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Eosinophil Activation in the Allergic Lung Limits Pneumococcal Superinfection During Influenza 2267175
Abstract Introduction Respiratory co-infections with influenza A virus (IAV) and Streptococcus pneumoniae (Spn) drive severe morbidity and mortality during influenza pandemics; however, epidemiologic data from 2009 revealed that individuals with allergic asthma and IAV infection were paradoxically less likely to develop bacterial pneumonia, require ICU care, or die compared to influenza patients without asthma. Methods We developed a triple-disease murine model that recapitulates this protection and investigated the underlying mechanisms. Results Allergic mice co-infected with IAV and Spn maintained body weight, had significantly reduced lung bacterial load, and exhibited less tissue inflammation and epithelial injury compared to non-allergic controls. The allergic lung is characterized by increased eosinophils and preserved alveolar macrophages during influenza. Eosinophils were activated by viral exposure, upregulating CD69, ICAM-1 and IL-5Rα, maintaining viability, and displaying heightened phagocytosis through receptor-mediated uptake and bacterial killing without cytolysis or extracellular trap formation. Macrophages from allergic mice retained antibacterial killing capacity following IAV infection, in contrast to macrophage depletion observed in non-allergic hosts. Antibiotic depletion of airway eosinophils and macrophages abrogated this protection, demonstrating that these innate cells cooperate to counter viral-bacterial synergy. Conclusion Together, these findings identify eosinophils as direct antiviral and antibacterial effectors that maintain barrier protection and limit bacterial superinfection. Our data suggest that allergic inflammation uniquely “pre-arms” eosinophils and sustains macrophage function, creating a lung microenvironment more resistant to lethal viral-bacterial co-infection. Ongoing work is focused on dissecting molecular pathways that license these eosinophil responses and translating this biology toward host-directed therapeutic strategies. Funding Source R01 HL171137 and the American Lung Association Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)
The Impact of Moringa oleifera Feed Supplementation on Circulating White Blood Cell Counts and T Lymphocyte Proliferation in Weaned Piglets 2267351
Abstract Introduction The post-weaning period for piglets is a highly challenging time. When weaned at or before 21 days, piglets do not have a mature immune system. Thus, piglets are susceptible to infectious diseases threatening their welfare and swine production. To prevent production limitations, antibiotics are used to eliminate infections. However, the continuous use of antibiotics can lead to antibiotic resistance and increase the cost of production. To address these issues, we sought to evaluate potential alternatives to supporting piglet immunity. Moringa oleifera is a plant often used in traditional medicine that is known to be rich in vitamins and antioxidants. Moringa is also known to modulate immune activity and acts as a feed supplement in the literature. These studies sought to determine whether supplementing piglet feed with Moringa oleifera alters white blood cell recruitment. We also measured T lymphocyte proliferation in response to direct stimulation when given a Moringa-supplemented diet. Methods For this study, weaned 21-day-old piglets were fed either a Control diet (n = 3) or a diet supplemented with 3% dried Moringa leaf (n = 3) for 21 days. White blood cell (WBC) counts were compared by differential cell count on blood collected on days 0, 7, 14, and 21. Peripheral blood mononuclear cells (PMBCs) were isolated from the blood collected from each group at days 7, 14, and 21. T lymphocytes were stimulated using Concanavalin A (CON A) to determine if Moringa supplementation in the piglet diet altered T lymphocyte proliferation. We evaluated T lymphocyte proliferation through the MTT assay. Results We report no significant difference in the numbers of macrophages, lymphocytes, or neutrophils between groups or in the proliferation of T lymphocytes isolated from piglets fed control diets and those fed diets with 3% Moringa supplementation. Conclusion We conclude that 3% Moringa feed supplementation does not impact WBC counts in weaned piglets or the responsiveness of T lymphocytes to stimulation. Funding Source Grant support from the National Institute of Food and Agriculture (GRANT#: NC.X321-5-19-120-1) Topic Categories Veterinary and Comparative Immunology (VET)
A biologically informed antibody language model framework to simulate somatic hypermutation and guide native-like antibody design 2309391
Abstract Introduction Somatic hypermutation (SHM) involves activation-induced cytidine deaminase (AID)-mediated DNA targeting, followed by error-prone repair which introduces mutations. However, existing computational models do not reflect this, limiting their ability to model the mechanism of affinity maturation in silico. Here, we develop a biologically grounded, transformer-based framework that mirrors SHM. Our framework employs two independent antibody language models (AbLMs): an AID-like targeting model to select mutation sites and a DNA repair-like substitution model to predict resulting amino acids. Methods We sequenced memory B cell repertoires from eight healthy donors using high-accuracy bulk NGS of unpaired VH/VL chains. These data were used for pretraining the two AbLMs to perform in silico SHM. Using AntiBERTa2-derived metrics as a correlate for native-like antibodies, we compared model-generated sequences to the natural human immune repertoire. Results Bulk NGS produced ∼84 million high-quality, productive memory B cell receptor sequences for AbLM training. Model predicted mutations matched the spatial distribution and overall load of true SHM. AntiBERTa2 embedding projections and log likelihood scoring revealed that model-generated sequences closely resemble native antibodies and strongly mimic SHM mutational patterns. Model-generated sequences also exhibited significantly increased levels of expression in HEK293F cells, indicating learning of beneficial mutations that enhance protein fitness. Conclusion Our framework models SHM to generate native-like human antibodies, providing a biologically grounded tool for guiding design within the natural sequence space. Unlike motif-based or single-stage SHM simulators, our framework explicitly decouples targeting and substitution to enable faithful reproduction of both hotspot localization and amino acid substitution. This approach advances in silico modeling of humoral immunity and may reveal new mechanistic insights into antibody clonal dynamics. Funding Source Endowed Fellowship in the Skaggs Graduate School of Chemical and Biological Sciences, Achievement Rewards for College Scientists (ARCS) Foundation San Diego Chapter, National Institute of Allergy and Infectious Diseases (NIAID) Topic Categories Computational and Systems Immunology (COMP)
Acute Babesia microti Infection Is Associated With Marked Changes In The Expression Of Peripheral Blood Coding And Noncoding RNA 2301453
Abstract Introduction Babesiosis, an emerging tick-borne disease in the US caused by Babesia microti (Bm), has limited data on protective immune responses and host-parasite interactions. Peripheral blood transcriptomes have not previously been used to study the host immune response during babesiosis. Therefore, we studied peripheral blood transcriptomes in a timed infection mouse model to identify correlates of early, acute, and resolution stages of infection. Methods Female BALB/cJ mice were infected intraperitoneally with Bm and monitored for parasitemia by Giemsa-stained blood smears. Mice and controls were euthanized at days 5, 6, 7, 9, and 12 post-infection, and blood was collected for RNA isolation. RNA sequencing was performed using Illumina’s Stranded Total RNA Prep with Ribo-Zero Plus Kit and on a NextSeq2000. EdgeR assessed differentially expressed genes (DEGs), and QIAGEN Ingenuity Pathway Analysis was used for pathway analyses. Results Parasitemia increased through day 7, peaked at day 8, declined by day 9, and partially resurged on day 12 prior to resolution of parasitemia. The number of DEGs increased during infection. The host transcriptome on day 5 showed early innate immune activation, such as type I and II interferon pathways. Day 7 marked a major transition with more crisis parasite forms and robust activation of immune, metabolic, and proliferative pathways. On day 12 during resurgence, many of these pathways were further activated, including clotting cascade pathways. Conclusion This study characterizes temporal peripheral blood transcriptome changes during babesiosis. Early immune activation suggests rising parasitemia is not due to failed immune activation. Parasite clearance on day 7 aligns with activation of immune and non-traditional immune pathways. Upregulation of coagulation and other pathways during early resolution may contribute to clinical complications. These findings will guide therapeutic development and inform human transcriptome studies to identify correlates of disease severity. Funding Source Department of Defense W81XWH-20-1-0508 to D. Mordue Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)
Mirror‑Induced Field Compression Drives Tunable Strong Exciton–Plasmon Polaritons in WS <sub>2</sub> /h‐BN/Au Heterostructures
ABSTRACT Deep‑subwavelength confinement and strong coupling at visible frequencies are central to scalable nanophotonic and quantum technologies. While transition metal dichalcogenides are promising candidates for such confinement, achieving tunable strong coupling often relies on patterned plasmonic nanostructures or chemical modification of the excitonic material. Furthermore, in metal‐coupled systems, the distinct role of metallic mirror‐induced electromagnetic confinement is often experimentally obscured by exciton‐plasmon energy hybridization. Here we introduce a vdW‐integrated, chemically non‐invasive WS 2 /h‐BN/Au heterostructure in which the h‐BN spacer forms a controllable nanogap that tunes image‐charge confinement while preserving the excitonic material. Scattering‑type near‑field microscopy directly maps propagating interference fringes and reveals a collapse of the TM‑polariton wavelength to ∼172 nm under 633‑nm excitation as the spacer is reduced to 5 nm ( λ 0 / λ p ≈3.7, corresponding to ∼71% wavelength reduction), which is one of the highest degrees of optical confinement reported for room‐temperature TMDC polaritons. Full‑wave simulations and transfer‑matrix analysis, aided by boundary‑condition engineering from an ideal conductor to real Au, separate a purely geometric mirror mode from plasmon‑assisted hybridization. This platform establishes a deterministic route to deeply subwavelength field control, offering a scalable architecture for nonlinear optical enhancement and integrated quantum devices.
STAT4 controls pathogenicity of CD4 Th17 via IL-10 suppression 2310000
Abstract Introduction CD4 T cells, including Th17 cells (Th17), are central to the development of numerous autoimmune and chronic inflammatory diseases, such as Multiple Sclerosis (MS) and Inflammatory Bowel Disease (IBD). Furthermore, mutations in the STAT4 locus have been identified in IBD and MS patients, diseases driven by pathogenic Th17. Our lab has revealed that STAT4 expression in Th17 is required for autoimmune experimental encephalitis (EAE) induction. Our preliminary findings indicate that CD4 Type 1 Regulatory cells (Tr1) and Th17 produce more anti-inflammatory IL-10 in the absence of STAT4. Given the role of pathogenic Th17 in both diseases, we hypothesize that STAT4 induces a pathogenic transcriptional program in Th17 while reducing IL-10 expression in Tr1 and Th17, thus aggravating CD4 T cell-driven colitis. Methods To test this hypothesis, naïve CD4 T cells were isolated from wild type (WT) and STAT4 knockout (KO) IL-10 reporter mice, activated in vitro under Th17 or Tr1 conditions and analyzed for cytokine production via flow cytometry, ELISA, and RT-qPCR. We performed RNA sequencing of in vitro differentiated IL-10+ WT and STAT4 KO Th17 to identify differentially expressed genes. To probe the pathogenic function of STAT4 in vivo, we transferred WT and STAT4 KO naïve CD4 T cells to induce colitis. Disease severity was assessed by the Disease Activity Index and fecal lipcalin-2. We analyzed the CD4 profiles from the spleen, mesenteric lymph nodes, and colon using flow cytometry. To test the STAT4-IL-10 axis in colitis, we depleted IL-10+ CD4 T cells during colitis and evaluated disease severity. Results We found that STAT4 confers a pathogenic transcriptional program in Th17 in vitro. Notably, STAT4 suppresses IL-10 in both Th17 and Tr1 cells. In colitis, STAT4 modulates disease severity by downregulating IL-10, worsening disease. Conclusion Taken together, STAT4 plays a role in Th17 pathogenicity by inducing a pathogenic transcriptional program that antagonizes IL-10 expression and production. Funding Source R01AI186373-01A1, R01DK125870, R01DK125870-04, T32AI007051 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)
MicroRNA-1246 regulates macrophage lipid metabolism and is involved in resistance to human Mycobacterium tuberculosis infection 2259565
Abstract Introduction Resistance to Mycobacterium tuberculosis (Mtb) infection despite known exposure varies among individuals, but the molecular mechanisms underlying this resistance remain poorly understood. It is unclear whether microRNAs (miRNAs) influence the development of resistance to tuberculosis (TB) among individuals exposed to Mtb who remain uninfected or do not progress to active disease. Methods We analyzed blood samples from healthy household contacts (HHCs) of patients with active pulmonary TB. As reported in our previous study, 460 HHCs were recruited from 443 index TB cases, of which 293 (64.8%) remained interferon gamma release assay negative during a two-year follow-up period. Whole-transcriptome sequencing was performed at baseline (0 months) and at follow-up (24 months) to identify differentially expressed miRNAs between nonconverters, converters, and progressors. Candidate miRNAs were validated through confirmation studies, and mechanistic investigations were conducted using proteomics and computational analyses in macrophage models. Results Differential expression analysis revealed that hsa-miR-1246 (downregulated) and hsa-miR-125b (upregulated) were associated with resistance to Mtb infection in nonconverters compared with converters and progressors. Functional assays demonstrated that inhibition of hsa-miR-1246 reduced Mtb growth in macrophages by enhancing lipase activity through its target, alpha/beta hydrolase domain-containing protein 2 (ABHD2). Moreover, hsa-miR-1246 inhibition promoted glycolytic reprogramming and metabolic activation of macrophages, creating a cellular environment favorable for bacterial clearance. Conclusion Our findings identify hsa-miR-1246 as aa important regulator of macrophage metabolism and host resistance to Mtb infection. These results provide mechanistic insight into miRNA-driven immune protection and suggest potential miRNA-based therapeutic strategies to enhance resistance against tuberculosis. Funding Source CRDF Global, the Cain Foundation for Infectious Disease Research, the Department of Pulmonary Immunology, and the Department of Biotechnology (BT/PR9622/MED/15/109/2013 to VLV), New Delhi, India. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)
Epithelial barrier function in skin-gut crosstalk in a model of food allergy 2260278
Abstract Introduction Food allergy is a worldwide public health issues that continues to grow every year. However, diagnosis is difficult, as the only way to definitively diagnose a food allergy is through oral food challenge. This is time consuming and often results in anxiety as adverse reactions, including anaphylaxis, are common. Previous data found that children who develop severe reactions during oral food challenges have an increase in transepidermal water loss (TEWL) prior to reacting, indicating that TEWL may help to predict which patients will react. Methods We used a mouse model of food allergy to better understand the interplay between skin barrier function and anaphylactic reactions. Animals were dermally sensitized with ovalbumin, then challenged by oral gavage. Transepidemal water loss was measured before and after challenge. Small intestinal tissue was collected following challenge to evaluate mast cell density and cytokine expression. Results We found mice accumulated mast cells in the small intestine, and that this correlated with increased transepidermal waters loss (TEWL). We also measured an increase in the expression Th2-associated alarmins in the intestinal tissue, including IL-33 and TSLP. These effects were enhanced in mice with genetic barrier defects, indicating a potential link between intestinal mast cell accumulation and skin barrier function. Additionally, we found that mice with barrier defects had increased TEWL prior to skin sensitization, suggesting that skin barrier function may play a role in the severity of food allergy. Conclusion This model will provide us with a platform to explore the mechanisms behind increased TEWL observed in patients during oral food challenge, and may lead to better diagnoses of food allergy. Funding Source R01 AI 167957 Topic Categories Mucosal and Regional Immunology (MUC)
Differential Expression of Immunomodulatory Markers in the Tumor Microenvironment of High-Grade Gliomas 2259573
Abstract Introduction High-grade IDH-mutant gliomas are increasingly appreciated to have distinct biology in the tumor microenvironment (TME) relative to high-grade IDH-wild-type tumors, including glioblastoma (GBM). Comparative analysis of the TME from different Central Nervous System tumors before treatment is relatively unexplored. Methods To compare these high-grade gliomas, intraoperative ultrasonic aspirate was collected during tumor resection from recently diagnosed patients with GBM or Grade 3/4 Astrocytoma (IDH mutant). High-dimensional flow cytometry was performed using a 5-laser Cytek Aurora, and the differences in the TME between high-grade gliomas grouped by IDH mutation status were evaluated using FlowJo. Immune checkpoint proteins were assessed in well-defined myeloid cell types, including macrophages, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), non-classical monocytes (NCM), and monocytic myeloid-derived suppressor cells (mMDSCs). Additionally, differences in regulatory T cells (Tregs) were examined. Results We found decreased immune suppression markers (CTLA-4) in PMN-MDSC from IDH-mutant Astrocytomas, relative to GBM (55.04% ± 24.56). Decreased immune suppression markers (TIGIT) in M2 polarized monocyte-derived macrophages was also noted in Astrocytomas compared to GBM (44.57% ± 15.54). Conclusion This study allows for in-depth characterization of the TME at the time of surgery, offering unique insight into the immunosuppressive environment. A further understanding of immune system regulation between Central Nervous System tumor types will ideally lead to the development of novel therapeutics for these profoundly immunosuppressive tumors. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Activating Inflammation Resolution Programs Improves Immunosuppressive Therapy and Prevents Toxicity in Autoimmune Bone Marrow Failure 2267406
Abstract Introduction Chronic inflammatory and autoimmune diseases are among the leading causes of morbidity and mortality worldwide, yet immunosuppressive therapy (IST) often fails to achieve durable remission and induces toxicity. Severe aplastic anemia (SAA) is a lethal bone marrow failure driven by autoreactive T cells. Patients treated with cyclosporine A (CsA) exhibit sustained inflammation, frequent relapse, and secondary complications. Specialized pro-resolving lipid mediators, such as Resolvin E1 (RvE1), promote resolution of inflammation and restore tissue homeostasis. Using a preclinical murine model, we examined how immunosuppressive and resolution-targeted therapies shape disease outcomes, and whether their combination improves recovery. Methods SAA was induced in sub-lethally irradiated mice via MHC-mismatched splenocyte transfer. Mice were treated with 10 mg/kg CsA and/or 0.0125 mg/kg RvE1 after disease onset. Long-term recovery was assessed 30-90 days post-withdrawal. scRNAseq, ligand-receptor analyses, receptor knockouts, and reciprocal chimeras were used to determine cell-specific mechanisms. Results CsA improved survival (75%), but caused persistent T cell activation, Th17 expansion, granulocytic skewing, and renal toxicity. Conversely, RvE1 (50% survival) normalized T cells and restored hematopoietic output without organ injury. Combination therapy achieved 100% survival, restored immune profiles, and prevented systemic toxicity. ChemR23 on immune cells was required for RvE1 protection. scRNAseq revealed CsA-induced transcriptional dysregulation, inflammatory cell-cell crosstalk, and aberrant histone gene expression, consistent with durable immune remodeling. RvE1 co-therapy normalized these transcriptional networks. Conclusion CsA impairs inflammation resolution and long-term organ function. Co-treatment with RvE1 restores immune and hematopoietic homeostasis, supporting integration of pro-resolving therapy with IST for safer, durable remission for autoimmune and inflammatory diseases. Funding Source CDMRP Bone Marrow Failure Research Program-IDA (BM190079 and BM220031) and NHLBI R01HL159411 Topic Categories Therapeutic Approaches to Autoimmunity (THER)
Integrating in silico Humanization and DNA Delivery to engineer anti-Influenza Monoclonal Antibodies for improved in vivo expression 2267274
Abstract Introduction Highly pathogenic avian influenzas (HPAI) of the H5 subtype represent an ongoing zoonotic threat to human and animal health. Broadly neutralizing antibodies (bnAbs) offer a powerful tool for pandemic preparedness, yet translation to the clinic often requires humanization to avoid immune reactions against murine antibodies, often impacting its function across divergent viral strains. Methods We developed a computational pipeline integrating BioPhi with in-house refinement to generate humanized variants of 5C2, a murine antibody elicited against a clade 2.3.2.1 H5N1 virus. To assess whether humanized antibodies could retain the breadth and potency of the parental clone, we designed a panel of unique humanized constructs and compared them to a VH/VL chimera and the murine wild-type mAb, which were all genetically optimized for in vivo expression. Results We confirmed in vitro expression of all constructs and subsequently delivered them as DNA-encoded monoclonal antibody (DMAbs) via injection and in vivo electroporation (EP) to wild-type mice. Sera from DMAb treated mice exhibited strong binding and pseudovirus neutralization to multiple H5N1 clades, including the currently circulating panzootic clade 2.3.4.4b virus. In vivo DMAb delivery supported sustained expression across constructs for several months. Conclusion These data demonstrate that optimized in silico humanization can preserve key functional properties, including cross-reactivity against multiple clades. Our results support the use of this computational workflow for rapid generation of humanized antibodies with broad activity, highlighting its potential application against emerging seasonal or pandemic threats. Funding Source NIH/NIAID CIVICs (75N93019C00051) Topic Categories Vaccines and Immunotherapy (VAC)
TGF-β drives uterine tissue-resident NK cell differentiation crucial for murine pregnancy 2309469
Abstract Introduction Conventional natural killer (cNK) cells differentiate in response to tissue-specific cues, generating specialized NK cell subsets. Within the uterus, this process gives rise to uterine NK cells (uNK), a heterogeneous population largely composed of tissue-resident NK (trNK) cells. Our prior work shows that uNK cells are critical for reproductive success, as their absence results in adverse pregnancy outcomes in mice. However, the molecular cues mediating uterine trNK cell differentiation remain poorly understood. TGF-β is abundant in uterine tissues and has been implicated in immune cell differentiation. We therefore hypothesized that TGF-β drives the differentiation of peripheral cNK cells into uterine trNK cells to support pregnancy. Methods To test this, we generated mice lacking TGF-β receptor II in Ncr1+ NK cells by crossing TGF-βRIIfl/fl with Ncr1icre mice. We then characterized innate lymphoid cell subsets in the pregnant uterus of TGF-βRIINcr1Δ and littermate dams using flow cytometry. Pregnancy outcomes were assessed by evaluating spiral artery morphology, fetal resorption at midgestation, and litter size at birth. Splenic cNK cells were adoptively transferred into TGF-βRIINcr1Δ dams to restore the uterine trNK cell population. Results We found that peripheral cNK cells extravasate into the gravid murine uterus, where they adopt a trNK cell phenotype. Loss of TGF-βRII in Ncr1+ cells profoundly disrupted this conversion, significantly reducing uterine trNK cells during gestation. Impaired TGF-β—dependent uterine trNK cell differentiation resulted in defective spiral artery remodeling and increased fetal resorption at midgestation, ultimately reducing litter sizes at birth. Restoration of uterine trNK cells rescued fetal viability at midgestation. Conclusion This study defines a pivotal role for TGF-β signaling in directing peripheral cNK cells to become uterine trNK cells during murine pregnancy and highlights the physiologic importance of this conversion for reproductive success. Funding Source n/a Topic Categories Mucosal and Regional Immunology (MUC)
CX-01 Improves Survival and Attenuates Organ Failure in a Rat Polytrauma Model 2300256
Abstract Introduction Severe polytrauma can induce devastating complications, including acute kidney injury, acute respiratory distress syndrome, and other organ failure. If left treated, these severe complications can lead to high mortality. The pathological mechanisms remain inconclusive, but innate immune dysfunction may contribute to trauma-induced organ failure. Methods Male Sprague Dawley rats were anesthetized and given proper analgesics, underwent polytrauma (soft tissue injury, fibula facture and pressure-controlled hemorrhage), received blood resuscitation to maintain a MAP of 90 mmHg, and then monitored for 72 hours, mortality, or reaching the humane endpoint. The animals were randomly assigned to either injury control (polytrauma, n = 9), or therapeutic treatment (polytrauma+CX-01, n = 7) groups. The vital signs, hemodynamics, blood chemistry, inflammation, and tissue damage were recorded and analyzed at baseline (BL), 2h, 2.5h, 24h, 48h, and 72h post-injury. Results In the injury group, 3 out of 9 animals survived to the end of the study (mortality=67%), while 6 out of 7 animals in the CX-01 treatment group survived (mortality=14%, p &lt; 0.05). CX-01 treatment significantly reduced creatinine and BUN levels and mitigated the decline in GFR caused by polytrauma. Furthermore, CX-01 treatment reduced HMGB1 levels, inflammatory cytokines (MCP-1, RANTES, IL-10 etc.). Conclusion CX-01, as an immunotherapeutic, mitigates trauma-induced immune and organ dysfunctions, and may save lives for combat casualties. Funding Source US Army Medical Research & Development Command (Grants numbers: CO240046, CO250068 and DM230026). Topic Categories Translational and Interventional Immunology (TI)
Crystallization Modulation for Stable Wide‐Bandgap Perovskite Solar Cells and Modules
ABSTRACT As the power conversion efficiency (PCE) of single‐junction perovskite solar cells (PSCs) approaches the Shockley–Queisser theoretical limit, perovskite‐based tandem solar cells (TSCs) have been widely recognized as a key pathway to surpass single‐junction PSCs and enable next‐generation high‐performance photovoltaics. However, wide‐bandgap (WBG) perovskites, particularly mixed‐halide systems, still face significant challenges, including photoinduced phase segregation, high defect densities, and interfacial mismatches. These issues largely stem from their complex crystallization processes. This review describes how inhomogeneous crystallization of WBG perovskites underlies the following challenges: initial phase segregation, defect formation, and stability issues. Following this, a comprehensive review of recent advances in crystallization modulation was carried out. Strategies such as interface engineering, composition engineering, solvent engineering, process optimization, and additive engineering are discussed, with a focus on precisely modulating nucleation and growth to achieve high‐quality WBG perovskites. Finally, the development of large‐area fabrication of WBG perovskites and stability issues are summarized, and future research directions are outlined.
Turning Unpredictable Biomolecule Adsorption to Controlled Corona Formation: Focus on Carbon Nanomaterials
ABSTRACT With unique optical and physicochemical properties, carbon nanomaterials (CNMs), including carbon nanotubes, graphene‐related materials, nanodiamonds, and carbon dots, are extensively explored as platforms for cancer diagnosis and treatment. However, in biofluids, CNMs spontaneously adsorb biomolecules to form an unpredictable corona, obstructing the implementation of their designed functions. In this review, we summarize how the intrinsic and acquired properties of CNMs affect protein corona formation, and the consequent biological and toxicological outcomes, as well as strategies to reshape the composition and structural organization of adsorbed proteins. This comprehensive knowledge will provide insights into developing CNMs with tailored corona and requested functions in cancer nanomedicine, advancing their translations into clinics.
Adaptor SLP-76 couples the TCR to glucose metabolism in T-cells with augmented obesity 2310033
Abstract Introduction The adaptor protein SLP-76 is indispensable for thymic T-cell development, yet its contribution to peripheral T-cell signaling and metabolic programming remains poorly defined. T-cell receptor (TCR) engagement rapidly induces a glycolytic switch that supports effector differentiation, but the TCR-proximal signaling mechanisms initiating this metabolic reprogramming are unknown. Methods Here, we generated a knock-in mouse expressing a single point mutation in SLP-76 (K56E) that permits normal thymic development and maintains a numerically intact peripheral CD4+ and CD8+ T-cell compartment. Results Despite preserved T-cell numbers, K56E T cells exhibited markedly impaired effector function, including reduced interferon-γ production and defective CD8+ cytolytic activity. Integrated transcriptomic, metabolomic, and bioenergetic analyses revealed a selective failure of glycolytic commitment, with diminished 13C-glucose flux through glycolysis and the tricarboxylic acid cycle. These data identify SLP-76 as a critical signaling node linking TCR engagement glycolytic metabolic reprogramming. At the organismal level, K56E mice displayed a spontaneous Th2 bias and accelerated weight gain on a standard low-fat diet, a phenotype exacerbated under high-fat feeding. Immune profiling revealed increased M1 macrophages and effector CD8+ T cells, accompanied by reduced γδ T cells and NK cells in fat tissue. Conclusion Together, these findings uncover SLP-76 as a previously unrecognized upstream regulator of glycolytic programming and weight gain that governs CD8+ T-cell effector fate and systemic immunometabolic homeostasis, with implications for tumor immunity. Funding Source Canadian institute of health research Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)
Th10 and activated Tfh1 expansion correlate with strong, while Tfr expansion correlate with poor responses to Fluzone High Dose in older adults 2259592
Abstract Introduction Seasonal influenza poses a significant health risk to older adults (&gt;65 years), who exhibit reduced vaccine effectiveness compared to younger populations. Although enhanced influenza vaccines are commonly used, their efficacy remains suboptimal. Moreover, the cellular and molecular drivers of poor influenza vaccine responses remain unclear, limiting strategies to improve vaccine-induced immunity in aging. Methods To study this, we vaccinated older adults (n = 62) with Fluzone High-Dose during the 2022-2023 season and observed heterogenous antibody responses at day 35 post-vaccination. Based on antibody titers, we selected the top 10 responders and bottom 10 non-responders for in-depth T cell profiling. Results Using 5’ single-cell RNA-seq of longitudinal PBMCs, we identified a significant expansion of Th10 cells at day 7 in responders, a population shown to promote B cell help via the extrafollicular pathway. This expansion correlated positively with increased frequencies of total IgG+ and H1N1-specific plasmablasts. Notably, responders also exhibited an expansion of influenza-specific Th10 cells as inferred from paired single-cell TCR-seq data. Parallel CITE-seq analyses of sorted peripheral T follicular helper cells (Tfh) revealed that responders have higher pre-vaccination frequencies of Tfh1 cells and increased day 7 frequencies of activated Tfh1 (ICOS+, CD38+) cells, which showed higher expression of the CD38 protein. In contrast, non-responders showed an expansion of regulatory Tfr (FOXP3+ Tfh) cells at day 7, suggesting a potential suppression effect on humoral immunity. Conclusion Together, these data highlight Th10 and Tfh1 cells as positive immunological correlates of robust antibody responses to high-dose influenza vaccine in older adults, while Tfr expansion emerges as a negative correlate. These findings provide mechanistic insight into the T cell determinants of vaccine responsiveness in aging and may inform future strategies to enhance immunogenicity among older populations. Funding Source NIAID U01 AI165452 Topic Categories Computational and Systems Immunology (COMP)
Modeling Infection-Associated Chronic Illness: Murine Borrelia burgdorferi-Driven Connective Tissue Alterations and MAESTRO Clinical Correlates 2260529
Abstract Introduction Borrelia burgdorferi (Bb), the bacterium that causes Lyme disease, is linked to chronic illness in an estimated two million Americans. The mechanisms driving these persistent symptoms remain unclear, particularly the balance between immune- and pathogen-mediated processes. This project combines a murine Bb infection model with data from the MAESTRO clinical study to define immune responses, downstream effects, and their translational relevance. Methods C57BL/6 and C3H/HeJ mice of different ages were infected with Borrelia burgdorferi and followed longitudinally via in vivo imaging and tissue analyses. Ex vivo nonlinear imaging, histology, and in vitro assays using blood and tissue-derived cells were performed. Human data from the MAESTRO study, including medical history, symptom reports, and clinical evaluations, were incorporated for translational analysis. Results Overall infection level correlated with higher bacterial burden in the tail and increased tail flexibility - a hypermobile phenotype observed only in infected C3H mice. Significant Bb filamentation and elevated NAD(P)H per bacterial unit occurred in B6 but not C3H mice, while FAD levels showed a linear trend across strain and age. Shorter Bb forms correlated with larger, metabolically active macrophages displaying lower optical redox ratios, and evidence of phagocytosis was greater near shorter Bb. Mast cell distribution, degranulation, and directionality varied by strain and age, correlating with changes in collagen II intensity. Human MAESTRO data similarly revealed increased prevalence of hypermobility, mast cell disorders, and related symptom burden among chronically ill cohorts. Conclusion Findings indicate that persistent Borrelia infection promotes mast cell—mediated collagen II degradation and connective tissue hypermobility, offering mechanistic insight and a model for therapeutic and infectious disease studies. Funding Source NIH, Emily and Malcolm Fairbairn Foundation Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)
Caspase-8 regulates cell death and inflammatory responses in complex respiratory infection 2259631
Abstract Introduction Lung infections represent a major global health burden, with pneumonia remaining one of the leading causes of death in the United States. Secondary bacterial pneumonia following infection with influenza A virus (IAV) significantly increases disease severity and mortality, largely due to disruption of host resistance and tolerance mechanisms. Among bacterial pathogens, Streptococcus pneumoniae (S.p) is most commonly associated with influenza co-infection, a condition characterized by excessive inflammation, tissue damage, and poor therapeutic outcomes. Macrophages, as key orchestrators of pulmonary immune responses, regulate both pathogen clearance and inflammation through tightly controlled cell death pathways. Indeed, the progression of infection relies on the ability of host cells to trigger the appropriate programmed cell death response, which is usually inflammatory (pyroptosis and necroptosis). Pathogens redirect host cell death signaling towards cell death modalities that favor their adaptation, usually anti-inflammatory (apoptosis). These mechanisms lead to the occurrence of PANoptosis, a programmed cell death that incorporates elements of pyroptosis, apoptosis, and necroptosis and where caspase-8 serves as a central regulator. Methods To study the role of caspase-8 in co-infection by IAV and S.p, we infected macrophages derived from mouse bone marrow and human macrophages (THP1 cells) with a specific deletion of caspase-8 obtained using the lox cre and CRISPR methods, respectively. Results We found that the loss of caspase-8 led to a reduction in bacterial growth but an increase in necroptotic cell death, in a manner dependent on RIPK3 and MLKL. Furthermore, caspase-8-deficient macrophages showed reduced production of IL-1β and pro-inflammatory cytokines. Conclusion These results indicate that caspase-8 plays a protective and regulatory role during co-infection by IAV and S.p. by coordinating macrophage PANoptosis through the control of inflammation and pathogen replication. Funding Source n/a Topic Categories Viral Immunology (VIR)
Validated high throughput microneutralization assay for anti-AAV2 neutralizing antibodies (NAbs) in clinical trials in support of gene therapy 2247247
Abstract Introduction Recombinant adeno-associated (AAV) viral vectors are being widely used in gene therapy. One of the challenges for AAV-based therapy is the presence of pre-existing neutralizing antibodies (NAbs) that humans develop against AAV throughout life. These NAbs inhibit the binding of viral vector to the cells resulting in failure of therapeutic gene delivery. Evaluating pre-existing anti-AAV antibodies is required for many AAV-based clinical trials and approved gene therapies. CTL developed a novel anti-AAV2 NAb assay based on enumeration of viable cells infected with AAV2 carrying a fluorescent reporter. Methods Green Fluorescent Protein (GFP)-carrying AAV2 vector was used to transduce target cells. The vector was incubated with positive/negative controls or with test sample and then added to the target cells and GFP-fluorescent cells were counted thereafter. The percentage of neutralization was calculated based on the ratio between the number of GFP cells after incubation with and without the sample. A sample was considered positive for NAbs with a reduction of vector transduction greater or equal to 50%. Results CTL screened 78 human samples of three matrix types (CSF, Serum, Plasma) as well as samples from non-human primates, cats and pigs. Positive and negative samples were identified by anti-AAV2 NAb assay. Dilution starting points were defined to resolve the matrix effect observed during testing serum samples. Specificity of viable cell-based anti-AAV2 NAb assay was proven and the assay was validated. This assay showed sensitivity comparable to ELISA luciferase assay and can be used for testing NAb in different species. Conclusion CTL developed and validated a highly reliable and sensitive NAb assay with direct acquisition and enumeration of fluorescent AAV2-GFP transduced cells which allows high throughput evaluation in preclinical as well as clinical trials. The potential advantage of this assay is the ability to quantify the individual virus-infected cells without additional steps. Funding Source private (funded by Cellular Technology Limited) Topic Categories Technological Innovations in Immunology (TECH)