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Immport Dataset Available (21)
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HIPC Centers
Benaroya Research Institute (13)
Columbia University (19)
HIPC 1 (2010) (699)
HIPC 2 (2015) (725)
HIPC 3 (2022) (180)
Icahn School of Medicine at Mount Sinai (29)
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Publication Keywords
Immport Dataset Available (21)
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Pallarés HM, González López Ledesma MM, Oviedo-Rouco S, Castellano LA, Costa Navarro GS, Fernández-Alvarez AJ, D'Andreiz MJ, Aldas-Bulos VD, Alvarez DE, Bazzini AA, Gamarnik AV
Nucleic acids research
2024-10-14
PMID: 38917323
Animals
Cell Line
Chlorocebus aethiops
eIF-2 Kinase
HEK293 Cells
HIPC 3 (2022)
Humans
Icahn School of Medicine at Mount Sinai
Protein Biosynthesis
RNA, Untranslated
RNA, Viral
Virus Replication
Zika Virus
Zika Virus Infection
Abstract:
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that causes severe outbreaks in human populations. ZIKV infection leads to the accumulation of small non-coding viral RNAs (known as sfRNAs) that are crucial for evasion of antiviral responses and for viral pathogenesis. However, the mechanistic understanding of how sfRNAs function remains incomplete. Here, we use recombinant ZIKVs and ribosome profiling of infected human cells to show that sfRNAs block translation of antiviral genes. Mechanistically, we demonstrate that specific RNA structures present in sfRNAs trigger PKR activation, which instead of limiting viral replication, enhances viral particle production. Although ZIKV infection induces mRNA expression of antiviral genes, translation efficiency of type I interferon and interferon stimulated genes were significantly downregulated by PKR activation. Our results reveal a novel viral adaptation mechanism mediated by sfRNAs, where ZIKV increases its fitness by repurposing the antiviral role of PKR into a proviral factor.
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.
Kang N, Chawla A, Hillman H, Tippalagama R, Kim C, Mikulski Z, Seumois G, Vijayanand P, Scriba TJ, De Silva AD, Balmaseda A, Harris E, Weiskopf D, Sette A, Arlehamn CL, Peters B, Burel JG
bioRxiv : the preprint server for biology
2024-09-23
PMID: 39386643
HIPC 2 (2015)
HIPC 3 (2022)
La Jolla Institute for Immunology
Abstract:
Communication between immune cells through direct contact is a critical feature of immune responses. Here, we developed a novel high-throughput method to study the transcriptome and adaptive immune receptor repertoire of single cells forming complexes without needing bioinformatic deconvolution. We found that T cells and monocytes forming complexes in blood during active tuberculosis (TB) and dengue hold unique transcriptomic signatures indicative of TCR/MCH-II immune synapses. Additionally, T cells in complexes showed enrichment for effector phenotypes, imaging and transcriptomic features of active TCR signaling, and increased immune activity at diagnosis compared to after anti-TB therapy. We also found evidence for bidirectional RNA exchange between T cells and monocytes, since complexes were markedly enriched for "dual-expressing" cells (i.e., co-expressing T cell and monocyte genes). Thus, studying immune cell complexes at a single-cell resolution offers novel perspectives on immune synaptic interactions occurring in blood during infection.
Holmes EC, Krammer F, Goodrum FD
Cell
2024-09-19
PMID: 39303682
COVID-19
HIPC 3 (2022)
History, 21st Century
Host-Pathogen Interactions
Humans
Icahn School of Medicine at Mount Sinai
Pandemics
SARS-CoV-2
Virology
Virus Diseases
Viruses
Abstract:
Virology has made enormous advances in the last 50 years but has never faced such scrutiny as it does today. Herein, we outline some of the major advances made in virology during this period, particularly in light of the COVID-19 pandemic, and suggest some areas that may be of research importance in the next 50 years. We focus on several linked themes: cataloging the genomic and phenotypic diversity of the virosphere; understanding disease emergence; future directions in viral disease therapies, vaccines, and interventions; host-virus interactions; the role of viruses in chronic diseases; and viruses as tools for cell biology. We highlight the challenges that virology will face moving forward-not just the scientific and technical but also the social and political. Although there are inherent limitations in trying to outline the virology of the future, we hope this article will help inspire the next generation of virologists.
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.
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