Search Results (9,420)

Background/Objectives: Cancer-associated fibroblasts (CAFs) play a pivotal role in the tumor microenvironment. We conducted an analysis using RNA sequencing to identify specific markers for CAFs compared to normal fibroblasts (NFs) in non-small-cell carcinoma (NSCLC). Methods: CAFs and NFs were isolated and cultured from tumor tissues (primary tumor or metastatic lymph nodes) and matched non-tumor tissues, respectively. Bulk RNA sequencing was conducted on isolated CAFs and normal fibroblast NFs. Differential expressions, gene set enrichment, and CAF subpopulation prediction analyses were performed. Results: During the study period, 27 CAFs and 12 NFs were isolated and cultured from tumor and non-tumor tissues in patients with treatment-naïve NSCLC. Among them, 22 CAFs and 11 NFs were included in the RNA sequencing analysis. The 22 CAF samples consisted of 12 adenocarcinomas and 10 squamous cell carcinomas (SqCC), with 16 samples from the lungs and 6 samples from the lymph nodes. Notably, COL11A1, GREM1, CD36, and GAS6 showed a higher expression in CAFs than in NFs, whereas TNC and CXCL2 were more abundantly expressed in NFs. CD36 levels were elevated in CAFs from lymph nodes (LN-CAFs) compared with those from lung specimens (Lung-CAFs) and NFs. COL11A1 levels in Lung-CAFs surpassed those in LN-CAFs and NFs. Both GREM1 and GAS6 showed a strong expression in Lung-CAFs and LN-CAFs relative to NFs. CAFs exhibited features of the myofibroblast CAF subpopulation, whereas NFs displayed traits of the antigen-presenting CAF subtype. In the co-culture model of CAFs and THP-1 cells, the knockdown of GREM1 or GAS6 in CAFs significantly decreased the M2 marker expression in macrophages. Conclusions In NSCLC, GREM1 and GAS6 can be valuable diagnostic targets for CAFs from primary tumors and metastatic sites; they warrant further study. Full article

Immunotherapy, particularly approaches that combine tumor-specific vaccines with immune checkpoint modulation, represents a promising strategy for overcoming tumor immune evasion. While most mRNA-based cancer vaccines focus solely on antigen delivery, there is a need for platforms that simultaneously enhance antigen presentation and modulate the tumor microenvironment to increase therapeutic efficacy. This study presents a novel dual-nanolipid exosome (NLE) platform that simultaneously delivers MUC1 mRNA and CTLA-4-targeted siRNA in a single system. These endogenous lipid-based nanoparticles are structurally designed to mimic exosomes and are modified with mannose to enable selective targeting to dendritic cells (DCs) via mannose receptors. The platform was evaluated both in vitro and in vivo in terms of mRNA encapsulation efficiency, nanoparticle stability, and uptake by DCs. The co-delivery platform significantly enhanced antitumor immune responses compared to monotherapies. Flow cytometry revealed a notable increase in tumor-infiltrating CD8⁺ T cells (p < 0.01), and ELISPOT assays showed elevated IFN-γ production upon MUC1-specific stimulation. In vivo CTL assays demonstrated enhanced MUC1-specific cytotoxicity. Combined therapy resulted in immune response enhancement compared to vaccine or CTLA-4 siRNA alone. The NLE platform exhibited favorable biodistribution and low systemic toxicity. By combining targeted delivery of dendritic cells, immune checkpoint gene silencing, and efficient antigen expression in a biomimetic nanoparticle system, this study represents a significant advance over current immunotherapy strategies. The NLE platform shows strong potential as a modular and safe approach for RNA-based cancer immunotherapy. Full article

Background: Host genetic factors significantly influence individual susceptibility to severe COVID-19, potentially explaining the observed disparities in clinical outcomes across populations. One of the key effectors in innate immunity and antiviral defense is the CD209 gene. This study explored the potential correlation of the CD209 gene SNP rs2287886 with diverse COVID-19 patient outcomes. Materials and Methods: A total of 176 patients (87 in the moderate group and 89 in the severe/critical/death group) were included in the study. Genotyping of patients was performed using the qPCR methodology, through the TAQMAN system. The results were analyzed adopting a significance level of p < 0.05. Results: The GG genotype (compared to AG + AA) and the G allele (compared to the A allele) of the rs2287886 SNP were significantly associated with an increased severity of COVID-19 (p = 0.0005 and p < 0.0001, respectively). The G allele was more frequent in individuals with more severe clinical outcomes (49.43% vs. 25.28%). Furthermore, expression quantitative trait loci (eQTL) analysis indicated that the GG genotype of rs2287886 is associated with higher CD209 gene expression. Furthermore, the observed interaction analysis suggests that the interactions between CD209 and its associated proteins may play a role in modulating the immune response. Conclusions: Our findings suggest that Brazilian patients homozygous for the GG genotype of the rs2287886 polymorphism in the CD209 gene may be at increased risk of severe COVID-19 in the Brazilian population and may act as a potential prognostic marker of disease severity. Full article

A novel skin test for an in vivo assessment of SARS-CoV-2-specific T-cell immunity was developed using CoronaDermPS, a multiepitope recombinant polypeptide encompassing MHC II–binding CD4+ T-cell epitopes of the SARS-CoV-2 structural proteins (S, E, M) and full length nucleocapsid (N). In silico epitope prediction and modeling guided antigen design, which was expressed in Escherichia coli, was purified (>95% purity) and formulated for intradermal administration. Preclinical evaluation in guinea pigs, mice, and rhesus macaques demonstrated a robust delayed type hypersensitivity (DTH) response at optimal doses (10–75 µg), with no acute or chronic toxicity, mutagenicity, or adverse effects on reproductive organs. An integrated clinical analysis included 374 volunteers stratified by vaccination status (EpiVacCorona, Gam-COVID-Vac, CoviVac) prior to COVID-19 infection (Wuhan/Alpha, Delta, Omicron variants), and SARS-CoV-2–naïve controls. Safety assessments across phase I–II trials recorded 477 adverse events, of which >88% were mild and self-limiting; no severe or anaphylactic reactions occurred. DTH responses were measured at 24 h, 72 h, and 144 h post-injection by papule and hyperemia measurements. Overall, 282/374 participants (75.4%) exhibited a positive skin test. Receiver operating characteristic analysis yielded an overall AUC of 0.825 (95% CI: 0.726–0.924), sensitivity 79.5% (95% CI: 75.1–83.3%), and specificity 85.5% (95% CI: 81.8–88.7%), with comparable diagnostic accuracy across vaccine, and variant subgroups (AUC range 0.782–0.870). CoronaDerm-PS–based skin testing offers a simple, reproducible, and low-cost method for qualitative evaluation of T-cell–mediated immunity to SARS-CoV-2, independent of specialized laboratory equipment (Eurasian Patent No. 047119). Its high safety profile and consistent performance across diverse cohorts support its utility for mass screening and monitoring of cellular immune protection following infection or vaccination. Full article

Background: Breast cancer is a complex, multifactorial malignancy characterized by the uncontrolled proliferation of epithelial cells, with certain subtypes exhibiting resistance to conventional therapies. Plant-derived essential oils have been proposed as potential anticancer agents due to their bioactive compounds. Recent studies have demonstrated that Decatropis bicolor essential oil exhibits activity against breast cancer, attributed to diverse secondary metabolites such as δ-cadinene. Aberrant expression of adhesion and invasion proteins, including MMPs, CD44, N-cadherin, and ZEB-2, are key signs of breast cancer progression and metastasis; they represent relevant molecular targets. Objectives: To investigate the interaction of δ-cadinene with these proteins using in silico approaches and in vitro evaluations. Methods: In silico analyses were conducted to assess the interaction and stability of δ-cadinene with target proteins. In vitro assays, including cytotoxicity, morphological analysis, and cell invasion assays, were performed using MDA-MB-231 and MCF10-A cell lines. Results: Interaction analysis suggest that δ-cadinene interacts with key catalytic residues in MMP-2, sharing features with Quercetin. Blind docking revealed a second high-affinity site in the Fibronectin type II domain.Molecular dynamics simulations confirmed the stability of these complexes. In vitro studies showed that δ-cadinene significantly reduced MDA-MB-231 cell viability in a concentration-dependent manner, without affecting MCF10-A cells, and significantly inhibited invasion and MMP-2 activity after 24 h. Conclusions: δ-cadinene exhibits selective cytotoxic and anti-invasive activity in MDA-MB-231 cells, likely through dual inhibition of the catalytic and adhesion domains of MMP-2. These findings support δ-cadinene as a potential candidate for future therapeutic development in metastatic breast cancer. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) do not provide promising benefits to patients with advanced epithelial ovarian cancer (EOC). This study analyzed preoperative peripheral blood mononuclear cells (PBMCs) from these patients to evaluate the prognostic and therapeutic checkpoints. Methods: Preoperative PBMCs of 69 advanced EOC cases were collected to analyze the correlation between IC-expressing immune cells and survivals of patients. Co-expression of various ICs on the T lymphocytes from these patients was examined. Activation potential of programmed cell death 1 (PD-1)⁺herpes virus entry mediator (HVEM)⁺ T cells in PBMCs from the healthy donors and tumoricidal abilities of PMBCs treated with various ICIs were evaluated in vitro. Impact of respective ICIs on activation of T cells in PMBCs was investigated. Results: Percentages of PD-1⁺ CD4⁺ and CD8⁺ T cells in the PBMCs of patients could positively correlate with disease-free or overall survival. HVEM was highly co-expressed on these T lymphocytes. Prediction potential for overall survival of patients by the subpopulation of PD-1⁺ CD4⁺ or CD8⁺ T cells was higher than that by other parameters. The PD-1⁺HVEM⁺ CD4+ and CD8⁺ T cells showed characteristics of activated phenotype under activation signals. PBMCs receiving anti-B and T lymphocyte attenuator (BTLA) plus anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) or anti-PD-1 Ab had potent tumor-killing ability. Anti-BTLA Ab can drive T cells in the PBMCs toward an effector status. Conclusions: Percentages of PD-1⁺ T cells in the PBMCs could predict survival of EOC patients. Targeting HVEM-BTLA axis may be considered for ICI treatment of EOCs. Full article

Background: Cucurbitacin B (CuB) is a relatively unique and valuable component in plants of the Cucurbitaceae family due to its diverse and remarkable physiological activities, but its specific mechanisms in regulating tumor metabolism and immune response remain unclear. The hypoxic tumor microenvironment (TME) of pancreatic cancer induces metabolic reprogramming in cancer cells, causing them to rely on glycolysis for energy. LDHA, a key enzyme in glycolysis, can suppress glycolysis and tumor growth when inhibited. Objective: The objective of this study was to investigate the mechanism of CuB against pancreatic cancer and its effect on the immune system. Methods: In this study, cell migration/invasion assays, immunofluorescence, ELISA, Western blot, CETSA, flow cytometry, mouse models, and metabolomic and transcriptomic analyses were utilized to systematically elucidate the mechanism by which CuB inhibits pancreatic cancer and activates the immune system. Results: This study confirms that CuB inhibits pancreatic cancer by suppressing the PI3K/Akt/mTOR pathway and activating PINK1/Parkin to induce mitophagy, thereby inhibiting cell migration, invasion, and proliferation. It downregulates the expression of LDHA to block glycolysis, reduce lactate production and efflux, and improve the acidic TME. CuB also induces ICD to activate dendritic cells, promote CD8+ T-cell and M1 macrophage infiltration, and reduce the levels of regulatory T cells. Metabolomic and transcriptomic analyses validate CuB’s dual effects on metabolic reprogramming and immune activation. Conclusions: This study, for the first time, reveals that CuB induces mitophagy via the PI3K/Akt/mTOR and PINK1/Parkin pathways to selectively eliminate damaged mitochondria and suppress tumor energy metabolism. CuB inhibits pancreatic cancer through a triple mechanism—inducing mitophagy, inhibiting glycolysis, and activating immunity—which provides innovative insights for pancreatic cancer therapy. Full article

Circular RNAs (circRNAs) are increasingly recognized as regulators of gene expression, although their roles in hematopoietic differentiation remain relatively understudied. This study compares circRNA expression profiles between erythroblasts derived from human fetal liver and bone marrow CD34⁺ hematopoietic stem cells using publicly available RNA-seq datasets (GEO: GSE90878). Twelve samples from each developmental source were analyzed. Differential expression analysis was performed, and circAtlas 3.0 was employed to predict interactions between circRNAs, microRNAs (miRNAs), and RNA-binding proteins. Differentially expressed miRNAs were curated from miRNA-seq data (GEO: GSE110936) profiling the same cell types. Principal component analysis of circRNA expression profiles demonstrated clear separation between erythroblasts from fetal liver and bone marrow, which was statistically confirmed by PERMANOVA (p = 0.001); though this effect size is small (R² = 0.065). One circRNA, circALS2(4).1, was significantly upregulated in bone marrow-derived erythroblasts (adjusted p < 0.05), and ten additional circRNAs showed suggestive evidence for differential expression (adjusted p < 0.1). The resulting interaction networks reveal distinct circRNA landscapes and suggest regulatory circuits that may contribute to developmental differences in human erythropoiesis, indicating that the functions of circRNAs in hematopoietic development remain to be further elucidated. Full article

Background: Atezolizumab plus bevacizumab and lenvatinib are standard treatments for advanced hepatocellular carcinoma, but conventional tumor markers such as alpha-fetoprotein and des-gamma-carboxy prothrombin have a limited ability to reflect treatment responses. Circulating tumor cells with cancer stem cell characteristics have emerged as promising biomarkers. We examined the dynamics of cancer stem cell-related circulating tumor cell subsets and tumor markers at early and maximal response phases in patients with unresectable hepatocellular carcinoma undergoing systemic therapy. Methods: Sixty-two patients treated with either atezolizumab plus bevacizumab or lenvatinib were retrospectively analyzed. Peripheral blood was collected at baseline, during the early phase (during one to three months), and at maximal response. Circulating tumor cell subsets expressing cancer stem cell markers (CD90, epithelial cell adhesion molecule; CD133, vimentin) were assessed using multiparametric flow cytometry and compared with alpha-fetoprotein and des-gamma-carboxy prothrombin. Results: Early decreases in CD90-positive circulating tumor cells after therapy were associated with tumor shrinkage, longer periods of progression-free survival in both groups, and prolonged overall survival in the atezolizumab plus bevacizumab group. By contrast, early changes in alpha-fetoprotein and des-gamma-carboxy prothrombin were not consistently related to tumor size, progression-free survival, or overall survival. At maximal response, changes in CD90-positive circulating tumor cells reflected tumor burden more accurately than alpha-fetoprotein or des-gamma-carboxy prothrombin. Conclusions: These findings indicate that cancer stem cell-related circulating tumor cell subsets, particularly CD90-positive cells, may serve as valuable biomarkers for monitoring treatment response and predicting prognosis in unresectable hepatocellular carcinoma. CD90-positive circulating tumor cells perform dynamic monitoring superior to conventional markers such as alpha-fetoprotein and des-gamma-carboxy prothrombin. Full article

The epidermal growth factor receptor (EGFR), as an important target protein for inhibiting and intervening in osteoporosis, is associated with cell migration, proliferation, and apoptosis. Peptides derived from food have been shown to have a strong affinity for EGFR, thereby regulating downstream cellular-signaling pathways and participating in stimulating bone formation. However, it is still a “black box” as to how active peptides affect the conformational changes in the EGFR-binding domain when interacting with its ligand EGF. To shed light on the roles, peptides in EGFR binding, which is involved in the osteoblast differentiation, a high EGFR affinity soybean peptide (HEP) was isolated and purified from soy yogurt. Firstly, the osteogenic activity of HEP was identified through cellular alkaline-phosphatase (ALP) and calcium influx. HEP promoted ALP activity from 0.01897 ± 0.00165 to 0.04051 ± 0.00402 U/mg after 100 μM of peptide treatment, and free intracellular calcium ions and calcium deposition both increased in a dose-dependent manner at 1–100 μg/mL. Secondly, the interaction between HEP and EGFR was detected by bioinformatics, spectroscopy analysis, and Western blot. The Molecular docking results showed that HEP (VVELLKAFEEKF) exhibited high affinity among all the peptides, with -CDOCKER energy values of 184.077 kcal/mol on one EGFR. Moreover, a different loop conformation has been detected in HEP, comparing it to that of EGF, which influences HEP interactions with EGFR. GlU3, LEU4, and LEU5 (HEP) match GLU40, LEU26, and GLU40 (EGF). Moreover, the CD data showed that HEP could interact with extracellular domain protein of EGFR, but the secondary structure did not change after HEP was mixed with Mutant extracellular domain protein. Furthermore, treatment with HEP increased the expression of EGFR and the activation of the PI3K-RUNX2-signaling pathway. These results suggested that HEP may have the function of promoting bone remodeling, which could promote the binding between EGF and EGFR and may be used as a potential active factor for functional food development to prevent osteoporosis. Full article

Background/Objectives: Plasma cell gingivitis (PCG) is a rare, benign, non-dental-plaque-induced inflammatory condition characterized by dense subepithelial infiltration of polyclonal plasma cells. Due to its nonspecific clinical presentation, PCG represents a diagnostic challenge. This case report aims to describe a clinical case of PCG, highlighting the diagnostic process, histopathological correlation, and therapeutic approach. Methods: A 57-year-old male presented with a polypoid, erythematous, and edematous gingival lesion in the anterior maxillary region, with spontaneous bleeding on probing. Following clinic assessment, an incisional biopsy was performed, alongside complete hematological and inflammatory profiling. Histological and immunohistochemical analyses revealed the presence of an inflammatory infiltrate. Results: Histological evaluation revealed spongiotic squamous epithelium characterized by a dense plasma cell infiltrate with a liquenoid pattern of CD3-positive T and CD20-positive B lymphocytes. A polytypic expression of kappa and lambda light chains was also detected. The patient underwent topical corticosteroid therapy, showing progressive clinical improvement and resolution of symptoms, although minor mucosal involvement persisted. Conclusions: PCG remains a rare and underdiagnosed condition requiring integration of clinical, hematological, and histopathological data for accurate diagnosis. While corticosteroids remain the first-line therapy, emerging treatments, including photobiomodulation, may offer future adjunctive strategies to improve outcomes and reduce recurrence. Full article

Rhabdomyolysis is characterized by the breakdown of skeletal muscle tissue, frequently leading to acute kidney injury (AKI). Traditional conservative treatments have shown limited effectiveness in modifying the disease course, thereby necessitating targeted pharmacological approaches. Zileuton (Z), a selective inhibitor of 5-lipoxygenase (5-LOX), has demonstrated efficacy in enhancing renal function recovery in animal models of AKI induced by agents such as cisplatin, aminoglycosides, and polymyxins. The present study aimed to evaluate the therapeutic potential of a single dose of Z in mitigating rhabdomyolysis-induced AKI (RI-AKI) via modulation of myeloid-derived suppressor cells (MDSCs). Male C57BL/6 mice were assigned to four experimental groups: Sham (intraperitoneal administration of 0.9% saline), Z (single intraperitoneal injection of Z at 30 mg/kg body weight), glycerol (Gly; single intramuscular dose of 50% glycerol at 8 mL/kg), and glycerol plus Z (Z + Gly; concurrent administration of glycerol intramuscularly and Z intraperitoneally). Animals were sacrificed 24 h post-glycerol injection for analysis. Zileuton administration significantly improved renal function, as indicated by reductions in blood urea nitrogen (BUN) levels (129.7 ± 17.9 mg/dL in the Gly group versus 101.7 ± 6.8 mg/dL in the Z + Gly group, p < 0.05) and serum creatinine (Cr) levels (2.2 ± 0.3 mg/dL in the Gly group versus 0.9 ± 0.3 mg/dL in the Gly + Z group p < 0.05). Histopathological assessment revealed a marked decrease in tubular injury scores in the Z + Gly group compared to the Gly group. Molecular analyses demonstrated that Z treatment downregulated mRNA expression of macrophage-inducible C-type lectin (mincle) and associated macrophage infiltration-related factors, including Areg-1, Cx3cl1, and Cx3CR1, which were elevated 24 h following glycerol administration. Furthermore, the expression of NLRP-3, significantly upregulated post-glycerol injection, was attenuated by concurrent Z treatment. Markers of mitochondrial biogenesis, such as mitochondrial DNA (mtDNA), transcription factor A mitochondrial (TFAM), and carnitine palmitoyltransferase 1 alpha (CPT1α), were diminished 24 h after glycerol injection; however, their expression was restored upon simultaneous Z administration. Additionally, Z reduced protein levels of BNIP3, a marker of mitochondrial autophagy, while enhancing the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), suggesting that Z ameliorates RI-AKI severity through the regulation of mitochondrial quality control mechanisms. Zileuton also decreased infiltration of CD11b(+) Gr-1(+) MDSCs and downregulated mRNA levels of MDSC-associated markers, including transforming growth factor-beta (TGF-β), arginase-1 (Arg-1), inducible nitric oxide synthase (iNOS), and iron regulatory protein 4 (Irp4), in glycerol-injured kidneys relative to controls. These markers were elevated 24 h post-glycerol injection but were normalized following concurrent Z treatment. Collectively, these findings suggest that Zileuton confers reno-protective effects in a murine model of RI-AKI, potentially through modulation of mitochondrial dynamics and suppression of MDSC-mediated inflammatory pathways. Further research is warranted to elucidate the precise mechanisms by which Z regulates MDSCs and to assess its therapeutic potential in clinical contexts. Full article

Wenchang Chickens (WCCs) and Recessive White Feather Chickens (RWFCs) are two important broiler breeds in China, although their susceptibility to E. tenella has not been compared. This study explores these differences in susceptibility. The results showed that WCCs exhibited lower susceptibility, as evidenced by no mortality and significantly reduced oocyst production compared to RWFCs. Additionally, WCCs had higher levels of CD3⁺CD4⁺ T lymphocytes and lower levels of CD3⁺CD8α⁺ T lymphocytes, both before and after infection, compared to RWFCs. Notably, serum IgA and IgG antibody levels in WCCs were significantly higher than those in RWFCs. RNA−seq analysis at 2, 4, and 7 days post-infection (dpi) revealed a consistent upward trend in gene expression in WCCs, while RWFCs exhibited a fluctuating pattern. Functional analysis indicated that the stable immune response, as annotated by the differentially expressed genes (DEGs) in WCCs, along with distinct metabolic alterations, may contribute to their enhanced resistance. Several hub genes, including SLC7A11, CCL19, CD4, HSPA5, and HSP90AA1, were identified within gene interaction networks specific to each breed. These findings provide valuable insights into the molecular mechanisms underlying the differential susceptibility of WCCs and RWFCs, offering potential targets for new coccidiosis control strategies. Full article

Regulatory T (Treg) cells are essential for maintaining self-tolerance and regulating immune responses. In this study, we report the identification of Treg cell epitopes in human α-tubulin that were capable of enhancing IL-10-producing Foxp3⁺ Treg cells and LAG-3⁺CD49b⁺FoxP3⁻ Tr1 cells in vitro, using human peripheral blood mononuclear cells. Similarly, we also demonstrate that a peptide pool containing the identified Treg cell epitopes (αTBL pool) suppressed the T cell responses elicited by HLA class I- and class II-restricted T cell epitopes. Moreover, stimulation of naive CD4⁺ T cells with autologous monocyte-derived dendritic cells in the presence of the αTBL pool promoted the differentiation of functional FoxP3⁺ Treg cells, which suppressed the proliferation of CD3/CD28-activated T cells. Finally, we show that one of the identified epitopes, identical between human and mouse, also stimulated FoxP3⁺ Treg cells in splenocytes isolated from C57BL/6 mice. Considering the elevated expression of α-tubulin in all cell types, the presence of Treg cell epitopes in this protein may facilitate a broad mechanism of immune regulation. Moreover, α-tubulin Treg cell epitopes may prove useful in creating novel treatments for conditions marked by excessive or misdirected immune responses. Full article

The emergence of the SARS-CoV-2 JN.1 lineage in late 2023 marked a major shift in viral evolution. By January 2024, it had displaced XBB variants to become the dominant strain worldwide. JN.1 and its descendants are antigenically distinct from earlier Omicron subvariants, with approximately 30 additional spike mutations compared to XBB-derived viruses. The combination of these features alongside growing evidence of considerable immune evasion prompted the FDA to recommend that vaccine formulations be updated to target JN.1 rather than XBB.1.5. The continued dominance of JN.1-derived variants necessitates the characterization of viral infection in established animal models to inform vaccine efficacy and elucidate host–pathogen interactions driving disease outcomes. In this study, transgenic mice expressing human ACE2 were infected with SARS-CoV-2 subvariants JN.1, KP.2, and EG.5.1 to compare the pathogenicity of JN.1-lineage and XBB-lineage SARS-CoV-2 viruses. Infection with JN.1 and KP.2 resulted in attenuated disease, with animals exhibiting minimal clinical symptoms and no significant weight loss. In contrast, EG.5.1-infected mice exhibited rapid progression to severe clinical disease, substantial weight loss, and 100% mortality within 7 days of infection. All variants replicated effectively within the upper and lower respiratory tracts and caused significant lung pathology. Notably, EG.5.1 resulted in neuroinvasive infection with a significantly high viral burden in the brain. Additionally, EG.5.1 infection resulted in a significant increase in CD8⁺ T cell and CD11b⁺ CD11c⁺ dendritic cell populations in infected lungs. Full article