Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae

Swank, Zoe; Senussi, Yasmeen; Alter, Galit; Walt, David R.

doi:10.1101/2022.06.14.22276401

Cited by 48 publications

(40 citation statements)

References 33 publications

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“…These findings are consistent with results from analysis of PBMC populations, such as TEX increases suggesting chronic immune responses directed against viral antigens within the Long COVID group. Intriguingly, circulating Spike protein has also been observed in Long COVID participants, but not in convalescent controls 53 . Furthermore, these findings are supported by prior reports of persistent viral antigen in intestinal biopsies of convalescent COVID-19 individuals, and suggest persistent antigen might drive the continuous elevation in antibody responses among people with Long COVID [33][34][35][36] .…”

Section: Discussionmentioning

confidence: 94%

Distinguishing features of Long COVID identified through immune profiling

Klein

Wood

Jaycox

et al. 2022

Preprint

209

220

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SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease called post-acute sequelae of COVID-19 (PASC) or Long COVID. Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Here, 215 individuals were included in an exploratory, cross-sectional study to perform multi-dimensional immune phenotyping in conjunction with machine learning methods to identify key immunological features distinguishing Long COVID. Marked differences were noted in specific circulating myeloid and lymphocyte populations relative to matched control groups, as well as evidence of elevated humoral responses directed against SARS-CoV-2 among participants with Long COVID. Further, unexpected increases were observed in antibody responses directed against non-SARS-CoV-2 viral pathogens, particularly Epstein-Barr virus. Analysis of circulating immune mediators and various hormones also revealed pronounced differences, with levels of cortisol being uniformly lower among participants with Long COVID relative to matched control groups. Integration of immune phenotyping data into unbiased machine learning models identified significant distinguishing features critical in accurate classification of Long COVID, with decreased levels of cortisol being the most significant individual predictor. These findings will help guide additional studies into the pathobiology of Long COVID and may aid in the future development of objective biomarkers for Long COVID.

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Section: Discussionmentioning

confidence: 94%

Distinguishing features of Long COVID identified through immune profiling

Klein

Wood

Jaycox

et al. 2022

Preprint

209

220

View full text Add to dashboard Cite

show abstract

“…The observations described here, derived from computational analysis of SARS-CoV-2 sequence, structure and interactions, as well as RNA sequencing, TCR and BCR repertoire analysis, autoantibody arrays, and proteomics analysis performed on samples collected from MIS-C and COVID-19 patients, point towards a role for the SAg-like motif (residues E661-R685) we identified in SARS-CoV-2 spike in promoting hyperinflammation and potentially autoimmunity in PASC, including MIS-C and long COVID. This is of particular importance in view of a recent study showing that persistence of circulating SARS-CoV-2 Spike may be associated with post-acute COVID-19 sequelae ( 156 ). However, further studies are still required to validate our hypotheses.…”

Section: Discussionmentioning

confidence: 98%

Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis

et al. 2022

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Multisystem inflammatory syndrome in children (MIS-C) is a febrile pediatric inflammatory disease that may develop weeks after initial SARS-CoV-2 infection or exposure. MIS-C involves systemic hyperinflammation and multiorgan involvement, including severe cardiovascular, gastrointestinal (GI) and neurological symptoms. Some clinical attributes of MIS-C—such as persistent fever, rashes, conjunctivitis and oral mucosa changes (red fissured lips and strawberry tongue)—overlap with features of Kawasaki disease (KD). In addition, MIS-C shares striking clinical similarities with toxic shock syndrome (TSS), which is triggered by bacterial superantigens (SAgs). The remarkable similarities between MIS-C and TSS prompted a search for SAg-like structures in the SARS-CoV-2 virus and the discovery of a unique SAg-like motif highly similar to a Staphylococcal enterotoxin B (SEB) fragment in the SARS-CoV-2 spike 1 (S1) glycoprotein. Computational studies suggest that the SAg-like motif has a high affinity for binding T-cell receptors (TCRs) and MHC Class II proteins. Immunosequencing of peripheral blood samples from MIS-C patients revealed a profound expansion of TCR β variable gene 11-2 (TRBV11-2), which correlates with MIS-C severity and serum cytokine levels, consistent with a SAg-triggered immune response. Computational sequence analysis of SARS-CoV-2 spike further identified conserved neurotoxin-like motifs which may alter neuronal cell function and contribute to neurological symptoms in COVID-19 and MIS-C patients. Additionally, autoantibodies are detected during MIS-C, which may indicate development of post-SARS-CoV-2 autoreactive and autoimmune responses. Finally, prolonged persistence of SARS-CoV-2 RNA in the gut, increased gut permeability and elevated levels of circulating S1 have been observed in children with MIS-C. Accordingly, we hypothesize that continuous and prolonged exposure to the viral SAg-like and neurotoxin-like motifs in SARS-CoV-2 spike may promote autoimmunity leading to the development of post-acute COVID-19 syndromes, including MIS-C and long COVID, as well as the neurological complications resulting from SARS-CoV-2 infection.

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“…Recent clinical cohort data showed a risk of incident cardiovascular problems, including blood clots, abnormal heart rhythms, and stroke 1 year after SARS-CoV-2 infection [ 22 ]. The SARS-CoV-2 antigens, including the S1 subunit of the spike, full-length spike, and nucleocapsid are present in 65% of patients with long covid [ 2 ]. It is becoming increasingly clear that SARS-CoV-2-induced cardiovascular impairment and neurological disorders are not restricted to individuals with severe COVID.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies show that many patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) experience fatigue and cognitive impairment or develop cardiovascular disease including cerebral vascular disorders (CVD), collectively termed long-COVID, after they recover from their initial illness. Some patients show such symptoms even 7 months post-infection and continue suffering from long COVID [ 1 ], which is associated with persistent residual SARS-CoV-2 antigen including the S1 subunit of the spike, full-length spike, and nucleocapsid [ 2 ]. A recent study demonstrates that cognitive impairment due to long COVID is equivalent to accelerated aging, the equivalent of 20 years [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%