Blood biomarkers-defined subgroups show heterogeneity in post-acute COVID-19 syndrome: a rationale for precision medicine. (preprint)

Acute COVID-19 can cause a post-infectious syndrome in a significant percentage of patients, with multifacted and long lasting symptoms. We hypothesized that this Post-Acute COVID syndrome (PASC) could result from various underlying causes, which may compromise the demonstration of efficacy for treatments evaluated on cohorts of heterogeneous patients. To assess the feasibility of stratifying or characterizing subgroups of post-COVID-19 patients consistent with different indications in a precision medicine perspective, we tested serum biomarkers in a pilot cross-sectional study of patients with neuro-cognitive symptoms from the Northwestern University post-COVID-19 clinic (Chicago,USA). Patient health status was evaluated with the use of standardized PROMIS questionnaires and underwent validated cognitive tests with the NIH Toolbox. Serum biomarkers were chosen as proteins known to be involved in the pathogenic features of a neuro-inflammatory disease, i.e., multiple sclerosis, with a final selection of the most discriminant ones. A multi-isotypes serology against SARS-CoV-2 spike and nucleocapsid antigens was performed to allow detailed analyses of the humoral immune status. Despite the limited numbers of this feasibility study, results showed that clinical data could not differentiate PASC patients with persisting neuro-cognitive impairment, while three major PASC subgroups were identified with serum biomarkers according to the presence or absence of the HERV-W ENV soluble protein combined with neurofilaments light chains and, to a lesser extent, with elevated levels of IL-6. SARS-CoV-2 serological results in PASC compared to healthy controls also revealed a significant increase of anti-Spike and/or Nucleocapsid IgM, IgA and, unexpectedly, IgE. For IgG, a significant difference was observed with Nucleocapsid only since anti-Spike IgG titers were normally elevated in vaccinated controls. This multi-Ig isotypes serology may provide additional information on the infectious and immunological status of individual patients and should be considered in face of a potential viral persistence in some individuals. Altogether the results show the feasibility of using serum biomarkers to discriminate relevant subgroups or individual patients for precision medicine indications in post-COVID syndromes. This pilot study paves the way to further exploring biological assays for the definition of subtypes of PASC, also called long COVID, useful for the choice of relevant therapeutic strategies.

SARS-CoV-2 induces transcription of human endogenous retrovirus RNA followed by type W envelope protein expression in human lymphoid cells. (preprint)

Patients with COVID-19 may develop abnormal inflammatory response and lymphopenia, followed in some cases by delayed-onset syndromes, often long-lasting after resolution of the initial SARS-CoV-2 infection. As viral infections may activate human endogenous retroviral elements (HERV), we studied the effect of SARS-CoV-2 on HERV-W and HERV-K envelope (ENV) expression, known to be involved in immunological and neurological pathogenesis of human diseases. We demonstrate here that an initial exposure to SARS-CoV-2 virus activates early HERV-W and K transcription in peripheral blood mononuclear cell (PBMC) cultures from healthy donors. Within a week of primary PBMC culture, only HERV-W ENV protein expression was detected in lymphoid cells of some donors, although SARS-CoV-2 infection of PBMC was not observed. HERV activation was reproduced with UV-inactivated virus and with a recombinant spike protein. Interestingly, exposure to SARS-CoV-2 protein induced a significant production of interleukin 6 in PBMC, independently from detectable HERV expression. Altogether, these results show that SARS-CoV-2 viral protein could induce HERV-W ENV expression in lymphocytes from some individuals, underlying the importance to further address the implicated molecular pathways, to understand patients‘ genetic susceptibility associated to the activation of HERV-W and its possible relevance for targeting therapeutic intervention in COVID-19 associated syndromes.

First Evidence of Pathogenic HERV-W Envelope Expression in T Lymphocytes in Association with the Respiratory Outcome of COVID-19 Patients (preprint)

Background: Despite an impressive effort in clinical research, no standard therapeutic approach for coronavirus disease 2019 (COVID-19) patients has been established, highlighting the need to identify early biomarkers for predicting disease progression and new therapeutic intervention for patient management. The present study aimed to evaluate the involvement of the human endogenous retrovirus -W envelope (HERV-W ENV) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection considering recent findings that HERVs are activated in response to infectious agents and lead to various immunopathological effects. We analysed HERV-W ENV expression in blood cells of COVID-19 patients in correlation with clinical characteristics and have discussed its potential role in the outcome of the disease.Methods: We analysed HERV-W ENV expression in blood samples of Covid-19 patients and healthy donors by flow cytometry and quantitative reverse transcriptase PCR analysis, and evaluated its correlation with clinical signs, inflammatory markers, cytokine expression, and disease progression.Findings: HERV-W ENV was highly expressed in the leukocytes of COVID-19 patients but not in those of healthy donors. Its expression correlated with the markers of T-cell differentiation and exhaustion and blood cytokine levels. The percentage of HERV-W ENV-positive lymphocytes correlated with inflammatory markers and pneumonia severity in COVID-19 patients. Notably, HERV-W ENV expression reflects the respiratory outcome of patients during hospitalization.Interpretation: Given the known immuno- and neuro-pathogenicity of HERV-W ENV protein, it could promote certain pathogenic features of COVID-19 and therefore serve as a biomarker to predict clinical progression of disease and as a potential therapeutic target.Funding: Genero InnovationDeclaration of Interests: C.M. reports grant from Gilead, outside the submitted work; L.S. reports personal fees and other from Merck, Gilead, and Abbvie, grants from Gilead, outside the submitted work; HP and BC receive compensation for their work by Geneuro-Innovation. The other authors declare no competing interests.Ethics Approval Statement: Ethical approval for the collection and use of human samples was obtained from the ethical board of the Hospital, COronaVIrus Disease: Safety and Efficacy of Experimental Treatment (COVID_SEET prot.7562/2020, 9th April 2020, experimental register 46.20).