Francisco Heredia-Fernández, Javier Martínez-López, Laura C Terrón-Camero, Desiré Casares-Marfil, Pau Bosch-Nicolau, Israel Molina, Javier Martín, Marialbert Acosta-Herrera
{"title":"Integrated Methylome and Transcriptome Analysis in Chronic Chagas Cardiomyopathy Uncovers Alterations in Heart Development.","authors":"Francisco Heredia-Fernández, Javier Martínez-López, Laura C Terrón-Camero, Desiré Casares-Marfil, Pau Bosch-Nicolau, Israel Molina, Javier Martín, Marialbert Acosta-Herrera","doi":"10.1093/infdis/jiag145","DOIUrl":"https://doi.org/10.1093/infdis/jiag145","url":null,"abstract":"<p><strong>Background: </strong>Chagas disease, caused by Trypanosoma cruzi, remains a health concern worldwide. Its most severe clinical outcome, chronic Chagas cardiomyopathy (CCC), is marked by progressive cardiac dysfunction. Biological mechanisms underlying the differential development of CCC remain unclear. We hypothesized that alterations in the host DNA methylation and its influence on gene expression may contribute to this differential disease progression.</p><p><strong>Methods: </strong>We analyzed whole-blood methylation data from 42 CCC patients and 23 individuals with the indeterminate form, followed by an integrated transcriptomic analysis in a 22 individuals subset. We performed transcription factor (TF) and functional enrichment analyses to identify biological mechanisms underlying CCC severity.</p><p><strong>Results: </strong>Severe CCC patients exhibited higher methylation variability, particularly in immune regulation genes. Integrated analysis revealed dysregulation of genes regulating cardiac development, morphogenesis, and ion homeostasis, with GATA5 as a key TF regulating cardiac pathways. TF activity inferred from peripheral blood resembled cardiac signatures previously described, with RUNX TFs, key drivers of Th1 immune polarization, correlating strongly with disease severity.</p><p><strong>Conclusions: </strong>Our findings highlight a systemic epigenetic signature in blood that reflects cardiac pathology in CCC. These insights advance our understanding of CCC pathogenesis and facilitate novel blood-based biomarkers and therapeutic targets aimed at preventing disease progression.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148622039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Power of Public Science: Lessons from TV003 and Butantan-DV.","authors":"Felippe Lazar, Anna P Durbin","doi":"10.1093/infdis/jiag396","DOIUrl":"https://doi.org/10.1093/infdis/jiag396","url":null,"abstract":"","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148632545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Exosomal programmed death ligand 1 in patients with Mycobacterium avium complex lung disease.","authors":"Chi-Yu Hsu, Bo-Shiun Yan, Juo-Hsin Lai, Yu-Li Lin, Chun-Kai Pan, Tsung-Hsuan Huang, Jyy-Jih Tsai-Wu, Yin-Wen Shiue, Chin-Chung Shu","doi":"10.1093/infdis/jiag391","DOIUrl":"https://doi.org/10.1093/infdis/jiag391","url":null,"abstract":"<p><strong>Background: </strong>Mycobacterium avium complex lung disease (MAC-LD) is increasing worldwide. Exosomal programmed death-ligand 1 (PD-L1) has been scarcely investigated in MAC-LD.</p><p><strong>Methods: </strong>Plasma exosomes and their PD-L1 from MAC-LD patients and healthy controls were measured and used for co-culturing Jurkat cells with or without PD-L1/PD-1 blocking antibodies. MAC-infected mice were treated with exosome inhibitors to assess exosomal PD-L1 and bacterial burden.</p><p><strong>Results: </strong>Plasma exosomal PD-L1 levels were significantly higher in MAC-LD patients (1,477±1,243 pg/mL) vs. controls (183.8±113.9 pg/mL; P < .001), correlated with cavitary disease (2,415±1,309 vs. 844.1±652.2 pg/mL; P = .008) and decreased after treatment (1,474±961.3 vs. 738.5±820.4 pg/mL; P = .03). MAC-infected macrophage exosomes decreased Jurkat cell survival (72.9±11.5% vs. 98.2±0.6%; P < .01), which could be reversed by PD-L1/PD-1 antibodies. In the mouse study, GW4869 (an exosome biogenesis inhibitor) reduced lung exosomal PD-L1 (497.6±123.1 to 197.7±116.4 pg/mL; P = .008) and bacterial load (996,400±96,316 to 116,400±18,528 CFU; P = .008), whereas DMA (an exosome release inhibitor) showed no significant effect on lung exosome and bacterial load.</p><p><strong>Conclusions: </strong>Exosomal PD-L1 promotes immune suppression and reflects disease severity in MAC-LD. Inhibition of exosome biogenesis reduced exosomal PD-L1 levels and MAC burden in lung, supporting a potential therapeutic avenue that requires further validation.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148632495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Willem R Miellet, Sónia T Almeida, Raquel Sá-Leão, Krzysztof Trzciński
{"title":"Correspondence to \"Indirect Effect of Pneumococcal Conjugate Vaccines on Pneumococcal Colonization: Persistence and Dynamics of Vaccine Serotypes in Sicily (Italy) 11 Years Postintroduction, 2009-2020\" by Tramuto et al.","authors":"Willem R Miellet, Sónia T Almeida, Raquel Sá-Leão, Krzysztof Trzciński","doi":"10.1093/infdis/jiag387","DOIUrl":"https://doi.org/10.1093/infdis/jiag387","url":null,"abstract":"","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148609693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sultanah Alharthi, Nusrat J Epsi, David A Lindholm, Pavol Genzor, Milissa Jones, Heba H Mostafa, Anuradha Ganesan, Rupal Mody, Katrin Mende, Manish Bhomia, Carlos Maldonado, Timothy Burgess, David Tribble, Mark P Simons, Rhonda E Colombo, Stephanie A Richard, Brian K Agan, Clifton L Dalgard, John S Dumler, Simon D Pollett, Paul W Blair
{"title":"RNAemia and Severe COVID-19: Candidate Treatment Targets Identified Through Transcriptomics.","authors":"Sultanah Alharthi, Nusrat J Epsi, David A Lindholm, Pavol Genzor, Milissa Jones, Heba H Mostafa, Anuradha Ganesan, Rupal Mody, Katrin Mende, Manish Bhomia, Carlos Maldonado, Timothy Burgess, David Tribble, Mark P Simons, Rhonda E Colombo, Stephanie A Richard, Brian K Agan, Clifton L Dalgard, John S Dumler, Simon D Pollett, Paul W Blair","doi":"10.1093/infdis/jiag390","DOIUrl":"https://doi.org/10.1093/infdis/jiag390","url":null,"abstract":"<p><strong>Introduction: </strong>The presence of SARS-CoV-2 RNA in blood has been proposed as a marker of severe COVID-19, but it is unclear whether RNAemia mediates the pathway toward worsening disease. We hypothesized that RNAemia is associated with severe disease and distinct gene expression patterns are associated with RNAemia and severe COVID-19. These RNAemia-associated patterns may identify COVID-19 treatment targets.</p><p><strong>Methods: </strong>We analyzed 202 hospitalized COVID-19 participants from a multi-center U.S. Military Health System cohort using digital droplet PCR (ddPCR) to quantify SARS-CoV-2 RNA in plasma and performed host RNA sequencing of peripheral blood. Differential gene expression (DGE) logistic regression models were used to assess associations among RNAemia, host gene expression, and disease severity.</p><p><strong>Results: </strong>RNAemia was detected in 39.1% of participants and was associated with severe disease (54% vs. 32% in RNAemia-negative participants; p <0.001). In final adjusted models, independent predictors of severity included RNAemia (adjusted Odds Ratio [aOR] range 1.99-2.24, all p ≤ 0.04), as well as host genes ADAMTS2 (aOR = 1.58, p < 0.001), OLAH (aOR = 1.55, p < 0.001), and PCSK9 (aOR = 1.60, p < 0.001).</p><p><strong>Discussion: </strong>RNAemia is an independent predictor of COVID-19 severity. However, host gene expression changes associated with RNAemia, particularly involving OLAH, PCSK9, and ADAMTS2, had stronger statistical evidence of severe outcomes than RNAemia itself. PCSK9 is an intervenable treatment target worth further study.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148622284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Valeriia Timonina, Konstantin Popadin, Mariam Ait Oumelloul, Alexandra Calmy, Matthias Cavassini, Gioele Capoferri, Huldrych F Günthard, Laura N Walti, Patrick Schmid, Philip E Tarr, Christian W Thorball, Alexander G Bick, Jacques Fellay
{"title":"Epidemiology and Clinical Impact of Clonal Hematopoiesis in People with HIV.","authors":"Valeriia Timonina, Konstantin Popadin, Mariam Ait Oumelloul, Alexandra Calmy, Matthias Cavassini, Gioele Capoferri, Huldrych F Günthard, Laura N Walti, Patrick Schmid, Philip E Tarr, Christian W Thorball, Alexander G Bick, Jacques Fellay","doi":"10.1093/infdis/jiag393","DOIUrl":"https://doi.org/10.1093/infdis/jiag393","url":null,"abstract":"<p><strong>Background: </strong>Clonal hematopoiesis (CH), defined by the expansion of hematopoietic cells with somatic mutations in leukemogenic genes (CH of indeterminate potential (CHIP)) or with mosaic chromosomal alterations (mCAs), is associated with aging and adverse health outcomes in the general population. CHIP prevalence is higher in People with HIV (PWH) than in controls. However, the full spectrum, prevalence, and clinical consequences of CH in PWH remain incompletely understood.</p><p><strong>Methods: </strong>We assessed CHIP and mCAs in a large sample of PWH (N∼2,500) from the Swiss HIV Cohort Study. Using high-depth targeted sequencing of CHIP genes and genome-wide genotyping to call mCAs, we quantified the prevalence and clone size of both CH types and investigated an association of CH with clinical variables.</p><p><strong>Results: </strong>CHIP (25% of individuals) and mCAs (16% of individuals) were common, positively correlated with age, often co-occurring (OR=1.7, p=0.02 for autosomal mCAs), and associated with various clinical outcomes, including all-cause mortality (HR=1.3, p=0.02 for CHIP) and hematologic malignancies (HR=9.4, p=0.01 for the effect of CHIP on the risk of myeloid cancer; HR>20, p<0.001 for the effect of co-occurring CHIP and mCAs on the risk of lymphoid cancer). We also observed associations of CH with several proxies of inflammatory status (CD4:CD8 ratio, HIV viral load, late initiation of antiretroviral therapy, and toxicity of antiretroviral drugs).</p><p><strong>Conclusion: </strong>The study provides a comprehensive assessment of the CH landscape in PWH, highlighting potential causes and consequences in this population and suggesting an interaction between CH and chronic immune activation.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148609670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Metabolic Mechanisms of INSTI-Associated Weight Gain: A Multi-Omics Study in Male People with HIV.","authors":"Xin Huang, Ziyan Wang, Yixuan Wang, Xiaojing Song, Leidan Zhang, Liyuan Zheng, Fada Wang, Taisheng Li, Wei Cao","doi":"10.1093/infdis/jiag385","DOIUrl":"https://doi.org/10.1093/infdis/jiag385","url":null,"abstract":"<p><strong>Background: </strong>Integrase Strand Transfer Inhibitors (INSTI) are recommended as first-line antiretroviral therapy (ART) for HIV infection, yet are frequently associated with excessive weight gain.</p><p><strong>Methods: </strong>We conducted a multi-omics study on male people with HIV (PWH). A total of 64 male PWH were enrolled and stratified based on their therapeutic history and weight changes over the first year (G1 receiving INSTI with weight gain ≥ 5%; G2 switching to INSTI with weight gain ≥ 5%; and G3 switching to INSTI without weight gain). INSTI-based regimens included bictegravir-, elvitegravir-, and dolutegravir-containing combinations. 26 healthy male controls were also included. Plasma untargeted metabolomics and proteomics were analyzed longitudinally. Machine learning models were employed to integrate multi-omics data and identify predictive biomarkers.</p><p><strong>Results: </strong>Metabolomic analysis revealed that switching to INSTI induced a generalized hypometabolic state, characterized by a universal decline in thyroxine and an increase in N-acetylputrescine across all switching groups, independent of weight outcomes. In contrast, proteomic profiling identified distinct molecular drivers specific to the weight-gain groups. Random forest modeling identified transthyretin (TTR) as the top predictive biomarker among pre-INSTI multi-omics features.</p><p><strong>Conclusion: </strong>Our integrated multi-omics approach reveals that INSTI-based regimens induce universal metabolic changes. The change of thyroxine and the predictability of TTR in multi-omic studies show the critical role of thyroxine metabolism in INSTI-associated weight gain.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148609702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Hurt Immunity? Measles Increasing in the US Despite High Seroprevalence.","authors":"Robert Schechter","doi":"10.1093/infdis/jiag389","DOIUrl":"https://doi.org/10.1093/infdis/jiag389","url":null,"abstract":"","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148594329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Vaccines in the Golden Years.","authors":"H Keipp Talbot","doi":"10.1093/infdis/jiag382","DOIUrl":"https://doi.org/10.1093/infdis/jiag382","url":null,"abstract":"","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148563452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}