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HIPC Centers
Benaroya Research Institute (13)
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HIPC 1 (2010) (699)
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Icahn School of Medicine at Mount Sinai (28)
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Publication Keywords
Immport Dataset Available (21)
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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
2024-10-01
PMID: 39009691
Animals
Birds
Cell Line
Chickens
Chiroptera
Ducks
HIPC 3 (2022)
Histocompatibility Antigens Class II
Humans
Icahn School of Medicine at Mount Sinai
Influenza A Virus, H2N2 Subtype
Influenza, Human
Influenza in Birds
N-Acetylneuraminic Acid
Receptors, Virus
Swine
Virus Internalization
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.
Martino D, Kresoje N, Amenyogbe N, Ben-Othman R, Cai B, Lo M, Idoko O, Odumade OA, Falsafi R, Blimkie TM, An A, Shannon CP, Montante S, Dhillon BK, Diray-Arce J, Ozonoff A, Smolen KK, Brinkman RR, McEnaney K, Angelidou A, Richmond P, Tebbutt SJ, Kampmann B, Levy O, ...
Nature communications
2024-09-17
PMID: 39289350
DNA Methylation
Epigenesis, Genetic
Female
HIPC 2 (2015)
Humans
Infant, Newborn
Lymphocytes
Male
Neutrophils
Polymorphism, Single Nucleotide
Abstract:
Understanding of newborn immune ontogeny in the first week of life will enable age-appropriate strategies for safeguarding vulnerable newborns against infectious diseases. Here we conducted an observational study exploring the immunological profile of infants longitudinally throughout their first week of life. Our Expanded Program on Immunization - Human Immunology Project Consortium (EPIC-HIPC) studies the epigenetic regulation of systemic immunity using small volumes of peripheral blood samples collected from West African neonates on days of life (DOL) 0, 1, 3, and 7. Genome-wide DNA methylation and single nucleotide polymorphism markers are examined alongside matched transcriptomic and flow cytometric data. Integrative analysis reveals that a core network of transcription factors mediates dynamic shifts in neutrophil-to-lymphocyte ratios (NLR), which are underpinned by cell-type specific methylation patterns in the two cell types. Genetic variants are associated with lower NLRs at birth, and healthy newborns with lower NLRs at birth are more likely to subsequently develop sepsis. These findings provide valuable insights into the early-life determinants of immune system development.
Smith D, Eichinger A, Rech A, Wang J, Esteva E, Seyedian A, Yang X, Zhang M, Martinez D, Tan K, Luo M, Park C, Reizis B, Pillai V
bioRxiv : the preprint server for biology
2024-09-09
PMID: 39314418
Columbia University
HIPC 2 (2015)
HIPC 3 (2022)
Abstract:
Castleman disease (CD) is inflammatory lymphoproliferative disorder of unclear etiology. To determine the cellular and molecular basis of CD, we analyzed the spatial proteome of 4,485,009 single cells, transcriptome of 50,117 single nuclei, immune repertoire of 8187 single nuclei, and pathogenic mutations in Unicentric CD, idiopathic Multicentric CD, HHV8-associated MCD, and reactive lymph nodes. CD was characterized by increased non-lymphoid and stromal cells that formed unique microenvironments where they interacted with lymphoid cells. Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle zone B cells was associated with B cell activation and differentiation. VEGF, IL-6, MAPK, and extracellular matrix pathways were elevated in stromal cells of CD. CXCL13+ FDCs, PDGFRA+ T-zone reticular cells (TRC), and ACTA2-positive perivascular reticular cells (PRC) were identified as the predominant source of increased VEGF expression and IL-6 signaling in CD. VEGF expression by FDCs was associated with peri-follicular neovascularization. FDC, TRC and PRC of CD activated JAK-STAT, TGFβ, and MAPK pathways via ligand-receptor interactions involving collagen, integrins, complement components, and VEGF receptors. T, B and plasma cells were polyclonal but showed class-switched and somatically hypermutated IgG1+ plasma cells consistent with stromal cell-driven germinal center activation. In conclusion, our findings show that stromal cell activation and associated B-cell activation and differentiation, neovascularization and stromal remodeling underlie CD and suggest new targets for treatment.
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.
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
2024-09-01
PMID: 38961223
Adolescent
Adult
Aged
Aging
Biomarkers
Case-Control Studies
Female
HIPC 1 (2010)
HIPC 2 (2015)
HIPC 3 (2022)
Humans
Immune System Diseases
Machine Learning
Male
Middle Aged
Transcriptome
Yale University
Young Adult
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.
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.'}]
Narvaez F, Montenegro C, Juarez JG, Zambrana JV, Gonzalez K, Videa E, Arguello S, Barrios F, Ojeda S, Plazaola M, Sanchez N, Camprubi D, Kuan G, Paz-Bailey G, Harris E, Balmaseda A
medRxiv : the preprint server for health sciences
2024-07-31
PMID: 38405964
HIPC 2 (2015)
Abstract:
[{'@Label': 'BACKGROUND', '@NlmCategory': 'BACKGROUND', '#text': 'Dengue virus, a major global health threat, consists of four serotypes (DENV1-4) that cause a range of clinical manifestations from mild to severe and potentially fatal disease.'}, {'@Label': 'METHODS', '@NlmCategory': 'METHODS', '#text': 'This study, based on 19 years of data from the Pediatric Dengue Cohort Study and Pediatric Dengue Hospital-based Study in Managua, Nicaragua, investigates the relationship of serotype and immune status with dengue severity. Dengue cases were confirmed by molecular, serological, and/or virological methods, and sudy participants 6 months to 17 years old were followed during their hospital stay or as ambulatory patients.'}, {'@Label': 'RESULTS', '@NlmCategory': 'RESULTS', '#text': 'We enrolled a total of 15,266 participants, of whom 3,227 (21%) were positive for DENV infection. Of 2,630 cases with serotype result by RT-PCR, 557 corresponded to DENV1, 992 to DENV2, 759 to DENV3 and 322 to DENV4. Severe disease was more prevalent among secondary DENV2 and DENV4 cases, while similar disease severity was observed in both primary and secondary DENV1 and DENV3 cases. According to the 1997 World Health Organization (WHO) severity classification, both DENV2 and DENV3 caused a higher proportion of severe disease compared to other serotypes, whereas DENV3 caused the greatest percentage of severity according to the WHO-2009 classification. DENV2 was associated with increased odds of pleural effusion and low platelet count, while DENV3 was associated with both hypotensive and compensated shock.'}, {'@Label': 'CONCLUSIONS', '@NlmCategory': 'CONCLUSIONS', '#text': 'These findings demonstrate differences in dengue severity by serotype and immune status and emphasize the critical need for a dengue vaccine with balanced effectiveness against all four serotypes, particularly as existing vaccines show variable efficacy by serotype and serostatus.'}]
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.\.
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