Gene Expression Changes During Acute SARS-CoV-2 Infection May Decide Long-Term COVID Symptoms


A team of US-based scientists recently revealed changes in gene expression profiles associated with the long-term consequences of coronavirus disease 2019 (COVID-19). As observed in the study, the genetic signature of post-acute COVID-19 (long COV) can be detected in innate and adaptive immune cells already during the acute phase of severe acute respiratory syndrome coronavirus 2 infection ( SARS-CoV-2).

Study: Acute gene expression profiles of COVID-19 show multiple etiologies of long-term sequelae. Image Credit: Jom_Ariya / Shutterstock

A pre-printed version of the study is available on the website medRxiv* server while the article is subject to peer review.


The long-lasting clinical presentation of COVID-19, also known as COVID-19, is characterized by a wide range of symptoms that appear in 30% of COVID-19 patients after recovery. The most common symptoms of long-term COVID include general fatigue, headache, joint / muscle pain, difficulty breathing, trouble sleeping, and loss of smell or taste. Although long symptoms of COVID have been seen in 40% of hospitalized patients, some recent evidence has shown that people with asymptomatic or mildly symptomatic SARS-CoV-2 infections are more likely to develop long-term consequences.

Host immune responses to acute SARS-CoV-2 infection are associated with long-term consequences of COVID-19. In the current study, the scientists analyzed whole blood gene expressions and antibody levels in a large group of hospitalized COVID-19 patients who subsequently developed long COVID symptoms.

Characteristics of long-term COVID in the study population

The study was conducted on 495 hospitalized COVID-19 patients and 72 healthy and hospitalized controls. After six months of discharge, 251 patients were followed to examine the appearance of long symptoms of COVID.

Analysis of patient reports revealed two distinct clusters of post-COVID consequences related to pulmonary and neuropsychiatric symptoms. However, no significant correlation was observed between the severity of the disease and the onset of COVID along.

Gene expression profiles

Blood samples were taken from 180 of 251 patients followed for RNA sequencing. The analysis identified significant associations between a higher plasma cell level and a lower follicular helper T cell level with long-term COVID pneumonia and muscle pain.

Analysis of genes differentially expressed in whole blood did not reveal any significant association with symptoms. However, many symptom-related differential expression signatures have been observed in specific cell types. Specifically, plasma cells had the highest number of gene signatures related to various symptoms, including sleep disturbances, pulmonary complications, nausea / vomiting / diarrhea, rash, loss of smell or taste, and pneumonia. .

It is important to note that a complete downregulation of genes associated with pneumonia has been observed in patients. Among other cell types tested, significant associations of gamma-delta and CD8 + T cells, resting CD4 + T cells and CD4 + memory activated neutrophils and T cells with poorer quality of life, dental problems and memory problems were observed, respectively.

Shared models of differentially expressed genetic signatures

Two differential expression tests were performed to identify the group of genes that were differentially expressed in the two tests and were associated with the same symptoms (genes differentially expressed in the same direction). Likewise, a different group of genes was identified which exhibited differential expressions in the two tests but with opposite symptoms (genes expressed differently in the opposite direction).

In plasma cells, pairwise symptom comparison for the number of differentially expressed genes in the same direction identified two distinct symptom groups. These groups have been named “lung group” (lung problems and pneumonia) and “miscellaneous group” (sleep disturbances, nausea / vomiting / diarrhea, rash, and loss of smell or taste).

In the pulmonary cluster, downregulated expression of genes associated with antibody production and function has been observed. In contrast, upregulated expressions of the same genes were observed in the miscellaneous group.

Association between differentially expressed genes and antibody levels

A separate set of experiments was conducted to assess whether the host’s response to anti-spike antibodies can influence symptom-specific differential expression of genes in plasma cells.

The analysis revealed a significant correlation between the antibody response and the genes associated with most of the symptoms of various clusters, except rash and loss of smell / taste. In contrast, no such correlation was observed for genes associated with lung problems and pneumonia.

Importance of the study

Overall, the study results reveal that the host’s response to acute SARS-CoV-2 infection is directly associated with the onset of long symptoms of COVID. The study identifies two distinct sets of long COVID symptoms – one is primarily dependent on blood levels of anti-peak antibodies, and the other is independent of antibodies.

Additionally, the study highlights the importance of acute phase gene expression signatures in plasma cells to induce long symptoms of COVID.

*Important Notice

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

Journal reference:

  • Thompson, R. et al. (2021) “Acute COVID-19 gene expression profiles show multiple etiologies of long-term sequelae”. medRxiv. do I: 10.1101 / 2021.10.04.21264434.


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