Abstract
Abstract Postacute sequelae of SARS-CoV-2 infection (PASC) is the next public health concern of the pervasive COVID-19 pandemic. Molecular pathophysiology of PASC is undetermined, therefore this study evaluated pathways implicated in humoral responses associated with symptom resolution to identify predictive biomarkers of PASC. Individuals recovered from acute infection were recruited into a 6-week study. Initial health questionnaires and proof of previous SARS-CoV-2 infection were collected prior to study enrollment. Body mass indices were calculated with participant height and weight measurements. Blood samples were collected and isolated for plasma and PBMCs to evaluate a panel of immunological biomarkers and cellular profiling, respectively. A singular stool sample was collected for microbial DNA extraction for metagenomic sequencing. Data was integrated with IPA analysis to establish modulated pathways in PASC. Individuals suffering from symptoms of PASC showed evidence of poor immune responses with diminished rates of symptom resolution. Particularly prevalent in obese individuals, PASC associated with attenuated antibody responses and inability to maintain viral inhibition capacities, partially explained by elevated inflammation and inflammatory cellular landscapes. Individuals with worse humoral responses tended to display characteristics of a compromised gut microbiome, suggesting dysregulation of the immunoepigenetic-microbiome axis. Circulating high mobility group box 1 was shown to be a central mediator of this axis, with elevated levels conducive of poor adaptive immunity. Additionally, mediation analysis revealed baseline levels were predictive of viral inhibition at the time of final follow-up. This study was supported in part by funding provided by Hawaii Community Foundation under award 20HCF-101573. The comments expressed in this report are the sole responsibility of the authors and do not represent the official view of the Hawaii Community Foundation.
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