Sex-specific differences in the gene transcriptomics of peripheral blood cells are observed in vaccinated patients with post-COVID syndrome

The infection with severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) can lead to a new disease called long COVID or post-acute COVID-19 syndrome. This syndrome can occur in various populations, including children and young adults and those who had only mild COVID-19. Though they are still up for debate, the pathophysiological mechanisms of post-COVID syndrome are thought to involve autoimmune reactions, continuous inflammation, or immunological responses to the persistent SARS-CoV-2 infection. In this study, the Finnish authors investigated the gene transcriptomics of peripheral blood cells in vaccinated patients with post-COVID syndrome and particular gene signatures in various clinical groups. 

Transcriptomics (sometimes referred to as gene expression profiling) is the quantitative study of all genes expressed in a given biological state. Transcriptomics is commonly applied to compare gene expression in diseased and non-diseased tissues to provide a catalogue of genes that show altered expression in disease. These data can be utilized to identify individual genes that show large changes in disease or to create a global profile or “signature” comprised of multiple expression changes associated with disease. Such findings advance the understanding of disease pathogenesis and reveal transcripts that can be quantitatively assessed as new biomarkers. (Pedrotty DM et al. Transcriptomic Biomarkers of Cardiovascular Disease. Prog Cardiovasc Dis. 2012 Jul-Aug;55(1):64–69.)

According to the authors of this study, some earlier research showed that individuals with post-COVID syndrome may have impaired erythrocyte function. A previous study that utilized real-time deformability cytometry (RT-DC) to investigate the morphological and mechanical characteristics of RBCs in children and adolescents infected with SARS-CoV-2 or vaccinated against COVID-19 showed increased deformation of red blood cells (RBCs). The researchers discussed possible mechanisms that caused a loss of membrane integrity and increased deformation of RBCs, such as the fragmentation of the membrane-bound protein band-3 that coordinates the shape of RBCs, deposition of immune complexes on the membrane of RBCs, mechanical damage of RBCs through capillary shear stress, the release of NO from endothelial cells, and physiological compensatory mechanisms that prevent microthrombosis and hypoxemia during the infection.  https://discovermednews.com/increased-median-deformation-of-red-blood-cells-in-children-and-adolescents-following-sars-cov-2-infection-vaccination/

 

 

 

About the study

The study included cases with post-COVID syndrome and previously laboratory-confirmed SARS-CoV-2 infection (positive nucleic acid amplification test). All participants were between 18 and 65 years old. They received at least two COVID vaccines, either the Comirnaty mRNA vaccine (Pfizer) or the Vaxzevria adenoviral vector (Oxford–AstraZeneca). The study also included people who had recovered after a COVID-19 infection and healthy controls who were not infected with SARS-CoV-2. Among these recovered and control volunteers, persons with diseases that markedly affect the immune system were excluded.

The authors defined post-COVID syndrome as the continuation or development of new symptoms three months after the initial SARS-CoV-2 infection, lasting for at least two months and for which no other explanation exists. All patients with post-COVID syndrome completed questionnaires on lifestyle factors and quality of life. Physical function testing included assessments of dominant hand grip strength (HGST) in kilograms using a Jamar/Saehan dynamometer and a 6-minute walking test (6MWT) in meters. All participants provided blood samples.

 

Results

111 post-COVID patients from the SARS-CoV-2 Omicron variant era (54 patients with post-COVID syndrome and 57 who had recovered after COVID-19 infection) and 63 healthy controls were included in the study. They were recruited approximately 11-12 months after their positive SARS-CoV-2 nucleic acid amplification test. None of the patients with post-COVID syndrome were hospitalized during the acute COVID-19 infection.

Compared to recovered COVID-19 patients or controls, patients with post-COVID syndrome more often had comorbidities, like nervous system disorders, circulatory disorders, respiratory disorders, and musculoskeletal diseases. Asthma was more common among the patients with post-COVID syndrome than among the other groups.

The patients with post-COVID syndrome had significantly reduced functional capacity (self-reported), lower quality of life, and lower 6MWT distance.

 

Laboratory findings

33% of patients who recovered after COVID-19 infection and 21% of healthy controls had antibodies against the SARS-CoV-2 nucleocapsid protein, indicating that at least one-fifth of the control group also had asymptomatic COVID-19. The control group had lower antibody concentrations to nucleocapsid and spike-1 proteins compared to recovered COVID-19 patients or patients with post-COVID syndrome.

Only small differences were found in the transcriptome of peripheral blood mononuclear cells between patients with post-COVID syndrome, those who had recovered after COVID-19, and healthy controls, with only 3–6 differentially expressed genes (DEGs) identified in all comparisons. Despite the low number of DEGs, further analysis revealed changes in immune-related signaling pathways in patients with post-COVID syndrome. Compared to healthy controls, both patients with post-COVID syndrome and recovered COVID-19 patients showed significant changes in the expression of variable immunoglobulin light or heavy chain genes (IGKV2D-29 and IGHV1-2), which play a role in the antigen-binding activity of antibodies and B cell receptors. Further analysis revealed significant differences in some other immunoglobulin genes (IGHV3-53, IGKV6-21, and IGLV2-18) between women with post-COVID syndrome, women who had recovered from COVID-19, and control women.

The gene expression in men with post-COVID syndrome differed from that of men from the other two groups, with 399 DEGs compared to men who had recovered after COVID-19 and control men. These DEGs showed high enrichment in genes related to RBC development and differentiation and heme metabolism. According to the authors, high enrichment of genes related to RBC development and differentiation and heme metabolism observed in a subgroup of men with post-COVID syndrome may indicate a compensatory mechanism to overcome the effects of low iron concentration or dysfunctional erythroblasts.

 

Conclusion

This cross-sectional study of peripheral blood cell gene transcriptomics found that past COVID-19 disease or current post-COVID syndrome caused minor changes compared to each other or the controls. However, distinct changes in RBCs-related transcriptomic observed in a subset of men with post-COVID syndrome indicate a condition-specific effect rather than incidental findings. In addition, the results showed significant differences in some immunoglobulin genes (IGHV3-53, IGKV6-21, and IGLV2-18) between women with post-COVID syndrome, women who had recovered from COVID-19, and control women. According to the authors, these results could indicate possible sex-specific differences in the pathophysiology of post-COVID syndrome.

The authors concluded that due to the small sample size in men, further studies with larger cohorts of men and mechanistic studies focusing on RBCs are needed to validate these results.

 

Journal Reference

Patients with post-COVID-19 condition show minor blood transcriptomic changes, with altered erythrocyte gene expression in a male subgroup. Front. Immunol; 21 March 2025; Volume 16.  https://doi.org/10.3389/fimmu.2025.1500997