Frontiers in Immunology最新文献

{"title":"Lower pre-conditioning absolute lymphocyte counts are associated with worse outcomes in haploidentical stem cell transplantation with myeloablative regimen in children.","authors":"Kai Cui, Senlin Zhang, Yueke Du, Yutan Chai, Mingchu Liang, Shaoyan Hu, Jie Li","doi":"10.3389/fimmu.2025.1552263","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1552263","url":null,"abstract":"<p><strong>Background: </strong>Anti-thymocyte globulin (ATG) is frequently administered for preventing graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In patients with low absolute lymphocyte count (ALC) before conditioning, weight-based dosing of ATG may cause overexposure, negatively impacting prognosis.</p><p><strong>Method: </strong>Clinical data of patients with hematological malignancies undergoing haploidentical HSCT (haplo-HSCT) at the Children's Hospital of Soochow University from January 2020 to June 2023 were collected. This study primarily aims to investigate the association between pre-conditioning ALC and clinical outcomes in pediatric acute leukemia or myelodysplastic syndromes patients receiving myeloablative haplo-HSCT.</p><p><strong>Results: </strong>We included 130 patients treated at the Children's Hospital of Soochow University from January 2020 to June 2023. According to the cutoff of 500/μl, patients were divided into high and low ALC groups. Patients in the high ALC group experienced a higher incidence of II-IV acute GVHD (30.2% versus 13.6%, <i>P</i> = 0.034), 3-year overall survival (OS) and relapse-free survival (RFS) rates (OS: 88.5% ± 3.7% versus 66.9% ± 7.9%, <i>P</i> = 0.013; RFS: 81.4% ± 4.1% versus 56.5% ± 8.1%, <i>P</i> < 0.001), and lower cumulative incidence of relapse (11.3% versus 27.4%, <i>P</i> = 0.013). Pre-conditioning ALC < 500/μl independently predicted worse OS, RFS, and higher relapse risk in multivariate analysis. However, there was no significant difference in immune reconstitution between the two groups.</p><p><strong>Conclusion: </strong>Pre-conditioning ALC was a significant prognostic factor in pediatric patients undergoing myeloablative haplo-HSCT. Further research is needed to explore whether pre-conditioning ALC can serve as a reference for adjusting ATG dosing.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1552263"},"PeriodicalIF":5.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advocating the role of trained immunity in the pathogenesis of ME/CFS: a mini review.","authors":"Bart Humer, Willem A Dik, Marjan A Versnel","doi":"10.3389/fimmu.2025.1483764","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1483764","url":null,"abstract":"<p><p>Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic disease of which the underlying (molecular) mechanisms are mostly unknown. An estimated 0.89% of the global population is affected by ME/CFS. Most patients experience a multitude of symptoms that severely affect their lives. These symptoms include post-exertional malaise, chronic fatigue, sleep disorder, impaired cognitive functions, flu-like symptoms, and chronic immune activation. Therapy focusses on symptom management, as there are no drugs available. Approximately 60% of patients develop ME/CFS following an acute infection. Such a preceding infection may induce a state of trained immunity; defined as acquired, nonspecific, immunological memory of innate immune cells. Trained immune cells undergo long term epigenetic reprogramming, which leads to changes in chromatin accessibility, metabolism, and results in a hyperresponsive phenotype. Initially, trained immunity has only been demonstrated in peripheral blood monocytes and macrophages. However, more recent findings indicate that hematopoietic stem cells in the bone marrow are required for long-term persistence of trained immunity. While trained immunity is beneficial to combat infections, a disproportionate response may cause disease. We hypothesize that pronounced hyperresponsiveness of innate immune cells to stimuli could account for the aberrant activation of various immune pathways, thereby contributing to the pathophysiology of ME/CFS. In this mini review, we elaborate on the concept of trained immunity as a factor involved in the pathogenesis of ME/CFS by presenting evidence from other post-infectious diseases with symptoms that closely resemble those of ME/CFS.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1483764"},"PeriodicalIF":5.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing the immune infiltrate in secondary syphilis: implications for transmission and pathology.","authors":"Irène Gallais Sérézal, Joseph Kirma, Mrinal K Sarkar, Christopher Cole, Xianying Xing, Rachael Bogle, Jennifer Fox, Anthony Coon, Kelsey R vanStraalen, Craig Dobry, Linda H Xu, J Michelle Kahlenberg, Paul W Harms, Allison C Billi, Lam C Tsoi, Lorenzo Giacani, Johann E Gudjonsson","doi":"10.3389/fimmu.2025.1549206","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1549206","url":null,"abstract":"<p><strong>Introduction: </strong>Syphilis is a complex disease with variable clinical presentation where symptomatic and potentially infectious stages alternate with periods of latency, representing a fascinating model to study immune evasion and host immune responses.</p><p><strong>Methods: </strong>Immunohistochemistry (IHC), bulk, and single-cell RNA sequencing were performed on formalin-fixed paraffin-embedded skin biopsies collected from subjects with secondary syphilis. Additionally, PBMCs from healthy individuals and either primary or <i>MyD88</i> knock-out keratinocytes were exposed to live <i>Treponema pallidum</i> cells to define initial skin responses to the bacteria.</p><p><strong>Results: </strong>Immunohistochemistry of secondary syphilis skin lesions showed a polymorphous immune infiltrate with colocalization of T cells, B cells and antigen-presenting cells. Single-cell analysis revealed distinct cellular contributions to the immune response, with prominent immune-stromal crosstalk accompanied by altered keratinocyte differentiation and decreased intraepidermal communication. Notably, prominent inflammatory signals were countered by concomitant regulatory responses, particularly in infiltrating myeloid cells. Exposure of PBMCs to live <i>T. pallidum</i> inhibited immune responses, while exposure to sonicated cells triggered <i>CXCL1</i> and <i>CXCL3</i> upregulation. Keratinocytes responded to both intact and sonicated <i>T. pallidum</i> with upregulation of type-I interferon responses that, however, were abolished in MYD88-deficient but not in STING-deficient keratinocytes.</p><p><strong>Discussion: </strong>Our data provide novel insights into the contribution of epidermal TLR sensing through MYD88 to the host response to syphilis infection, highlighting mechanisms by which <i>T. pallidum</i> evades immune responses in skin that may facilitate transmission of this pathogen through the skin.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1549206"},"PeriodicalIF":5.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curcumin targets YAP1 to enhance mitochondrial function and autophagy, protecting against UVB-induced photodamage.","authors":"Quan Chen, Wenxin Lin, Yi Tang, Fengmei He, Bihua Liang, Jiaoquan Chen, Huaping Li, Huilan Zhu","doi":"10.3389/fimmu.2025.1566287","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1566287","url":null,"abstract":"<p><strong>Background: </strong>Ultraviolet B (UVB) radiation is a major environmental factor contributing to skin damage via DNA damage, oxidative stress, inflammation, and collagen degradation. It penetrates the epidermis, disrupts DNA integrity, and generates reactive oxygen species (ROS), activating pro-inflammatory pathways such as NF-κB and AP-1, and inducing matrix metalloproteinases (MMPs). These processes lead to structural skin changes, inflammation, and pigmentation disorders like melasma. Cumulative DNA damage from UVB also drives photocarcinogenesis, with nearly 90% of melanomas associated with UV radiation (UVR). Despite clinical interventions like phototherapy and antioxidants, effective treatments for UVB-induced damage remain limited due to side effects and efficacy issues.</p><p><strong>Methods: </strong>This study investigates the protective effects of curcumin on UVB-induced skin damage using a mouse UVB irradiation model and HaCaT cells exposed to UVB <i>in vitro</i>. Skin damage was assessed through histopathological and immunohistochemical analyses. Cellular functional changes were evaluated using assays for cell viability, mitochondrial function, ROS levels, and apoptosis. Transcriptomic analysis was employed to elucidate the molecular mechanisms underlying curcumin's protective effects on HaCaT cells post-UVB exposure. This integrated approach provides a comprehensive understanding of curcumin's molecular-level protection against UVB-induced skin damage.</p><p><strong>Results: </strong>Curcumin significantly alleviated UVB-induced skin lesions and inflammation <i>in vivo</i>. <i>In vitro</i>, it mitigated UVB-induced HaCaT cell damage, enhancing viability while reducing apoptosis and ROS levels. Transcriptomic analysis revealed that curcumin upregulated YAP signaling and mitochondrial autophagy while suppressing IL-18 expression.</p><p><strong>Conclusion: </strong>Curcumin treatment markedly improved UVB-induced skin lesions and reduced epidermal inflammation and thickness <i>in vivo</i>. <i>In vitro</i>, curcumin intervention alleviated UVB-induced HaCaT cell damage, including reduced viability, increased apoptosis, elevated ROS and DNA damage, and enhanced inflammatory responses. Transcriptomic analysis demonstrated that curcumin upregulated the YAP signaling pathway and mitochondrial autophagy while inhibiting the IL-18 pathway. Further studies revealed that curcumin directly interacts with YAP1, promoting mitochondrial autophagy, an effect blocked by the YAP1 inhibitor Verteporfin. Additionally, curcumin enhances mitochondrial function through YAP1, maintaining mitochondrial integrity and preventing the release of mitochondrial DNA (mtDNA) and mitochondrial ROS (mtROS), thereby suppressing NLRP3/IL-18 pathway activation.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1566287"},"PeriodicalIF":5.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction model of gastrointestinal tumor malignancy based on coagulation indicators such as TEG and neural networks.","authors":"Fulong Yu, Chudi Sun, Liang Li, Xiaoyu Yu, Shumin Shen, Hao Qiang, Song Wang, Xianghua Li, Lin Zhang, Zhining Liu","doi":"10.3389/fimmu.2025.1507773","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1507773","url":null,"abstract":"<p><strong>Objectives: </strong>Accurate determination of gastrointestinal tumor malignancy is a crucial focus of clinical research. Constructing coagulation index models using big data is feasible to achieve this goal. This study builds various prediction models through machine learning methods based on the different coagulation statuses under varying malignancy levels of gastrointestinal tumors. The aim is to use coagulation indicators to predict the malignancy of gastrointestinal tumors, expand the methods and ideas for coagulation index tumor prediction, and identify independent risk factors for gastrointestinal tumor malignancy.</p><p><strong>Methods: </strong>Clinical data of 300 patients with gastrointestinal diseases were collected from the Second Affiliated Hospital of Anhui Medical University from January 2024 to August 2024 and grouped according to TNM and G staging, representing tumor malignancy levels. First, independent influencing factors of gastrointestinal tumor malignancy were identified using stepwise multivariate logistic regression. ROC curves were used to assess the ability of TEG five items and other coagulation indicators to distinguish between malignancy levels of gastrointestinal tumors. Finally, we constructed a network model suitable for our task data based on residual networks, named the Residual Fully Connected Binary Classifier (RFCBC). This model was compared with other commonly used binary classification methods to select the optimal model.</p><p><strong>Results: </strong>The TEG five items (AUC values: R: 0.682; K: 0.731; α-angle: 0.736; MA: 0.699; CI: 0.747) showed better discrimination ability in the G group than other coagulation indicators. Although the TNM group showed moderate discrimination ability, it did not exhibit a significant advantage over other indicators. The R and MA values were identified as independent influencing factors in both TNM and G groups. Ultimately, the RFCBC prediction model showed the best predictive performance compared to other binary classification machine learning models (TEG five items: 87.56%; Thromboelastogram et al.: 88.6%).</p><p><strong>Conclusion: </strong>This study found that the R and MA values are independent predictive factors for the malignancy of gastrointestinal tumors. Compared to other coagulation indicators, the TEG five items have better discrimination ability regarding tumor malignancy. The RFCBC model created in this study outperforms other commonly used binary classification methods in predicting the malignancy of gastrointestinal tumors, providing a new model construction method and feasible approach for future coagulation index prediction of gastrointestinal tumor malignancy.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1507773"},"PeriodicalIF":5.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Commentary: Disulfidptosis-related gene signatures as prognostic biomarkers and predictors of immunotherapy response in HNSCC.","authors":"Jihao Xue, Cheng Xue, Qijia Yin, Ligang Chen, Ming Wang","doi":"10.3389/fimmu.2025.1575090","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1575090","url":null,"abstract":"","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1575090"},"PeriodicalIF":5.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asian elephant interferons alpha and beta and their anti-herpes viral activity.","authors":"Jonathan Haycock, Tanja Maehr, Akbar Dastjerdi, Falko Steinbach","doi":"10.3389/fimmu.2025.1533038","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1533038","url":null,"abstract":"<p><p>The type I interferons (IFNs) are a group of key cytokines of the vertebrate innate immune system that induce an antiviral state in uninfected cells. Experimental <i>in-vitro</i> and <i>in-vivo</i> data have proven the fundamental role these cytokines possess in the protective response to a wide variety of pathogens, including herpesviruses. In a clinical setting, IFNs have been an important treatment in humans for several decades and increasing evidence demonstrates their potential in controlling viral haemorrhagic fevers when administered early in disease. In juvenile Asian elephants, elephant endotheliotropic herpesvirus haemorrhagic disease (EEHV-HD) often proves fatal when an effective adaptive immune response cannot be mounted in time, suggesting that an enhancement of the innate immune response could provide protection. This study sequenced six members of the Asian elephant type I IFNs, most closely related to sequences from the African elephant and Florida manatee. Subsequently, recombinant Asian elephant IFNα and IFNβ proteins were expressed and assessed for bioactivity <i>in-vitro</i>, relative to recombinant human IFNs, using a novel infection model incorporating primary Asian elephant fibroblasts and bovine alphaherpesvirus 1 (BoHV-1) as a surrogate for EEHV. In a dose-dependent manner, both Asian elephant IFNs and human IFNα2a protected cells from BoHV-1 infection in this proof-of-concept study, even if applied up to 24 hours post-infection <i>in-vitro</i>.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1533038"},"PeriodicalIF":5.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CTHRC1: a key player in colorectal cancer progression and immune evasion.","authors":"Qingjie Chen, Haohao Wang, Qinghua Liu, Changjiang Luo","doi":"10.3389/fimmu.2025.1579661","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1579661","url":null,"abstract":"<p><p>The multifunctional secreted protein, collagen triple helix repeat containing 1 (CTHRC1), has recently emerged as a significant focus within oncology research. CTHRC1 expression in tumors is governed by a complex interplay of regulatory signals, including methylation, glycosylation, and notably, non-coding RNAs, which constitute its predominant regulatory mechanism. Colorectal cancer (CRC), a highly prevalent epithelial malignancy, sees CTHRC1 influencing tumor progression and metastasis through its modulation of several downstream signaling cascades, such as Wnt/PCP, TGF-β/Smad, and MEK/ERK pathways. Furthermore, CTHRC1 contributes to immune evasion in CRC via diverse mechanisms. It is intricately associated with macrophage phenotypic switching within the tumor microenvironment (TME), favoring M2 macrophage polarization and facilitating the infiltration of T cells and neutrophils. CTHRC1 is also instrumental in immune escape by driving the remodeling of the extracellular matrix through interactions with cancer-associated fibroblasts. Additionally, CTHRC1's roles extend to the regulation of hypoxia-related pathways, metabolism of glycolysis and fatty acids, and involvement in tumor angiogenesis, all of which support tumor immune evasion. Considering its multifaceted activities, CTHRC1 emerges as a promising therapeutic target in CRC, with the potential to enhance the outcomes of existing radiotherapeutic and immunotherapeutic regimens. This review endeavors to delineate the mechanistic and therapeutic landscapes of CTHRC1 in CRC. Through a comprehensive discussion of CTHRC1's diverse functions, we aim to provide insights that could pave the way for innovative approaches in cancer therapy.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1579661"},"PeriodicalIF":5.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic studies on the role of CHI3L1 in eosinophilic inflammation in chronic sinusitis.","authors":"Ling Guo, Yi Peng, Cheng Yang, Xinghong Liu, Weilan Xiong, Weijiang Liao, Jiangang Fan","doi":"10.3389/fimmu.2025.1562546","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1562546","url":null,"abstract":"<p><p>More than 10% of adults suffer from chronic rhinosinusitis (CRS), a chronic inflammatory condition that lowers quality of life, reduces productivity, and shortens work hours. Every year, more than 1 million surgeries are performed worldwide as a result of CRS. In recent years, targeted therapy for CRS has become a hotspot of research at home and abroad and has made significant progress, but CRS still has a high recurrence rate. Therefore CRS urgently needs precise targeted therapy. In the pathological process of CRS, the involvement of eosinophils is an important inflammatory mechanism. And excessive aggregation of eosinophils often leads to severe inflammatory responses. Studies have shown that chitinase 3-like protein 1 (CHI3L1) plays a key role in the activation and migration of eosinophils. This review will combine the latest research results to analyse in detail the biological properties of CHI3L1, its expression pattern in CRS, and the possible mechanisms by which it affects eosinophil aggregation by regulating immune responses and inflammatory processes, which will provide insights into the key role of CHI3L1 in the pathological process of CRS and offer a new target for the treatment of CRS.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1562546"},"PeriodicalIF":5.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI discovery of TLR agonist-driven phenotypes reveals unique features of peripheral cells from healthy donors and ART-suppressed people living with HIV.","authors":"Robert Were Omange, Samuel C Kim, Nikita S Kolhatkar, Tempest Plott, Will Van Trump, Kenneth Zhang, Hope O'Donnell, Daniel Chen, Ahmed Hosny, Michael Wiest, Zach Barry, Elisa Cambronero Addiego, Meron Mengistu, Pamela M Odorizzi, Yanhui Cai, Rachel Jacobson, Jeffrey J Wallin","doi":"10.3389/fimmu.2025.1541152","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1541152","url":null,"abstract":"<p><strong>Background: </strong>Selective and potent Toll-like receptor (TLR) agonists are currently under evaluation in preclinical models and clinical studies to understand how the innate immune system can be harnessed for therapeutic potential. These molecules are designed to modulate innate and adaptive immune responses, making them promising therapeutic candidates for treating diseases such as cancer or chronic viral infections. Much is known about the expression and signaling of TLRs which varies based on cell type, cellular localization, and tissue distribution. However, the downstream effects of different TLR agonists on cellular populations and phenotypes are not well understood. This study aimed to investigate the impact of TLR pathway stimulation on peripheral blood mononuclear cell (PBMC) cultures from people living with HIV (PLWH) and healthy donors.</p><p><strong>Methods: </strong>The effects of TLR4, TLR7, TLR7/8, TLR8 and TLR9 agonists were evaluated on cytokine production, cell population frequencies, and morphological characteristics of PBMC cultures over time. Changes in the proportions of different cell populations in blood and morphological features were assessed using high-content imaging and analyzed using an AI-driven approach.</p><p><strong>Results: </strong>TLR4 and TLR8 agonists promoted a compositional shift and accumulation of small round (lymphocyte-like) PBMCs, whereas TLR9 agonists led to an accumulation of large round (myeloid-like) PBMCs. A related increase was observed in markers of cell death, most prominently with TLR4 and TLR8 agonists. All TLR agonists were shown to promote some features associated with cellular migration. Furthermore, a comparison of TLR agonist responses in healthy and HIV-positive PBMCs revealed pronounced differences in cytokine/chemokine responses and morphological cellular features. Most notably, higher actin contraction and nuclear fragmentation was observed in response to TLR4, TLR7, TLR7/8 and TLR9 agonists for antiretroviral therapy (ART)-suppressed PLWH versus healthy PBMCs.</p><p><strong>Conclusions: </strong>These data suggest that machine learning, combined with cell imaging and cytokine quantification, can be used to better understand the cytological and soluble immune responses following treatments with immunomodulatory agents <i>in vitro.</i> In addition, comparisons of these responses between disease states are possible with the appropriate patient samples.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1541152"},"PeriodicalIF":5.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}