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Jones DC, Elz AE, Hadadianpour A, Ryu H, Glass DR, Newell EW
Nature methods
2025-05-22
PMID: 40404994
HIPC 2 (2015)
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 these data murky by misattributing large numbers of transcripts to nearby cells or conjuring nonexistent cells. We adopt methods from ab initio cell simulation, in a method called Proseg (probabilistic segmentation), to rapidly infer morphologically plausible cell boundaries. Benchmarking applied to datasets generated by three commercial platforms shows superior performance and computational efficiency of Proseg when compared to existing methods. We show that improved accuracy in cell segmentation aids greatly in detection of difficult-to-segment tumor-infiltrating immune cells such as neutrophils and T cells. Last, 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 samples from patients with renal cell carcinoma.
Davis-Porada J, Tozlu C, Aiello C, Apostolidis SA, Bar-Or A, Bove R, Espinoza DA, Ferreira Brito S, Jacobs D, Kakara M, Onomichi K, Ricci A, Sabatino JJ, Walker E, Wherry EJ, Zhang L, Zhu W, Xia Z, De Jager P, Wesley SF, Straus Farber R, Farber DL
NPJ vaccines
2025-05-17
PMID: 40382362
Columbia University
HIPC 2 (2015)
HIPC 3 (2022)
Abstract:
Immune-mediated protection generated to COVID-19 mRNA vaccines is associated with anti-Spike (S) protein neutralizing antibodies. However, humoral immunity is compromised in B cell depleting (BCD) therapies, used to treat autoimmune diseases such as Multiple Sclerosis (MS). To study the effect of BCD on the durability and protective efficacy of vaccine-induced immunity, we evaluated S-reactive antibodies and T cell responses 1-70 weeks post-vaccination in MS cohorts treated with BCD compared to non-BCD therapies from four centers. BCD-treated participants had significantly reduced antibody levels and enhanced frequencies of S-reactive CD4+ and CD8+ memory T cells to COVID-19 vaccination compared to the non-BCD group, with some variations among different BCD formulations. T cell memory responses persisted up to 14 months post-vaccination in both BCD and non-BCD cohorts, who experienced similar clinical protection from COVID-19. Together, our results establish a critical role for T cell-mediated immunity in anti-viral protection independent of humoral immunity.
Feng Y, de Jong SE, Oliveira APBN, Samaha H, Yang F, Hu M, Wang Y, Beydoun N, Xie X, Zhang H, Kazmin D, Fang Z, Zou J, Gewirtz AT, Boyd SD, Hagan T, Rouphael N, Pulendran B
Cell host & microbe
2025-05-14
PMID: 40252648
Anti-Bacterial Agents
Antibodies, Viral
Bile Acids and Salts
Female
Gastrointestinal Microbiome
HIPC 3 (2022)
Humans
Immunity, Humoral
Male
Rabies
Rabies Vaccines
Stanford
Th1 Cells
Vaccination
Abstract:
The gut microbiome plays a crucial role in modulating human immunity. Previously, we reported that antibiotic-induced microbiome perturbation affects influenza vaccine responses, depending on pre-existing immunity levels. Here, we employed a systems biology approach to analyze the impact of antibiotic administration on both primary and secondary immune responses to the rabies vaccine in humans. Antibiotic administration reduced the gut bacterial load, with a long-lasting reduction in commensal diversity. This alteration was associated with reduced rabies-specific humoral responses. Multi-omics profiling revealed that antibiotic administration induced (1) an enhanced pro-inflammatory signature early after vaccination, (2) a shift in the balance of vaccine-specific T-helper 1 (Th1) to T-follicular-helper response toward Th1 phenotype, and (3) profound alterations in metabolites, particularly in secondary bile acids in the blood. By integrating multi-omics datasets, we generated a multiscale, multi-response network that revealed key regulatory nodes, including the microbiota, secondary bile acids, and humoral immunity to vaccination.
Haralambieva IH, Ratishvili T, Goergen KM, Grill DE, Simon WL, Chen J, Ovsyannikova IG, Poland GA, Kennedy RB
Vaccine
2025-05-10
PMID: 40127573
Adult
Antibodies, Neutralizing
Antibodies, Viral
B-Lymphocytes
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Female
Hemagglutination Inhibition Tests
HIPC 1 (2010)
Humans
Influenza, Human
Influenza Vaccines
Killer Cells, Natural
Lymphocytes
Male
MicroRNAs
Middle Aged
Vaccines, Inactivated
Young Adult
Abstract:
Alterations of gene expression by miRNAs contribute substantially to genetic regulation and cellular functions. We conducted a comprehensive study in 53 individuals before and after seasonal inactivated influenza vaccine to characterize lymphocyte-specific miRNA expression (in purified B cells, CD4+ T cells, CD8+ T cells, and NK cells) and its effect on influenza vaccine-induced immune outcomes (hemagglutination inhibition antibody titers/HAI, viral neutralizing antibody titers /VNA, and memory B cell ELISPOT). Overall, we observed relatively stable miRNA expression before and after influenza vaccination. Statistical analysis uncovered three baseline miRNAs (miR-150-3p, miR-629-5p, and miR-4443) that were significantly correlated with influenza vaccine-induced immune outcomes in different cell types. Predictive modeling of influenza vaccine-induced HAI/VNA titers identified a set of specific baseline miRNAs in CD4+ T cells as factors predictive of antibody responses. A pathway enrichment analysis on the putative target genes revealed several regulated signaling pathways and functions: TGF-β signaling, PI3K-Akt signaling, p53 signaling, MAPK signaling, TNF signaling, and C-type lectin receptor signaling, as well as cell adhesion and adherens junctions, and antiviral host response. In conclusion, our study offers evidence for the role of epigenetic modification (miRNAs) on influenza vaccine-induced immunity. After validation, identified miRNAs may serve as potential biomarkers of immune response after influenza vaccination.
Krammer F, Hermann E, Rasmussen AL
Journal of virology
2025-04-15
PMID: 40145745
Animals
Birds
Cattle
Disease Outbreaks
HIPC 3 (2022)
History, 20th Century
History, 21st Century
Humans
Icahn School of Medicine at Mount Sinai
Influenza A Virus, H5N1 Subtype
Influenza, Human
Influenza in Birds
Pandemics
Poultry
Viral Zoonoses
Zoonoses
Abstract:
The H5N1 avian panzootic has resulted in cross-species transmission to birds and mammals, causing outbreaks in wildlife, poultry, and US dairy cattle with a range of host-dependent pathogenic outcomes. Although no human-to-human transmission has been observed, the rising number of zoonotic human cases creates opportunities for adaptive mutation or reassortment. This Gem explores the history, evolution, virology, and epidemiology of clade 2.3.4.4b H5N1 relative to its pandemic potential. Pandemic risk reduction measures are urgently required.
Wan M, Simonin EM, Johnson MM, Zhang X, Lin X, Gao P, Patel CJ, Yousuf A, Snyder MP, Hong X, Wang X, Sampath V, Nadeau KC
EMBO molecular medicine
2025-04-01
PMID: 39870881
Environmental Exposure
Exposome
HIPC 3 (2022)
Humans
Molecular Medicine
Precision Medicine
Stanford
Abstract:
The exposome is the measure of all the exposures of an individual in a lifetime and how those exposures relate to health. Exposomics is the emerging field of research to measure and study the totality of the exposome. Exposomics can assist with molecular medicine by furthering our understanding of how the exposome influences cellular and molecular processes such as gene expression, epigenetic modifications, metabolic pathways, and immune responses. These molecular alterations can aid as biomarkers for the diagnosis, disease prediction, early detection, and treatment and offering new avenues for personalized medicine. Advances in high throughput omics and other technologies as well as increased computational analytics is enabling comprehensive measurement and sophisticated analysis of the exposome to elucidate their cumulative and combined impacts on health, which can enable individuals, communities, and policymakers to create programs, policies, and protections that promote healthier environments and people. This review provides an overview of the potential role of exposomics in molecular medicine, covering its history, methodologies, current research and applications, and future directions.
Hart TM, Cui Y, Telford SR, Marín-López A, Calloway K, Dai Y, Matias J, DePonte K, Jaycox J, DeBlasio M, Hoornstra D, Belperron AA, Cibichakravarthy B, Johnson EE, Alameh MG, Dwivedi G, Hovius JWR, Bockenstedt LK, Weissman D, Ring AM, Fikrig E
Science translational medicine
2025-03-26
PMID: 40138454
Animals
Antigens
Feeding Behavior
Female
Guinea Pigs
HIPC 1 (2010)
HIPC 2 (2015)
HIPC 3 (2022)
Humans
Immunoglobulin G
Ixodes
Lyme Disease
Mice
Proteome
Tick Bites
Vaccination
Yale University
Abstract:
Ixodes scapularis is a primary vector of tick-borne pathogens in North America. Repeated exposure to these ticks can induce a humoral response to tick antigens and acquired tick resistance. However, identifying antigens contributing to this resistance is challenging because of the vast number of I. scapularis proteins secreted during feeding. To address this, we developed I. scapularis rapid extracellular antigen monitoring (IscREAM), a technique to detect antibody responses to more than 3000 tick antigens. We validated IscREAM with immunoglobulin G (IgG) from guinea pigs vaccinated with tick antigens, including a cement antigen cocktail that induced tick resistance. Furthermore, we explored the natural response to tick bites by profiling antigens recognized by IgG isolated from a tick-resistant individual, as well as from others with Lyme disease and tick-bitten guinea pigs and mice, to identify 199 recognized antigens. We observed that several antigens contained histamine-binding domains. This work enhances our understanding of the host immune response to I. scapularis and defines immunogen candidates for future antitick vaccines.
Chen G, Mohsin A, Zheng H, Rosenberg-Hasson Y, Padilla C, Sarin KY, Dekker CL, Grant P, Maecker HT, Lu Y, Furman D, Shen-Orr S, Khatri P, Davis MM
Proceedings of the National Academy of Sciences of the United States of America
2025-03-25
PMID: 40117305
Adult
Aged
Aged, 80 and over
Age Factors
Aging
Cellular Senescence
Cytokines
Female
HIPC 1 (2010)
Humans
Longitudinal Studies
Male
Middle Aged
Neoplasms
Abstract:
Aging is associated with increased variability and dysregulation of the immune system. We performed a system-level analysis of serum cytokines in a longitudinal cohort of 133 healthy individuals over 9 y. We found that cancer incidence is a major contributor to increased cytokine abundance variability. Circulating cytokines increase up to 4 y before a cancer diagnosis in subjects with age over 80 y. We also analyzed cytokine expression in 10 types of early-stage cancers from The Cancer Genome Atlas. We found that a similar set of cytokines is upregulated in tumor tissues, specifically after the age of 80 y. Similarly, cellular senescence activity and CDKN1A/p21 expression increase with age in cancer tissues. Finally, we demonstrated that the cytokine levels in serum can be used to predict cancers among subjects age at 80+ y. Our results suggest that latent senescent cancers contribute to age-related chronic inflammation.
Cardona-Ospina JA, Roy V, Marcano-Jiménez DE, Bos S, Duarte E, Zambrana JV, Bal A, Dias AG, Zhiteneva J, Huffaker J, Montenegro C, Kuan G, Ramos-Benitez MJ, Balmaseda A, Alter G, Harris E
medRxiv : the preprint server for health sciences
2025-03-24
PMID: 40162272
HIPC 2 (2015)
Abstract:
The four dengue virus serotypes (DENV1-4) and the related Zika flavivirus (ZIKV) are major public health concerns worldwide. Primary immunity against ZIKV increases the risk of a subsequent severe DENV2 infection, presenting a significant challenge for developing safe and effective ZIKV vaccines. However, the mechanisms driving this phenomenon remain unclear. Leveraging our long-standing Pediatric Dengue Cohort Study in Nicaragua, we show that serum anti-NS1 IgA antibodies elicited after a primary ZIKV infection drive neutrophil activation and correlate with increased risk of subsequent severe DENV2 disease. Depletion experiments combined with ex vivo functional NETosis assays confirmed that anti-NS1 IgA antibodies drive neutrophil activation in dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Moreover, increased neutrophil degranulation in paired serum samples obtained during the acute DENV2 infection from the same individuals correlated with IgA binding to DENV2 NS1 and preceded the development of vascular leakage. This finding was corroborated in an orthogonal hospital-based study. Thus, serum anti-NS1 IgA enhances neutrophil activation in severe dengue, with implications for prognostics, therapeutics, and vaccines.
Rao V, Sapse I, Cohn H, Yoo DK, Tong P, Clark J, Bozarth B, Chen Y, Srivastava K, Singh G, Krammer F, Simon V, Wesemann D, Bajic G, Coelho CH
bioRxiv : the preprint server for biology
2025-03-10
PMID: 40161664
HIPC 3 (2022)
Icahn School of Medicine at Mount Sinai
Abstract:
Public antibodies that recognize conserved epitopes are critical for vaccine development, and identifying somatic hypermutations (SHMs) that enhance antigen affinity in these public responses is key to guiding vaccine design for better protection. We propose that affinity-enhancing SHMs are selectively enriched in public antibody clonotypes, surpassing the background frequency seen in antibodies carrying the same V genes, but with different epitope specificities. Employing a human IGHV4-59/IGKV3-20 public antibody as a model, we compare SHM signatures in antibodies also using these V genes, but recognizing other epitopes. Critically, this comparison identified clonotype-enriched mutations in the light chain. Our analyses also show that these SHMs, in combination, enhance binding to a previously uncharacterized viral epitope, with antibody responses to it increasing after multiple vaccinations. Our findings offer a framework for identifying affinity-enhancing SHMs in public antibodies based on convergence and clonotype-enrichment and can help guide vaccine design aimed to elicit public antibodies.
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