealed increased T cell clones in SARS-CoV-2 reactive cells. These cells were already manifested in individuals before being infected with COVID-19.

Scientists have reported that every individual’s reaction to SARS-CoV-2 is different owing to differences in their immune response. For instance, in some cases, T cell reactivity has been reported 5-10 days after the onset of the symptoms; however, in other cases, the presence of cross-reactive T cells from previous seasonal coronavirus exposure has been observed. Additionally, this study hypothesized that B cell responses might lag and play a less important role in rapid viral clearance in asymptomatic and non-severely infected individuals.

One of the limitations of this study is that owing to the analysis of bulk RNA samples for transcriptional profiling and TCR sequencing, transcriptional heterogeneity at the cellular level was not determined. In the future, a comparison between the severe and non-severe COVID-19 must be conducted with a greater sample size. Scientists believe that even though mass vaccination is the strategy to contain the ongoing pandemic, determining the factors that govern natural immunity would play an important role in developing novel vaccines. Identifying the antigenic determinants of the earliest T cell responses in asymptomatic SARS-CoV-2 infection would help in the development of universal coronavirus vaccines.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Chandran, Aneesh et al. (2021) Non-severe SARS-CoV-2 infection is characterised by very early T cell proliferation independent of type 1 interferon responses and distinct from other acute respiratory viruses. medRxiv. doi:,

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Tags: Autoantibodies, Biomarker, Blood, CD4, Cell, Cell Proliferation, Coronavirus, Coronavirus Disease COVID-19, Cytometry, Diagnostic, Flow Cytometry, Gene, Genes, Genetic, Genome, Immune Response, in vivo, Leukocyte, Pandemic, Proliferation, Receptor, Research, Respiratory, RNA, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Transcriptomics, Virus

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Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.

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