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Benaroya Research Institute (6)
Columbia University (52)
HIPC 1 (2010) (699)
HIPC 2 (2015) (474)
HIPC 3 (2022) (169)
Icahn School of Medicine at Mount Sinai (26)
La Jolla Institute for Immunology (50)
Massachusetts Institute of technology (10)
Seattle Children's Research Institute (20)
Stanford (50)
Yale University (51)
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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.'}]
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.
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.
Ou BS, Baillet J, Filsinger Interrante MV, Adamska JZ, Zhou X, Saouaf OM, Yan J, Klich JH, Jons CK, Meany EL, Valdez AS, Carter L, Pulendran B, King NP, Appel EA
bioRxiv : the preprint server for biology
2024-06-27
PMID: 37577608
HIPC 3 (2022)
Stanford
Abstract:
[{'@Label': 'UNLABELLED', '#text': 'Over the past few decades, the development of potent and safe immune-activating adjuvant technologies has become the heart of intensive research in the constant fight against highly mutative and immune evasive viruses such as influenza, SARS-CoV-2, and HIV. Herein, we developed a highly modular saponin-based nanoparticle platform incorporating toll-like receptor agonists (TLRas) including TLR1/2a, TLR4a, TLR7/8a adjuvants and their mixtures. These various TLRa-SNP adjuvant constructs induce unique acute cytokine and immune-signaling profiles, leading to specific Th-responses that could be of interest depending on the target disease for prevention. In a murine vaccine study, the adjuvants greatly improved the potency, durability, breadth, and neutralization of both COVID-19 and HIV vaccine candidates, suggesting the potential broad application of these adjuvant constructs to a range of different antigens. Overall, this work demonstrates a modular TLRa-SNP adjuvant platform which could improve the design of vaccines for and dramatically impact modern vaccine development.'}, {'@Label': 'TEASER', '@NlmCategory': 'UNASSIGNED', '#text': 'Saponin-TLRa nanoadjuvants provide distinct immune signatures and drive potent, broad, durable COVID-19 and HIV vaccine responses.'}]
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
2024-06-25
PMID: 38917323
HIPC 3 (2022)
Icahn School of Medicine at Mount Sinai
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.
Suryadevara V, Hudgins AD, Rajesh A, Pappalardo A, Karpova A, Dey AK, Hertzel A, Agudelo A, Rocha A, Soygur B, Schilling B, Carver CM, Aguayo-Mazzucato C, Baker DJ, Bernlohr DA, Jurk D, Mangarova DB, Quardokus EM, Enninga EAL, Schmidt EL, Chen F, Duncan FE, Cambuli F, Kaur G, Kuchel GA, ...
Nature reviews. Molecular cell biology
2024-06-03
PMID: 38831121
HIPC 1 (2010)
HIPC 2 (2015)
HIPC 3 (2022)
Yale University
Abstract:
Once considered a tissue culture-specific phenomenon, cellular senescence has now been linked to various biological processes with both beneficial and detrimental roles in humans, rodents and other species. Much of our understanding of senescent cell biology still originates from tissue culture studies, where each cell in the culture is driven to an irreversible cell cycle arrest. By contrast, in tissues, these cells are relatively rare and difficult to characterize, and it is now established that fully differentiated, postmitotic cells can also acquire a senescence phenotype. The SenNet Biomarkers Working Group was formed to provide recommendations for the use of cellular senescence markers to identify and characterize senescent cells in tissues. Here, we provide recommendations for detecting senescent cells in different tissues based on a comprehensive analysis of existing literature reporting senescence markers in 14 tissues in mice and humans. We discuss some of the recent advances in detecting and characterizing cellular senescence, including molecular senescence signatures and morphological features, and the use of circulating markers. We aim for this work to be a valuable resource for both seasoned investigators in senescence-related studies and newcomers to the field.
Viode A, Smolen KK, van Zalm P, Stevenson D, Jha M, Parker K, Levy O, Steen JA, Steen H
Science advances
2024-05-24
PMID: 38787940
Adult
Aged
Biomarkers
Blood Proteins
COVID-19
Female
HIPC 1 (2010)
HIPC 2 (2015)
HIPC 3 (2022)
Hospitalization
Humans
Longitudinal Studies
Male
Middle Aged
Prognosis
Proteome
Proteomics
SARS-CoV-2
Severity of Illness Index
Yale University
Abstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by highly heterogeneous manifestations ranging from asymptomatic cases to death for still incompletely understood reasons. As part of the IMmunoPhenotyping Assessment in a COVID-19 Cohort study, we mapped the plasma proteomes of 1117 hospitalized patients with COVID-19 from 15 hospitals across the United States. Up to six samples were collected within ~28 days of hospitalization resulting in one of the largest COVID-19 plasma proteomics cohorts with 2934 samples. Using perchloric acid to deplete the most abundant plasma proteins allowed for detecting 2910 proteins. Our findings show that increased levels of neutrophil extracellular trap and heart damage markers are associated with fatal outcomes. Our analysis also identified prognostic biomarkers for worsening severity and death. Our comprehensive longitudinal plasma proteomics study, involving 1117 participants and 2934 samples, allowed for testing the generalizability of the findings of many previous COVID-19 plasma proteomics studies using much smaller cohorts.
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