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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
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
Cyclin-Dependent Kinase Inhibitor p21
Cytokines
Female
HIPC 1 (2010)
Humans
Inflammation
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.
Haralambieva IH, Ratishvili T, Goergen KM, Grill DE, Simon WL, Chen J, Ovsyannikova IG, Poland GA, Kennedy RB
Vaccine
2025-03-23
PMID: 40127573
HIPC 1 (2010)
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.
Bustos Carrillo FA, Ojeda S, Sanchez N, Plazaola M, Collado D, Miranda T, Saborio S, Lopez Mercado B, Carey Monterrey J, Arguello S, Campredon L, Chu Z, Carlson CJ, Gordon A, Balmaseda A, Kuan G, Harris E
medRxiv : the preprint server for health sciences
2025-03-22
PMID: 39830280
HIPC 2 (2015)
Abstract:
[{'@Label': 'BACKGROUND', '@NlmCategory': 'UNASSIGNED', '#text': 'Dengue, chikungunya, and Zika are diseases of major human concern. Differential diagnosis is complicated in children and adolescents by their overlapping clinical features (signs, symptoms, and complete blood count results). Few studies have directly compared the three diseases. We aimed to identify distinguishing pediatric characteristics of each disease.'}, {'@Label': 'METHODS', '@NlmCategory': 'UNASSIGNED', '#text': 'Data were derived from laboratory-confirmed cases aged 2-17 years enrolled in a longitudinal cohort study in Managua, Nicaragua, and attending a primary health care center from January 2006 through December 2023. We collected clinical records and laboratory results across the first 10 days of illness. Data were analyzed with generalized additive models, generalized linear mixed models, and machine learning models.'}, {'@Label': 'FINDINGS', '@NlmCategory': 'UNASSIGNED', '#text': 'We characterized 1,405 dengue, 517 chikungunya, and 522 Zika pediatric cases. The prevalence of many clinical features exhibited by dengue, chikungunya, and Zika cases differed substantially overall, by age, and by day of illness. Dengue cases were differentiated most by abdominal pain, leukopenia, nausea, vomiting, and basophilia; chikungunya cases were differentiated most by arthralgia and the absence of leukopenia and papular rash; and Zika cases were differentiated most by rash and the lack of fever and lymphocytopenia. Dengue and chikungunya cases exhibited similar temperature dynamics during acute illness, and their temperatures were higher than Zika cases. Sixty-two laboratory-confirmed afebrile dengue cases, which would not be captured by any widely used international case definition, presented very similarly to afebrile Zika cases, though some exhibited warning signs of disease severity. The presence of arthralgia, the presence of basophilia, and the absence of fever were the most important model-based distinguishing predictors of chikungunya, dengue, and Zika, respectively.'}, {'@Label': 'INTERPRETATIONS', '@NlmCategory': 'UNASSIGNED', '#text': 'These findings substantially update our understanding of dengue, chikungunya, and Zika in children while identifying various clinical features that could improve differential diagnoses. The occurrence of afebrile dengue warrants reconsideration of current case definitions.'}, {'@Label': 'FUNDING', '@NlmCategory': 'UNASSIGNED', '#text': 'US National Institutes of Health R01AI099631, P01AI106695, U01AI153416, U19AI118610.'}, {'@Label': 'RESEARCH IN CONTEXT', '@NlmCategory': 'UNASSIGNED', '#text': 'Evidence before this study: Dengue, chikungunya, and Zika co-occur in tropical and subtropical settings and cause fever, rash, and other clinical features. We reviewed widely used international case definitions for the three diseases; the Pan American Health Organization\'s (PAHO) 2022 report on differential diagnosis of the diseases; and the 80 studies underlying PAHO\'s diagnostic recommendations. On March 15, 2025, we queried PubMed without restrictions for "pediatric cohort" AND "dengue" AND "chikungunya" AND "Zika," revealing that no other pediatric cohort simultaneously reported clinical differences between the three diseases. The literature suggests that dengue, chikungunya, and Zika have a broad and overlapping set of clinical manifestations that hamper differential diagnosis and case management absent definitive laboratory testing. Mild forms of the diseases during acute illness typically produce the greatest overlap in presentation. Most studies on the diseases\' clinical manifestations are in adults, and these studies constitute the main evidence base for existing case definitions. For example, only one of 80 studies summarized in PAHO\'s recent report directly compared clinical features across cases experiencing dengue, chikungunya, and Zika, and that study mainly focused on adults. Disease presentation is more non-specific in children and adolescents than in adults, further impeding differential diagnoses in pediatric populations. Current guidelines suggest that the presence of thrombocytopenia, progressive increases in hematocrit, and leukopenia tend to distinguish dengue from chikungunya and Zika; that arthralgia is more common in chikungunya; and that pruritis is more common in Zika. All dengue case definitions in widespread use require that patients exhibit fever.Added value of this study: This study follows a cohort of Nicaraguan children through multiple dengue epidemics, two large chikungunya epidemics, and one explosive Zika epidemic. By synthesizing 18 years\' worth of primary care medical records, we find clinically meaningful differences in the prevalence of many clinical features, including by day of illness and across age, but not by sex. In addition to verifying the clinical features PAHO identified as key distinguishing features, we also identified others, including papular rash, nausea, hemorrhagic manifestations, abdominal pain, and basophilia, that could aid differential diagnoses. As the PAHO report is based on a multitude of studies with varied age ranges, health care accessibility, overall research quality, and patient populations, this study is a complementary and important counterpart that draws from a single, well-characterized source population. Further, we identified 62 laboratory-confirmed cases of afebrile dengue (7·1% of all dengue cases since we started testing any suspected case exhibiting afebrile rash). The disease manifestations of afebrile dengue cases were generally clinically indistinguishable from afebrile Zika, although several displayed warning signs of severity. We found that cases of the three diseases exhibited different temperature dynamics across the acute period of illness. Machine learning models best distinguished chikungunya (an alphaviral disease) from dengue and Zika (flaviviral diseases) based on clinical features. Our dengue model performed well, especially in classifying febrile dengue cases. However, our Zika model struggled to properly distinguish afebrile dengue cases from afebrile Zika cases, likely due to their very similar and minimal disease presentation.Implications of all the available evidence: Despite clinical overlap in the pediatric manifestations of dengue, chikungunya, and Zika, we identify meaningful differences in their presentation and in laboratory markers that can be leveraged to improve diagnoses in the absence of definitive laboratory-based diagnostic testing. Afebrile dengue should be studied more and incorporated into future case definitions, as not accounting for its existence can impede surveillance, laboratory testing strategies, clinical management, and research efforts.'}]
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.
Petrova B, Syphurs C, Culhane AJ, Chen J, Chen E, Cotsapas C, Esserman D, Montgomery R, Kleinstein S, Smolen K, Mendez K, Lasky-Su J, Steen H, Levy O, Diray-Arce J, Kanarek N
medRxiv : the preprint server for health sciences
2025-03-03
PMID: 40093216
HIPC 2 (2015)
Abstract:
While the public health burden of SARS-CoV-2 infection has lessened due to natural and vaccine-acquired immunity, the emergence of less virulent variants, and antiviral medications, COVID-19 continues to take a significant toll. There are > 10,000 new hospitalizations per week in the U.S., many of whom develop post-acute sequelae of SARS-CoV-2 (PASC), or "long COVID", with long-term health issues and compromised quality of life. Early identification of individuals at high risk of severe COVID-19 is key for monitoring and supporting respiratory status and improving outcomes. Therefore, precision tools for early detection of patients at high risk of severe disease can reduce morbidity and mortality. Here we report an untargeted and longitudinal metabolomic study of plasma derived from adult patients with COVID-19. One-carbon metabolism, a pathway previously shown as critical for viral propagation and disease progression, and a potential target for COVID-19 treatment, scored strongly as differentially abundant in patients with severe COVID-19. A follow-up targeted metabolite profiling revealed that one arm of the one-carbon metabolism pathway, the methionine cycle, is a major driver of the metabolic profile associated with disease severity. The methionine cycle produces S-adenosylmethionine (SAM), the methyl group donor important for methylation of DNA, RNA, and proteins, and its high abundance was reported to correlate with disease severity. Further, genomic data from the profiled patients revealed a genetic contributor to methionine metabolism and identified the C677T allele of the MTHFR gene as a pre-existing predictor of disease trajectory - patients homozygous for the MTHFR C677T have higher incidence of experiencing severe disease. Our results raise the possibility that screening for the common genetic MTHFR variant may be an actionable approach to stratify risk of COVID severity and may inform novel precision COVID-19 treatment strategies.
Bos S, Zambrana JV, Duarte E, Graber AL, Huffaker J, Montenegro C, Premkumar L, Gordon A, Kuan G, Balmaseda A, Harris E
The Lancet. Infectious diseases
2025-03-01
PMID: 39489898
Adolescent
Child
Child, Preschool
Cohort Studies
Dengue
Dengue Virus
Enzyme-Linked Immunosorbent Assay
Female
HIPC 2 (2015)
Humans
Male
Nicaragua
Prospective Studies
Serogroup
Serotyping
Abstract:
[{'@Label': 'BACKGROUND', '@NlmCategory': 'BACKGROUND', '#text': 'Dengue is the most prevalent mosquito-borne viral disease and a major public health problem worldwide. Most primary infections with the four dengue virus serotypes (DENV1-4) are inapparent; nonetheless, whether the distribution of symptomatic versus inapparent infections by serotype varies remains unknown. Here, we present (1) the evaluation of a DENV1-4 envelope domain III multiplex microsphere-based assay (EDIII-MMBA) to serotype inapparent primary infections and (2) its application leveraging 17 years of prospective sample collection from the Nicaraguan Pediatric Dengue Cohort Study (PDCS).'}, {'@Label': 'METHODS', '@NlmCategory': 'METHODS', '#text': 'We analysed primary DENV infections in the PDCS from 2004 to 2022 detected by inhibition ELISA (iELISA) or RT-PCR. First, we evaluated the performance of the EDIII-MMBA for serotyping with samples characterised by RT-PCR or focus reduction neutralisation test. Next, we analysed a subset of inapparent primary DENV infections in the PDCS with the EDIII-MMBA to evaluate the epidemiology of inapparent infections. Remaining infections were inferred using stochastic imputation, taking year and neighbourhood into account. Infection incidence and percentage of inapparent, symptomatic, and severe infections were analysed by serotype.'}, {'@Label': 'FINDINGS', '@NlmCategory': 'RESULTS', '#text': 'Between Aug 30, 2004, and March 10, 2022, a total of 5931 DENV-naive participants were followed in the PDCS. There were 1626 primary infections (382 symptomatic, 1244 inapparent) detected by iELISA or RT-PCR over the study period. The EDIII-MMBA demonstrated excellent overall accuracy (100%, 95% CI 95·8-100) for serotyping inapparent primary DENV infections when evaluated against gold-standard serotyping methods. Of the 1244 inapparent infections, we analysed 574 (46%) using the EDIII-MMBA. We found that the majority of primary infections were inapparent, with DENV3 exhibiting the highest likelihood of symptomatic (pooled odds ratio compared with DENV1: 2·13, 95% CI 1·28-3·56) and severe (6·75, 2·01-22·62) primary infections, whereas DENV2 was similar to DENV1 in both analyses. Considerable within-year and between-year variation in serotype distribution between symptomatic and inapparent infections and circulation of serotypes undetected in symptomatic cases were observed in multiple years.'}, {'@Label': 'INTERPRETATION', '@NlmCategory': 'CONCLUSIONS', '#text': 'Our study indicates that case surveillance skews the perceived epidemiological footprint of DENV. We reveal a more complex and intricate pattern of serotype distribution in inapparent infections. The substantial differences in infection outcomes by serotype emphasises the need for vaccines with balanced immunogenicity and efficacy across serotypes.'}, {'@Label': 'FUNDING', '@NlmCategory': 'BACKGROUND', '#text': 'National Institute of Allergy and Infectious Diseases (National Institutes of Health) and Bill & Melinda Gates Foundation.'}, {'@Label': 'TRANSLATION', '@NlmCategory': 'UNASSIGNED', '#text': 'For the Spanish translation of the abstract see Supplementary Materials section.'}]
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