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Sevim Bayrak C, Forst CV, Jones DR, Gresham DJ, Pushalkar S, Wu S, Vogel C, Mahal LK, Ghedin E, Ross T, García-Sastre A, Zhang B
Clinical immunology (Orlando, Fla.)
2024-09-01
PMID: 39089348
Adaptive Immunity
Antibodies, Viral
Antibody Formation
Hemagglutination Inhibition Tests
HIPC 3 (2022)
Humans
Icahn School of Medicine at Mount Sinai
Immunity, Innate
Immunoglobulin A
Influenza, Human
Influenza Vaccines
Multiomics
Proteomics
Seasons
Vaccination
Abstract:
Understanding the molecular mechanisms underpinning diverse vaccination responses is critical for developing efficient vaccines. Molecular subtyping can offer insights into heterogeneous nature of responses and aid in vaccine design. We analyzed multi-omic data from 62 haemagglutinin seasonal influenza vaccine recipients (2019-2020), including transcriptomics, proteomics, glycomics, and metabolomics data collected pre-vaccination. We performed a subtyping analysis on the integrated data revealing five subtypes with distinct molecular signatures. These subtypes differed in the expression of pre-existing adaptive or innate immunity signatures, which were linked to significant variation in baseline immunoglobulin A (IgA) and hemagglutination inhibition (HAI) titer levels. It is worth noting that these differences persisted through day 28 post-vaccination, indicating the effect of initial immune state on vaccination response. These findings highlight the significance of interpersonal variation in baseline immune status as a crucial factor in determining the effectiveness of seasonal vaccines. Ultimately, incorporating molecular profiling could enable personalized vaccine optimization.
Wang S, Al-Radhawi MA, Lauffenburger DA, Sontag ED
NPJ systems biology and applications
2024-08-27
PMID: 39191787
Algorithms
Computational Biology
Computer Simulation
Genomics
HIPC 3 (2022)
Humans
Massachusetts Institute of technology
Models, Biological
Single-Cell Analysis
Abstract:
Single-cell omics technologies can measure millions of cells for up to thousands of biomolecular features, enabling data-driven studies of complex biological networks. However, these high-throughput experimental techniques often cannot track individual cells over time, thus complicating the understanding of dynamics such as time trajectories of cell states. These "dynamical phenotypes" are key to understanding biological phenomena such as differentiation fates. We show by mathematical analysis that, in spite of high dimensionality and lack of individual cell traces, three time-points of single-cell omics data are theoretically necessary and sufficient to uniquely determine the network interaction matrix and associated dynamics. Moreover, we show through numerical simulations that an interaction matrix can be accurately determined with three or more time-points even in the presence of sampling and measurement noise typical of single-cell omics. Our results can guide the design of single-cell omics time-course experiments, and provide a tool for data-driven phase-space analysis.
McIntire KM, Meng H, Lin TH, Kim W, Moore NE, Han J, McMahon M, Wang M, Malladi SK, Mohammed BM, Zhou JQ, Schmitz AJ, Hoehn KB, Carreño JM, Yellin T, Suessen T, Middleton WD, Teefey SA, Presti RM, Krammer F, Turner JS, Ward AB, Wilson IA, Kleinstein SH, Ellebedy AH
The Journal of experimental medicine
2024-08-05
PMID: 38935072
Adult
Antibodies, Monoclonal
Antibodies, Viral
B-Lymphocytes
Female
Germinal Center
Hemagglutinin Glycoproteins, Influenza Virus
HIPC 1 (2010)
HIPC 2 (2015)
HIPC 3 (2022)
Humans
Influenza, Human
Influenza Vaccines
Male
Middle Aged
Vaccination
Yale University
Abstract:
Germinal centers (GC) are microanatomical lymphoid structures where affinity-matured memory B cells and long-lived bone marrow plasma cells are primarily generated. It is unclear how the maturation of B cells within the GC impacts the breadth and durability of B cell responses to influenza vaccination in humans. We used fine needle aspiration of draining lymph nodes to longitudinally track antigen-specific GC B cell responses to seasonal influenza vaccination. Antigen-specific GC B cells persisted for at least 13 wk after vaccination in two out of seven individuals. Monoclonal antibodies (mAbs) derived from persisting GC B cell clones exhibit enhanced binding affinity and breadth to influenza hemagglutinin (HA) antigens compared with related GC clonotypes isolated earlier in the response. Structural studies of early and late GC-derived mAbs from one clonal lineage in complex with H1 and H5 HAs revealed an altered binding footprint. Our study shows that inducing sustained GC reactions after influenza vaccination in humans supports the maturation of responding B cells.
Lerfald M, Allore H, Nilsen TIL, Eldholm RS, Martinez-Velilla N, Selbæk G, Ernstsen L
The journals of gerontology. Series A, Biological sciences and medical sciences
2024-08-01
PMID: 38894618
Adult
Aged
Blood Pressure
Cardiorespiratory Fitness
Dementia
Female
HIPC 1 (2010)
HIPC 2 (2015)
HIPC 3 (2022)
Humans
Hypertension
Longitudinal Studies
Male
Middle Aged
Norway
Prospective Studies
Risk Factors
Yale University
Abstract:
[{'@Label': 'BACKGROUND', '@NlmCategory': 'BACKGROUND', '#text': 'High blood pressure and poor cardiorespiratory fitness are independent risk factors for dementia. However, few studies have examined if combined longitudinal patterns of these modifiable risk factors are associated with dementia risk.'}, {'@Label': 'METHODS', '@NlmCategory': 'METHODS', '#text': 'In this prospective cohort study, we used data from the population-based Trøndelag Health (HUNT) Study, Norway. We applied group-based multidimensional trajectory modeling to identify age-specific multidimensional trajectories of SBP, DBP, and estimated cardiorespiratory fitness across 3 surveys (HUNT1, 1984-1986 to HUNT3, 2006-2008). Dementia was diagnosed in the HUNT4 70+ substudy in 2017-2019. We used multivariate logistic regression to estimate odds ratios (ORs) and risk differences (RDs) of dementia.'}, {'@Label': 'RESULTS', '@NlmCategory': 'RESULTS', '#text': 'In total, 7\xa0594 participants (54.9% women) were included, with a mean age of 44.7 (SD 6.3) years at HUNT1. Dementia was diagnosed in 1\xa0062 (14.0%) participants. We identified 2 multidimensional trajectories throughout adulthood within 3 age groups: one with higher systolic blood pressure (SBP) and diastolic blood pressure (DBP), and lower estimated cardiorespiratory fitness (the poorer group), and one with lower SBP and DBP, and higher cardiorespiratory fitness (the better group). After adjustment for sex, apolipoprotein E ε4 status, education, marital status, and diabetes, the better group had consistently lower risk of dementia in all age groups with the lowest OR in the middle-aged group of 0.63 (95% confidence intervals [95% CI]: 0.51, 0.78) with corresponding RD of -0.07 (95% CI: -0.10, -0.04).'}, {'@Label': 'CONCLUSIONS', '@NlmCategory': 'CONCLUSIONS', '#text': 'Having a beneficial multidimensional trajectory of SBP, DBP, and cardiorespiratory fitness in adulthood was associated with reduced dementia risk. Aiming for optimal SBP, DBP, and estimated cardiorespiratory fitness throughout adulthood may reduce dementia risk.'}]
Fantin RF, Clark JJ, Cohn H, Jaiswal D, Bozarth B, Civljak A, Rao V, Lobo I, Nardulli JR, Srivastava K, Yong J, Andreata-Santos R, Bushfield K, Lee ES, Singh G, Kleinstein SH, Krammer F, Simon V, Bajic G, Coelho CH
bioRxiv : the preprint server for biology
2024-07-16
PMID: 39071292
HIPC 3 (2022)
Icahn School of Medicine at Mount Sinai
Abstract:
The emergence of highly contagious and immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has required reformulation of coronavirus disease 2019 (COVID-19) vaccines to target those new variants specifically. While previous infections and booster vaccinations can enhance variant neutralization, it is unclear whether the monovalent version, administered using either mRNA or protein-based vaccine platforms, can elicit de novo B-cell responses specific for Omicron XBB.1.5 variants. Here, we dissected the genetic antibody repertoire of 603 individual plasmablasts derived from five individuals who received a monovalent XBB.1.5 vaccination either with mRNA (Moderna or Pfizer/BioNtech) or adjuvanted protein (Novavax). From these sequences, we expressed 100 human monoclonal antibodies and determined binding, affinity and protective potential against several SARS-CoV-2 variants, including JN.1. We then select two vaccine-induced XBB.1.5 mAbs, M2 and M39. M2 mAb was a de novo, antibody, i.e., specific for XBB.1.5 but not ancestral SARS-CoV-2. M39 bound and neutralized both XBB.1.5 and JN.1 strains. Our high-resolution cryo-electron microscopy (EM) structures of M2 and M39 in complex with the XBB.1.5 spike glycoprotein defined the epitopes engaged and revealed the molecular determinants for the mAbs' specificity. These data show, at the molecular level, that monovalent, variant-specific vaccines can elicit functional antibodies, and shed light on potential functional and genetic differences of mAbs induced by vaccinations with different vaccine platforms.\.
Karakus U, Sempere Borau M, Martínez-Barragán P, von Kempis J, Yildiz S, Arroyo-Fernández LM, Pohl MO, Steiger JA, Glas I, Hunziker A, García-Sastre A, Stertz S
Nature microbiology
2024-07-15
PMID: 39009691
HIPC 3 (2022)
Icahn School of Medicine at Mount Sinai
Abstract:
Influenza A viruses (IAV) pose substantial burden on human and animal health. Avian, swine and human IAV bind sialic acid on host glycans as receptor, whereas some bat IAV require MHC class II complexes for cell entry. It is unknown how this difference evolved and whether dual receptor specificity is possible. Here we show that human H2N2 IAV and related avian H2N2 possess dual receptor specificity in cell lines and primary human airway cultures. Using sialylation-deficient cells, we reveal that entry via MHC class II is independent of sialic acid. We find that MHC class II from humans, pigs, ducks, swans and chickens but not bats can mediate H2 IAV entry and that this is conserved in Eurasian avian H2. Our results demonstrate that IAV can possess dual receptor specificity for sialic acid and MHC class II, and suggest a role for MHC class II-dependent entry in zoonotic IAV infections.
Jones DC, Elz AE, Hadadianpour A, Ryu H, Glass DR, Newell EW
bioRxiv : the preprint server for biology
2024-07-09
PMID: 38712065
HIPC 3 (2022)
Seattle Children's Research Institute
Abstract:
Single-cell spatial transcriptomics promises a highly detailed view of a cell's transcriptional state and microenvironment, yet inaccurate cell segmentation can render this data murky by misattributing large numbers of transcripts to nearby cells or conjuring nonexistent cells. We adopt methods from ab initio cell simulation to rapidly infer morphologically plausible cell boundaries that preserve cell type heterogeneity. Benchmarking applied to datasets generated by three commercial platforms show superior performance and computational efficiency of this approach compared with existing methods. We show that improved accuracy in cell segmentation aids greatly in detection of difficult to accurately segment tumor infiltrating immune cells such as neutrophils and T cells. Lastly, through improvements in our ability to delineate subsets of tumor infiltrating T cells, we show that CXCL13-expressing CD8+ T cells tend to be more closely associated with tumor cells than their CXCL13-negative counterparts in data generated from renal cell carcinoma patient samples.
Zheng Y, Caron DP, Kim JY, Jun SH, Tian Y, Florian M, Stuart KD, Sims PA, Gottardo R
Research square
2024-07-08
PMID: 39041028
Columbia University
HIPC 3 (2022)
Seattle Children's Research Institute
Abstract:
CITE-seq enables paired measurement of surface protein and mRNA expression in single cells using antibodies conjugated to oligonucleotide tags. Due to the high copy number of surface protein molecules, sequencing antibody-derived tags (ADTs) allows for robust protein detection, improving cell-type identification. However, variability in antibody staining leads to batch effects in the ADT expression, obscuring biological variation, reducing interpretability, and obstructing cross-study analyses. Here, we present ADTnorm (https://github.com/yezhengSTAT/ADTnorm), a normalization and integration method designed explicitly for ADT abundance. Benchmarking against 14 existing scaling and normalization methods, we show that ADTnorm accurately aligns populations with negative- and positive-expression of surface protein markers across 13 public datasets, effectively removing technical variation across batches and improving cell-type separation. ADTnorm enables efficient integration of public CITE-seq datasets, each with unique experimental designs, paving the way for atlas-level analyses. Beyond normalization, ADTnorm includes built-in utilities to aid in automated threshold-gating as well as assessment of antibody staining quality for titration optimization and antibody panel selection. Applying ADTnorm to a published COVID-19 CITE-seq dataset allowed for identifying previously undetected disease-associated markers, illustrating a broad utility in biological applications.
Sparks R, Rachmaninoff N, Lau WW, Hirsch DC, Bansal N, Martins AJ, Chen J, Liu CC, Cheung F, Failla LE, Biancotto A, Fantoni G, Sellers BA, Chawla DG, Howe KN, Mostaghimi D, Farmer R, Kotliarov Y, Calvo KR, Palmer C, Daub J, Foruraghi L, Kreuzburg S, Treat JD, Urban AK, ...
Nature medicine
2024-07-03
PMID: 38961223
HIPC 1 (2010)
HIPC 2 (2015)
HIPC 3 (2022)
Yale University
Abstract:
Immunological health has been challenging to characterize but could be defined as the absence of immune pathology. While shared features of some immune diseases and the concept of immunologic resilience based on age-independent adaptation to antigenic stimulation have been developed, general metrics of immune health and its utility for assessing clinically healthy individuals remain ill defined. Here we integrated transcriptomics, serum protein, peripheral immune cell frequency and clinical data from 228 patients with 22 monogenic conditions impacting key immunological pathways together with 42 age- and sex-matched healthy controls. Despite the high penetrance of monogenic lesions, differences between individuals in diverse immune parameters tended to dominate over those attributable to disease conditions or medication use. Unsupervised or supervised machine learning independently identified a score that distinguished healthy participants from patients with monogenic diseases, thus suggesting a quantitative immune health metric (IHM). In ten independent datasets, the IHM discriminated healthy from polygenic autoimmune and inflammatory disease states, marked aging in clinically healthy individuals, tracked disease activities and treatment responses in both immunological and nonimmunological diseases, and predicted age-dependent antibody responses to immunizations with different vaccines. This discriminatory power goes beyond that of the classical inflammatory biomarkers C-reactive protein and interleukin-6. Thus, deviations from health in diverse conditions, including aging, have shared systemic immune consequences, and we provide a web platform for calculating the IHM for other datasets, which could empower precision medicine.
Sumida TS, Cheru NT, Hafler DA
Nature reviews. Immunology
2024-07-01
PMID: 38374298
Animals
Autoimmune Diseases
Cell Differentiation
Forkhead Transcription Factors
HIPC 1 (2010)
HIPC 2 (2015)
HIPC 3 (2022)
Humans
Mice
T-Lymphocytes, Regulatory
Yale University
Abstract:
The discovery of FOXP3+ regulatory T (Treg) cells as a distinct cell lineage with a central role in regulating immune responses provided a deeper understanding of self-tolerance. The transcription factor FOXP3 serves a key role in Treg cell lineage determination and maintenance, but is not sufficient to enable the full potential of Treg cell suppression, indicating that other factors orchestrate the fine-tuning of Treg cell function. Moreover, FOXP3-independent mechanisms have recently been shown to contribute to Treg cell dysfunction. FOXP3 mutations in humans cause lethal fulminant systemic autoinflammation (IPEX syndrome). However, it remains unclear to what degree Treg cell dysfunction is contributing to the pathophysiology of common autoimmune diseases. In this Review, we discuss the origins of Treg cells in the periphery and the multilayered mechanisms by which Treg cells are induced, as well as the FOXP3-dependent and FOXP3-independent cellular programmes that maintain the suppressive function of Treg cells in humans and mice. Further, we examine evidence for Treg cell dysfunction in the context of common autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis.
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