Periodic Reporting for period 2 - HERVCOV (SARS-CoV-2-induced activation of pathogenic endogenous retrovirus envelope HERV-W: towards personalized treatment of COVID-19 patients)
Reporting period: 2024-01-01 to 2025-06-30
Severe COVID-19 disease and the high frequency of its long-term complications remain an important health problem worldwide. As a result of an acute symptomatic COVID-19 episode, more than 30% of adult patients develop different clinical symptoms at 1-2 months and 10-15% at 6-8 months after the initial SARS-CoV-2 infection. Due to the significant heterogeneity of COVID-19 disease profiles, panels of biomarkers that allow the identification of patients with high fidelity, define subgroups of patients, or indicate pathological processes underlying the symptoms particular to these patients are scarce. The HERVCOV project aims to study the role of human endogenous retroviruses (HERVs), known for their high pro-inflammatory potential, in the immunopathogenesis of acute COVID-19 and its long-term complication, Long COVID, and to identify and evaluate a set of biomarkers which will be important for the diagnosis and follow-up of patients and their prioritization for targeted therapy. HERVCOV focuses on the biological pathways and functions that underlie the association of HERV expression and activation with severe COVID-19 forms and Long COVID. Results obtained from the project should help understanding the pathogenic role of HERV-W envelope protein in COVID-19 and Long COVID disease and developing of biomarker panels that define subgroups and suggest the underlying pathological process.
The project started in summer 2022, putting together 8 partners with complementary experience from 5 European countries. This study produced first evidence for the induction of a specific protein during COVID-19 disease. Recent data from the consortium has demonstrated that HERV-W envelope protein is highly expressed in lymphocytes of COVID-19 patients and correlates with inflammatory markers and respiratory outcome of the disease, strongly suggesting the role of HERVs in COVID-19 pathogenesis. Plasma and/or sera of COVID-19 patients from different cohorts, infected with successive SARS-CoV-2 variants including the Omicron, had detectable HERV-W envelope (ENV), and peaked with the disease severity. HERV-W ENV was also found in post-mortem tissues of lungs, heart, gastrointestinal tract, brain olfactory bulb and nasal mucosa from COVID-19 patients. Regarding the transcriptomic activity of HERVs, diverse sequencing technologies have been tested and the most efficient approach was selected for the quantitation of HERVs and characterization of different isoforms. We then analyzed placenta samples from uneventful pregnancies and samples from COVID-19 positive women. We also investigated publicly available datasets of placentas from women with COVID-19, preeclampsia and healthy controls, as well as frontal cortex post-mortem samples of COVID-19 patients and controls, to further enrich our understanding of HERV transcription in multiple tissues. After the abatement of the acute COVID-19 pandemic, the HERVCOV project has started the analysis of patients who suffer from post COVID-19 more commonly known as Long COVID. The first results suggest the presence of HERV-W ENV in the serum and plasma of these patients and the study of different other biomarkers specific for this disease is currently ongoing. Subgroups of Long COVID patients have now been identified, including those defined by HERV-W ENV. The presence of specific subgroups also defined by immunological, inflammatory, cardiovascular and serological markers, has been determined within three different cohorts. The presence of these subgroups across cohorts is now being established, and the underlying mechanisms are being addressed. Currently, we also conduct a preliminary bioinformatic analysis on HERV expression in publicly available datasets from Long COVID cohorts aiming to detect main trends in the expression of HERVs in Long COVID, starting from samples of olfactory epithelium. Finaly, the new cell line model has been developed within the consortium and should allow further analysis of the molecular and cellular mechanism of the regulation of HERV-W envelope protein expression
Biomarkers based on SARS-CoV-2-specific immune responses, cytokine production and mandatory medical blood analyses for COVID-19 clinical monitoring have been studied in samples from different forms of acute and Long COVID patients. Parameters have been determined to allow biomarker-based diagnostics of Long COVID disease and allow potential clustering of different bio-clinical profiles of COVID patients. Ongoing inclusion of biomarkers based on HERV pathogenic protein activation may improve diagnostics and bio-clinical profiles, allowing for future stratification of patients based on the clinical course (or clinical profile) of the disease and the severity of SARS-CoV-2-induced symptoms. Additionally, regarding HERV expression in placenta samples, transcriptional downregulation of the HERV-W family and syncytin-1 have been detected, while the presence of SARS-CoV-2 in the placenta lead to the additional downregulation of HERV-K (HML-6), HERV-FRD, HERV-I and HERV-9. These results indicate potential adverse outcomes regarding successful placentation during SARS-CoV-2 infection. Finlay, HERVCOV web site has been developed (https://www.hervcovproject.eu/(opens in new window)) and frequently updated with all the information relevant to the project, allowing the regular dissemination of the project results.