Autoantigen profiling reveals a shared post-COVID signature in fully recovered and Long COVID patients

Bodansky, Aaron; Wang, Chung‐Yu; Saxena, Akshar; Mitchell, Anthea; Takahashi, Saki; Anglin, Khamal; Huang, Beatrice; Hoh, Rebecca; Lu, Scott; Goldberg, Sarah A; Romero, Justin; Tran, Brandon; Kirtikar, Raushun A.; Grebe, Halle; So, Matthew; Greenhouse, Bryan; Durstenfeld, Matthew S; Hsue, Priscilla Y.; Hellmuth, Joanna; Kelly, John D.; Martin, Jeffrey N.; Anderson, Mark S.; Deeks, Steven G.; Henrich, Timothy J.; DeRisi, Joseph L.; Peluso, Michael J.

doi:10.1101/2023.02.06.23285532

Cited by 10 publications

(9 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results are consistent with the ongoing immunologic perturbations that have been consistently observed in individuals experiencing LC 12, 20–25 . Serological analyses have also found the presence of auto-antibodies during the acute or post-acute phases of infection to be associated with LC 11–13 , although this has not been observed consistently 19,26,27 . Elevated levels of SARS-CoV-2 antibodies have also been associated with LC 19 .…”

Section: Introductionmentioning

confidence: 99%

Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2

Yin

Peluso

Thomas

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Long COVID (LC), a type of post-acute sequelae of SARS-CoV-2 infection (PASC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood. Here, we used multiple omics assays (CyTOF, RNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of individuals with clear LC and non-LC clinical trajectories, 8 months following infection and prior to receipt of any SARS-CoV-2 vaccine. Our analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis. Our findings demonstrate that individuals with LC exhibit systemic inflammation and immune dysregulation. This is evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. Individuals with LC harbored increased frequencies of CD4+ T cells poised to migrate to inflamed tissues, and exhausted SARS-CoV-2-specific CD8+ T cells. They also harbored significantly higher levels of SARS-CoV-2 antibodies, and in contrast to non-LC individuals, exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses. Collectively, our data suggest that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in LC, and that this, perhaps in the context of persistent virus, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating condition.

show abstract

Section: Introductionmentioning

confidence: 99%

Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2

Yin

Peluso

Thomas

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…We previously utilized PhIP‐Seq technology to identify an autoreactive signature distinctive of prior SARS‐CoV‐2 infection within our LIINC cohort. However, the autoreactivities contained within this signature were similarly present in individuals with and without Long COVID symptoms 30 . To determine whether participants with a high breadth of SARS‐CoV‐2 cross‐variant neutralization as defined above and in Figure 3B had a distinctive autoantibody signature, we reanalyzed these PhIP‐Seq data for this particular study population.…”

Section: Resultsmentioning

confidence: 99%

“…To determine whether high neutralization breadth was associated with autoimmunity, we reanalyzed previously described PhIP‐Seq data corresponding to certain individuals within this cohort (i.e., those with the top 15% of neutralization ID 50 s in both the original SARS‐CoV‐2 and BA.5 variant) which is publicly available at: https://doi.org/10.7272/Q6Z60M99 30 . Logistic regression machine‐learning classifiers were performed using our described methods, which have been previously used to feature‐weight autoantibody signal in multiple autoimmune and COVID‐related diseases 30,31 . Utilizing the Scikit‐learn package, logistic regression classifiers were applied to z ‐scored PhIP‐Seq values from individuals with a designated disease category versus the designated control.…”

Section: Methodsmentioning

confidence: 99%

“…30 Logistic regression machine-learning classifiers were performed using our described methods, which have been previously used to feature-weight autoantibody signal in multiple autoimmune and COVID-related diseases. 30,31 Utilizing the Scikit-learn package, logistic regression classifiers were applied to z-scored PhIP-Seq values from individuals with a designated disease category versus the designated control. A liblinear solver was used with L1 regularization.…”

Section: Phenosense Sars Cov-2 Nab Assaymentioning

confidence: 99%

See 1 more Smart Citation

The breadth of the neutralizing antibody response to original SARS‐CoV‐2 infection is linked to the presence of Long COVID symptoms

Buck,

Deitchman,

Takahashi

et al. 2023

Journal of Medical Virology

View full text Add to dashboard Cite

The associations between longitudinal dynamics and the breadth of SARS‐CoV‐2 neutralizing antibody (nAb) response with various Long COVID phenotypes before vaccination are not known. The capacity of antibodies to cross‐neutralize a variety of viral variants may be associated with ongoing pathology and persistent symptoms. We measured longitudinal neutralizing and cross‐neutralizing antibody responses to pre‐ and post‐SARS‐CoV‐2 Omicron variants in participants infected early in the COVID‐19 pandemic, before widespread rollout of SARS‐CoV‐2 vaccines. Cross‐sectional regression models adjusted for clinical covariates and longitudinal mixed‐effects models were used to determine the impact of the breadth and rate of decay of neutralizing responses on the development of Long COVID symptoms, as well as Long COVID phenotypes. We identified several novel relationships between SARS‐CoV‐2 antibody neutralization and the presence of Long COVID symptoms. Specifically, we show that, although nAb responses to the original, infecting strain of SARS‐CoV‐2 were not associated with Long COVID in cross‐sectional analyses, cross‐neutralization ID50 levels to the Omicron BA.5 variant approximately 4 months following acute infection was independently and significantly associated with greater odds of Long COVID and with persistent gastrointestinal and neurological symptoms. Longitudinal modeling demonstrated significant associations in the overall levels and rates of decay of neutralization capacity with Long COVID phenotypes. A higher proportion of participants had antibodies capable of neutralizing Omicron BA.5 compared with BA.1 or XBB.1.5 variants. Our findings suggest that relationships between various immune responses and Long COVID are likely complex but may involve the breadth of antibody neutralization responses.

show abstract

“…The prevalent induction of anti-IFN-α autoantibodies in the nasal mucosa of mild/moderate (> 70%) and severely-infected (> 95%) COVID-19 patients reveal that autoreactive B-cell clones against IFN-α are ubiquitously present in the population. Indeed, recent studies show that a broad new-onset autoantibody response against inflammatory cytokines and chemokines is a common feature of the immune response against COVID-19 (17, 37, 39), and their neutralizing capacity likely plays a role in attenuating hyperinflammatory responses during infection (40). Notably, these autoantibodies were not associated with increased disease severity but with an efficient resolution, similar to our findings for airway anti-IFN-α.…”

Section: Discussionmentioning

confidence: 99%

Transient anti-interferon autoantibodies in the airways are associated with efficient recovery from COVID-19

Babcock,

Kosters,

Eddins

et al. 2024

Preprint

View full text Add to dashboard Cite

Pre-existing anti-interferon alpha (anti-IFN-α) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti-IFN-α autoantibodies in the airways -- the initial site of infection -- can also determine disease outcomes. In this study, we developed a new multiparameter technology, flowBEAT, to quantify and profile the isotypes of anti-IFN-α and anti-SARS-CoV-2 antibodies in longitudinal samples collected over 20 months from the airway and matching blood of 129 donors with mild, moderate, and severe COVID-19. We found unexpectedly that nasal anti-IFN-α autoantibodies were induced post-infection onset in more than 70% of mild to moderate COVID-19 cases and associated with robust anti-SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti-IFN-α autoantibodies followed the peak of host IFN-α production and waned with disease recovery, revealing a regulated balance between IFN-α and anti-IFN-α response. Notably, only a subset of mild to moderate patients progressed to develop systemic anti-IFN-α, which correlated with systemic inflammation and worsened symptoms. In contrast, patients with life-threatening COVID-19 sustained elevated anti-IFN-α in both airways and blood, coupled with uncontrolled viral load and IFN-α production. Our studies thereby reveal a novel protective role for nasal anti-IFN-α autoantibodies in the immunopathology of COVID-19 and, more broadly, suggest that anti-IFN-α may serve an important regulatory function to restore homeostasis following viral invasion of the respiratory mucosa.

show abstract

Autoantigen profiling reveals a shared post-COVID signature in fully recovered and Long COVID patients

Cited by 10 publications

References 29 publications

Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2

Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2

The breadth of the neutralizing antibody response to original SARS‐CoV‐2 infection is linked to the presence of Long COVID symptoms

Transient anti-interferon autoantibodies in the airways are associated with efficient recovery from COVID-19

Contact Info

Product

Resources

About