Unique molecular signatures sustained in circulating monocytes and regulatory T cells in convalescent COVID-19 patients

Hoffmann, Andrew D.; Weinberg, Sam; Swaminathan, Suchitra; Chaudhuri, Shuvam; Mubarak, Hannah; Schipma, Matthew; Mao, Chengsheng; Wang, Xinkun; El-Shennawy, Lamiaa; Dashzeveg, Nurmaa K.; Wei, Juncheng; Mehl, Paul J.; Shihadah, Laura; Wai, Ching Man; Ostiguin, Carolina; Jia, Yuzhi; D'Amico, Paolo; Wang, Neale R.; Luo, Yuan; Demonbreun, Alexis R.; Ison, Michael G.; Liu, Huiping; Fang, Deyu

doi:10.1016/j.clim.2023.109634

Cited by 9 publications

(4 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1a) . To identify and produce anti-spike antibodies, we first collect blood specimens from 42 patients recovered from early COVID-19 as described (24), flow sorted the RBD-bound IgM memory B cells for subsequent single-cell VDJ sequencing via the 5’ 10X genomics platform, and retrieved 1376 heavy-light chain pairs of IgG antibody sequences.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Physics-driven structural docking and protein language models accelerate antibody screening and design for broad-spectrum antiviral therapy

Almubarak,

Tan,

Hoffmann

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Therapeutic antibodies have become one of the most influential therapeutics in modern medicine to fight against infectious pathogens, cancer, and many other diseases. However, experimental screening for highly efficacious targeting antibodies is labor-intensive, which is exacerbated by evolving antigen targets under selective pressure such as fast-mutating viral variants. As a proof-of-concept, we developed a machine learning-assisted antibody generation pipeline that greatly accelerates the screening and re-design of immunoglobulins G (IgGs) against a broad spectrum of coronavirus variants. Using over 1300 IgG sequences derived from patient B cells bound with the viral spike's receptor binding domain (RBD), we first established protein structural docking models in assessing the IgG-RBD-ACE2 interaction interfaces and predicting their viral neutralizing activities with a confidence score. The confidence score is calculated as a fraction of IgG-blocking RBD binding sites versus all ACE2-interacting sites. Additionally, employing Gaussian process regression (also known as Kriging) in a latent space of an antibody language model, we predicted the IgGs' activity profiles against viral strains. Using functional analyses and experimental validations, we subsequently prioritized IgG candidates for neutralizing a broad spectrum of viral variants (wildtype, Delta, and Omicron) and preventing the infection of host cells in vitro and hACE2 transgenic mice in vivo. To further improve the blockade efficacy for the Delta strain (B.1.617), we rationally redesigned the IgG clones with single amino acid substitutions at the RBD-binding interface. Our work expedites applications of artificial intelligence in low-data regimes when limited data is available, including protein language models (using unlabeled data) and Kriging (using few labeled data) for antibody sequence analysis, activity prediction, and efficacy improvement, which are aided by physics-driven protein docking models for antibody-antigen interface structure analyses.

show abstract

Section: Resultsmentioning

confidence: 99%

“…RBD-647+ B cells were sorted on a FACS Aria (BD Biosciences) in the Robert H. Lurie Cancer Center Flow Cytometry core facility. Due to the small number of RBD-647+ B cells isolated from each patient, we combined B cells with monocytes isolated from the same patients, labeled with a different hashtag oligo (24) (Hoffmann et al, 2023).…”

Section: Methodsmentioning

confidence: 99%

Physics-driven structural docking and protein language models accelerate antibody screening and design for broad-spectrum antiviral therapy

Almubarak,

Tan,

Hoffmann

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Post-recovery from COVID-19, the immune system undergoes reconstruction 32 . However, the elevated interferon responsive genes in monocytes can still be found after 4 months since the infection 33 , which implies that the immune system is not fully recovered after 4 months, and constant attention must be paid to the patients. Our findings show that as time passes after initial infection with SARS-CoV-2, the risk of developing acute respiratory complications or post-acute respiratory sequelae gradually decreased.…”

Section: Discussionmentioning

confidence: 99%

Acute and post-acute respiratory complications of SARS-CoV-2 infection: population-based cohort study in South Korea and Japan

Choi,

Kim,

Park

et al. 2024

Nat Commun

View full text Add to dashboard Cite

Considering the significant burden of post-acute COVID-19 conditions among patients infected with SARS-CoV-2, we aimed to identify the risk of acute respiratory complications or post-acute respiratory sequelae. A binational population-based cohort study was conducted to analyze the risk of acute respiratory complications or post-acute respiratory sequelae after SARS-CoV-2 infection. We used a Korean nationwide claim-based cohort (K-COV-N; n = 2,312,748; main cohort) and a Japanese claim-based cohort (JMDC; n = 3,115,606; replication cohort) after multi-to-one propensity score matching. Among 2,312,748 Korean participants (mean age, 47.2 years [SD, 15.6]; 1,109,708 [48.0%] female), 17.1% (394,598/2,312,748) were infected with SARS-CoV-2. The risk of acute respiratory complications or post-acute respiratory sequelae is significantly increased in people with SARS-CoV-2 infection compared to the general population (acute respiratory complications: HR, 8.06 [95% CI, 6.92-9.38]; post-acute respiratory sequelae: 1.68 [1.62-1.75]), and the risk increased with increasing COVID-19 severity. We identified COVID-19 vaccination as an attenuating factor, showing a protective association against acute or post-acute respiratory conditions. Furthermore, while the excess post-acute risk diminished with time following SARS-CoV-2 infection, it persisted beyond 6 months post-infection. The replication cohort showed a similar pattern in the association. Our study comprehensively evaluates respiratory complications in post-COVID-19 conditions, considering attenuating factors such as vaccination status, post-infection duration, COVID-19 severity, and specific respiratory conditions.

show abstract

“…Транскриптомный анализ показал также, что функциональные нарушения Treg, проявляющиеся в виде уменьшения экспрессии FoxP3 и иммуносупрессивных цитокинов IL-10 и TGF-β, также позитивно коррелируют с тяжестью COVID-19 [121]. Наоборот, у реконвалесцентов после COVID-19 спустя 4 месяца и более происходит восстановление пула долгоживущих Treg с высоким уровнем экспрессии HLA-DRA, и появляется уникальный кластер Treg, оверэкспрессирующих TGF-β [124].…”

Section: Covid-19 Treg и инсультunclassified

Treg Cells in Ischemic Stroke: A Small Key to a Great Orchestrion

Zhukova,

Chudakova,

Belopasov

et al. 2023

Journal of Clinical Practice

View full text Add to dashboard Cite

Ischemic stroke is a global medical problem and one of the leading causes of death or disability worldwide. The main approach of ischemic stroke therapy in the most acute period, which can prevent or minimize the development of a neurological deficit, is the restoration of the blood flow in the ischemic brain tissue using enzymatic thrombolysis or endovascular thromboextraction. When the therapeutic window is missed, the modulation of the acute inflammatory response may play an important role in determining the fate of neurons in the penumbra. The key players in this process are T-regulatory cells (Tregs) an immunosuppressive population of CD4+ T-cells with the CD4+, CD25+ CD127low, FoxP3+ phenotype. Despite the existing reports that Tregs (or certain Treg subpopulations) can exacerbate microcirculatory disorders in the ischemic tissue, many stadies convincingly suggest the positive role of Tregs in ischemic stroke. Resident CD69+ Tregs found in the normal mammalian brain have neuroprotective activity, produce IL-10 and other anti-inflammatory cytokines, control astrogliosis, and downregulate cytotoxic subpopulations of T cells and microglia. Systemic administration of Treg in stroke is accompained by a decrease in the volume of cerebral infarction and decreased levels of secondary neuronal death. Thus, the methods allowing Treg activation and expansion ex vivo open up several new avenues for the immunocorrection not only in systemic and autoimmune diseases, but, potentially, in the neuroprotective therapy for ischemic stroke. The relationship between Treg, inflammation, and cerebrovascular pathology is of particular interest in the case of ischemic stroke and COVID-19 as a comorbidity. It has been demonstrated that systemic inflammation caused by SARS-CoV-2 infection leads to a significant suppression of Treg, which is accompanied by an increased risk for the development of ischemic stroke and other neurological complications. Overall, the information summarized herein about the possible therapeutic potential of Treg in cerebrovascular pathology may be of practical interest not only for researchers, but also for clinicians.

show abstract

Unique molecular signatures sustained in circulating monocytes and regulatory T cells in convalescent COVID-19 patients

Cited by 9 publications

References 57 publications

Physics-driven structural docking and protein language models accelerate antibody screening and design for broad-spectrum antiviral therapy

Physics-driven structural docking and protein language models accelerate antibody screening and design for broad-spectrum antiviral therapy

Acute and post-acute respiratory complications of SARS-CoV-2 infection: population-based cohort study in South Korea and Japan

Treg Cells in Ischemic Stroke: A Small Key to a Great Orchestrion

Contact Info

Product

Resources

About