Background: Inflammation and autoimmune responses contribute to the pathophysiology of Long COVID and its affective and chronic fatigue syndrome (CFS) symptoms labeled the physio-affective phenome. Objectives: To investigate whether Long COVID and its physio-affective phenome are linked to autoimmunity to the tight junction proteins zonulin and occludin (ZOOC) and immune reactivity to lipopolysaccharides (LPS) and whether the latter are associated with signs of human herpes virus-6 reactivation (HHV-6) autoimmunity directed against oligodendrocyte and neuronal proteins including myelin basic protein (MBP). Methods: IgA/IgM/IgG responses to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) HHV-6, ZOOC and neuronal proteins C-reactive protein (CRP) and advanced oxidation protein products (AOPP) were measured in 90 Long COVID patients and 90 healthy controls. The physio-affective phenome was conceptualized as a factor extracted from physical and affective symptom domains. Results: Neural network identified IgA directed to LPS (IgA-LPS) IgG-ZOOC IgG-LPS and IgA-ZOOC as the most important variables associated with Long COVID diagnosis with an area under the ROC curve of 0.755. Partial Least Squares analysis showed that 40.9% of the variance in the physio-affective phenome was explained by CRP, IgA-MPB and IgG-MBP. A large part of the variances in both autoimmune responses to MBP (36.3-39.7%) was explained by autoimmunity (IgA and IgG) directed to ZOOC. The latter was strongly associated with indicants of HHV-6 reactivation which in turn was associated with increased IgM-SARS-CoV-2. Conclusions: Autoimmunity against components of the tight junctions and increased bacterial translocation may be involved in the pathophysiology of Long COVIDs physio-affective phenome.

The authors have declared no competing interest.

Funding for the project was provided by the C2F program at Chulalongkorn University in Thailand, grant number 64.310/436/2565 to AFA, the Thailand Science Research, and Innovation Fund at Chulalongkorn University (HEA663000016), and a Sompoch Endowment Fund (Faculty of Medicine) MDCU (RA66/016) to MM.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Ethics Committee of the College of Medical Technology at the Islamic University of Najaf, Iraq, granted approval for this investigation (Document No. 34/2023). All procedures were consistent with Iraqi and international standards. Written informed assent was obtained from both patients and controls.

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