Epstein-Barr virus (EBV) causes multiple severe diseases, and its entry process is a promising prophylactic and therapeutic target. However, EBV entry is intricate with several unresolved mechanisms, and current research methods for it is limited, insensitive, and inefficient. Therefore, novels methods are urgently needed. Herein, we innovatively reported a recombinant virus system rEBV-VSV realizing complicated multi-glycoprotein synergized EBV entry with sensitive detection, which was especially suitable for accurate study of entry mechanisms and effective evaluation of entry-inhibitive therapies. First, rEBV-VSV efficiently entered host cells via multi-synergetic EBV glycoproteins on its membrane and simulated entry features and cellular tropisms of native EBV, also being sensitively detected via bioluminescence. Second, rEBV-VSV was an effective measuring system to evaluate entry-inhibiting potency of EBV-specific antibodies and population’s sera in a rapid and high-throughput manner. Third, via flexible mutations and recombination on rEBV-VSV, it was used to accurately study functions of glycoproteins and key residues during EBV entry to better understand entry mechanisms. Especially, via rEBV-VSV, glycoprotein H (gH) mutation L65A+L69A was found to have completely opposite effects on EBV entry into B and epithelia cells, which was manipulated by gp42, and gp42 also powerfully impacted the efficacy of gH-specific antibody E1D1. Conclusively, rEBV-VSV was a satisfactory system to study EBV entry features, mechanisms, and entry-targeted therapies, which could resolve the research dilemma of EBV entry and facilitate the development of EBV-specific drugs and vaccines.

Elderly adults are at high risk for severe coronavirus disease 2019 (COVID-19). Whether the use of corticosteroids in this population with mild to moderate COVID-19 could prevent disease progression remains controversial. The BEAT COV trial assessed corticosteroids treatments in elderly patients with mild to moderate COVID-19. Eligible patients were randomly allocated (1:1) to either the intervention group (oral corticosteroids in combination with standard of care (SOC)) or the control group (SOC alone). Non-randomized patients were enrolled in an observational cohort. The primary outcome was the rate of severe or critical COVID-19 within 28 days. The study was terminated prematurely due to low COVID-19 prevalence and decreasing severe cases, leading to an underpowered sample size. A total of 344 patients were screened, 193 patients were randomly allocated to receive corticosteroids in combination with SOC (95 patients) versus SOC alone (98 patients), 151 patients were included in the observational cohort. In the full analysis set (FAS) population, 1 (1.09

BackgroundDespite high DTaP coverage, pertussis resurgence persists. Infants under 2 months of age face severe outcomes due to vaccine ineligibility and rising macrolide-resistant B. pertussis (MRBP), yet treatment options remain limited.ObjectiveTo analyze epidemiology, clinical profiles, and antimicrobial management of hospitalized pertussis infants under 2 months of age, identifying risk factors for severity and evaluating real-world SMZ-TMP use.MethodsRetrospective study of PCR/culture-confirmed pertussis infants hospitalized at Shenzhen Children's Hospital (2015–2024). Data included transmission sources, clinical severity, and antimicrobial regimens. Logistic regression analysis was performed to analyze the risk factors for severe pertussis, and a P-value < 0.05 was considered statistically significant. The predictive value for severe pertussis was evaluated using the receiver operating characteristic (ROC) curve.ResultsAmong 321 infants with a history of exposure, parents constituted the primary infection source (46.1%, 148/321). 25 infants with Bordetella pertussis infection (aged 24–59 days) received off-label SMZ-TMP without bilirubin encephalopathy or renal dysfunction. Leukocytosis, and an elevated neutrophil-lymphocyte ratio were predictors of severe disease. Exposure history, apnea, decreased oxygen saturation, tachypnea, tachycardia, elevated white blood cell count, and an increased neutrophil-to-lymphocyte ratio were identified as significant risk factors for severe pertussis.ConclusionIn infants under 2 months of age with pertussis, parents are the primary source of infection. In infants under 2 months of age with macrolide-resistant pertussis, treatment with SMZ-TMP was effective and no severe adverse reactions were observed.

The specific role of γδ T cells in non-tuberculous mycobacteria (NTM) infections remains incompletely understood. Here we characterized the immune landscape of pulmonary tissues from a Mycobacterium abscessus-infected NTM mice model. Interleukin-17 (IL-17)A+ γδ T cells were essential for controlling M. abscessus infection by directly eliminating extracellular bacteria. These cells conferred protective immunity in two mouse models of infection combined with either pulmonary fibrosis or a lack of functional interferon-gamma (IFNγ)-mediated immunity. IL-17A+ γδ T cells exerted bactericidal activity via granzyme B-dependent cytotoxic pathways. Absence of IL-17A substantially impaired bacterial recognition and cytotoxic function of IL-17A+ γδ T cells, highlighting the cell-intrinsic requirement for IL-17A signalling in γδ T cell activation. M. abscessus recognition through Toll-like receptor 2 induced macrophage production of IL-1β and IL-23, promoting the expansion and activation of IL-17A+ γδ T cells. Single-cell RNA sequencing on human peripheral blood mononuclear cells suggests that anti-IFNγ autoantibodies compromise γδ T cell function. Our findings establish IL-17A+ γδ T cells as a promising therapeutic target for NTM infections, particularly when IFNγ-dependent immunity is compromised.

Objective Epstein-Barr virus (EBV) -associated diseases comprise a spectrum of conditions, including infectious mononucleosis (IM) and chronic active EBV infections (CAEBV), as well as malignant lymphomas. The study aimed to compare genomic variations of EBV across different subtypes of EBV-associated diseases to investigate the impact of EBV mutations on disease progression and clinical outcomes. Methods A total of 36 patients with EBV-associated diseases were enrolled. Peripheral blood DNA samples (400µL) were collected and sequenced using Illumina sequencing technology. Following quality control with FastQC, Fastp, and TriTrimmomatic, 27 samples meeting the critera of minimum effective coverage > 10 and coverage > 80% were retained. Single nucleotide polymorphisms (SNP) annotations were generated into VCF files, and mutation profiles were visualized using heatmaps. Mutational rates were compared using Fisher's exact test, based on disease subtype, presence of hemophagocytic lymphohistiocystosis (HLH), and clinical outcomes. Odds ratios (ORs) were calculated using the Haldane-Anscombe correction. Results Compared with the reference stain B95.8, a total of 2182 mutation sites were identified in 27 samples. The mutations located in coding region included 523 missense variants, 1 insertion mutations, and 2 deletion mutations, all of which only involved single amino acid changes in the encoded proteins. Although a large number of mutations were detected, no statistically significant differences were observed among the IM, CAEBV and lymphoma groups, or between patients with and without HLH. However, three mutation sites in BFLF1 were significantly more frequent in deceased patients compared to survivors, which detailedly refers to Ile35Thr, Asp44Glu and Val246Ile [ P = 0.0267, OR = 15.00, 95%CI= (0.7436,301.5)]. Conclusion Single amino acid changes in EBV proteins had no significant effect on the progression status of EBV-associated diseases, but the mutation in BFLF1 were associated with an increased risk of mortality.

Background:Close contacts of individuals with active pulmonary tuberculosis (TB) face an elevated risk of TB acquisition, necessitating systematic screening for latent TB infection and subsequent TB preventive treatment (TPT). Major TPT regimens require ≥3 months of drug exposure and demonstrate suboptimal safety profiles, significantly compromising treatment completion rates. Therefore, the development of shorter, safer chemoprophylaxis strategies represents a critical need in global TB control. Among close contacts, school-aged children and adolescents constitute the most vulnerable demographic subgroup, warranting prioritized intervention efforts. Objective:The primary objective of this study is to demonstrate noninferiority of an ultrashort, 1-month TPT regimen of isoniazid plus rifapentine, administered 3 times a week (1H3P3) compared with the standard 3-month daily isoniazid plus rifampicin (3HR) regimen in preventing active TB, as measured by the 24-month cumulative incidence of active TB following randomization. Methods:An investigator-initiated, prospective, multicenter, open-label, noninferiority, cluster-randomized controlled clinical trial is being implemented under the auspices of the national TB control program in China. Close contacts of school pulmonary TB index cases, regardless of diagnostic type, are actively screened for symptoms using interferon-gamma release assays, chest imaging, and sputum molecular diagnostic testing to detect TB infection and exclude active TB. Eligible latent TB infection cases will be randomized in a 1:1 cluster ratio to receive either the standard 3HR regimen or the novel ultrashort 1H3P3 regimen for TPT, with subsequent follow-up for up to 2 years to assess disease progression. The primary composite end point includes microbiologically confirmed TB (sputum culture or molecular diagnostic testing) or clinically diagnosed TB. With 80% power to detect noninferiority (20% margin), the study requires 1760 participants per arm, accounting for cluster design effects. Results:Recruitment started in September 2023. By the end of December 2025, a total of 2478 participants, comprising 627 index cases, had been enrolled, and recruitment is estimated to continue until September 2026. Data analysis will commence after the 2-year follow-up period, and the results are expected to be published by March 2029. Conclusions:This cluster randomized controlled trial aims to establish the noninferiority of a novel, ultrashort 1H3P3 regimen compared to the standard 3-month 3HR regimen for preventing active TB in infected school contacts. If successful, this well-tolerated 1-month regimen could significantly improve treatment completion and optimize preventive therapy delivery in high-transmission congregate settings, thereby contributing substantively to global TB control efforts.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by releasing inhibitory pathways that restrain antitumor T-cell responses. Their success has renewed interest in checkpoint blockade for infectious diseases, particularly chronic viral infections, sepsis-associated immunosuppression, and refractory opportunistic infections. In these settings, immune checkpoints may contribute to pathogen persistence by limiting effector function, but they also restrain tissue injury, cytokine excess, and immune-mediated organ damage. This dual role makes translation fundamentally different from oncology: the goal is not maximal immune activation, but controlled immune recalibration. Evidence is strongest for chronic viral infections and selected oncology-adjacent cohorts, whereas infection-directed trials remain early and heterogeneous. A precision framework based on pathogen burden, immune phenotype, tissue vulnerability, biomarker feasibility, safety monitoring, and implementation context is therefore essential before ICIs can be responsibly developed as host-directed therapies for infectious diseases. This review synthesizes the rationale, evidence, and safety considerations for ICIs in infectious diseases. We discuss chronic viral infections, including human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Epstein-Barr virus (EBV), and highlight EBV as a bridge between persistent viral infection, immune surveillance, lymphoproliferation, and cancer immunotherapy. We also examine tuberculosis, sepsis, fungal infections, and parasitic diseases, where checkpoint pathways may restore host defense or amplify immunopathology. Finally, we propose a precision-immunotherapy framework integrating pathogen biology, immune phenotype, tissue risk, biomarker feasibility, access, and trial design.

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare inborn error of immunity characterized by heightened susceptibility to low-virulence non-tuberculous mycobacteria. Despite the widespread application of next-generation sequencing, the molecular etiology of approximately 50% of patients remains elusive. To date, 22 genes have been implicated, all converging on the IL-12/23–IFN-γ circuit, underscoring its non-redundant role in controlling intracellular pathogens. Isolated MSMD is characterized by a selective predisposition to one or more mycobacterial and related infections. But syndromic MSMD’s clinical phenotypes are highly heterogeneous; apart from mycobacterial infections, patients may suffer from viral, bacterial, or fungal diseases, and can additionally manifest auto-inflammation, malignancy, or cutaneous involvement. Current MSMD management mainly hinges on prolonged antimicrobial therapy or align with recombinant human interferon-γ (rhIFN-γ), although allogeneic hematopoietic stem cell transplantation (HSCT) remains the sole curative yet high-risk option; gene editing is still experimental. Priorities are early high-risk identification, targeted intervention and full-process management.

INTRODUCTION:Sepsis-associated acute kidney injury (SA-AKI) is frequently complicated by immune paralysis and kidney infection. Despite the spleen's critical immunological role, the neural mechanisms regulating the splenic immune responses during SA-AKI remain unclear. METHODS:To examine this, we used splenic denervation, continuous intrasplenic infusion, single-cell sequencing and neutrophil-specific β2-adrenergic receptor Adrb2 knockout mice to define the role of the splenic norepinephrine-β2-adrenergic receptor (NE/β2-AR) axis in SA-AKI. RESULTS:Our findings indicate that pre-emptive splenic denervation in mice mitigates sepsis-induced kidney injury, whereas local intrasplenic norepinephrine infusion exacerbates kidney damage in a cecal ligation/puncture (CLP) mouse model. Targeted blockade of splenic β2-adrenergic receptor (β2-AR) signaling enhances survival and attenuates kidney damage in CLP mice. Local splenic depletion of neutrophil and neutrophil-specific conditional knockout of Adrb2 demonstrate that NE/β2-AR signaling influences splenic neutrophils, thereby driving the progression of acute sepsis. Mechanistic investigations reveal that splenic NE/β2-AR signaling enhances neutrophil prostaglandin E2 synthesis via the cAMP-response element binding protein pathway, thereby suppressing T helper 1 cell activation, increasing local bacterial infections, and aggravating SA-AKI. CONCLUSIONS:These findings clarify the role of splenic NE/β2-AR signaling in modulating neutrophil-mediated immunosuppression, thereby driving sepsis progression and aggravating kidney damage.

Epstein-Barr virus (EBV) -associated diseases comprise a spectrum of conditions, including infectious mononucleosis (IM) and chronic active EBV infections (CAEBV), as well as malignant lymphomas. The study aimed to compare genomic variations of Type 1 EBV across different subtypes of EBV-associated diseases to investigate the impact of EBV variants on disease progression and clinical outcomes. A total of 36 patients with EBV-associated diseases were enrolled. Targeted EBV genome sequencing on EBV genomic was performed with peripheral blood DNA samples (400µL) using Illumina sequencing technology. Following quality control with FastQC, Fastp, and TriTrimmomatic, 27 samples comprising 2 IM, 9 CAEBV and 16 NK/T-cell lymphoma cases meeting the critera of minimum effective coverage > 10 and coverage > 80

Individuals with asymptomatic tuberculosis (TB) are considered a significant risk to the disease burden and transmission. However, the progression and treatment for asymptomatic TB remain incompletely described. This prospective cohort study was embedded within a prevalence survey conducted in 2021 and 2022 in Lanxi County, China. All patients with pulmonary TB who consented to participate would be included in the study and were categorized as asymptomatic or symptomatic. For the primary analysis, asymptomatic TB was defined as the absence of current cough, fever, night sweats, weight loss, or hemoptysis. Patients were followed up until 10 November 2024. Among 109 345 individuals screened, 193 were included, of whom 101 (52.3%) were symptomatic and 92 (47.7%) were asymptomatic. The proportion of asymptomatic TB varied from 32.5% to 62.7% depending on varying symptom negative threshold. Fewer asymptomatic patients were bacteriologically confirmed compared to symptomatic patients (71.7% [66/92] vs 90.1% [91/101], P = .001). The median time for asymptomatic patients at screening to develop symptoms was 102 days. Most patients in both groups received treatment for active TB (97.8% vs 99.0%, P = .606). The treatment success rate among asymptomatic patients was comparable to that of symptomatic patients (93.3% vs 96.0%, P = .521), but their treatment duration was significantly shorter (196 vs 273 days, P < .001). In the community setting, a significant number of TB cases were asymptomatic and remained so for months. These cases demonstrated satisfactory treatment coverage and outcomes, with shorter durations compared to symptomatic TB, suggesting the potential for developing shorter regimens for asymptomatic TB.

Patients with fever of unknown origin (FUO) can sometimes be accompanied by haemophagocytic lymphohistiocytosis (HLH), a life-threatening disease. The prognostic model and specific markers for the early prognosis and the optimized treatment regimen are of considerable research interest. A total of 135 FUO/HLH patients were enrolled and classified according to the 60-day outcomes following diagnosis. 79 patients (including 5 patients lost in follow-up) enrolled from 2007 to 2015 served as the derivation cohort, and 56 patients from 2016 to 2023 served as the validation cohort. In the derivation cohort, 27 patients (27/74, 36.5

Background Close contacts of individuals with active pulmonary tuberculosis (TB) face an elevated risk of TB acquisition, necessitating systematic screening for latent tuberculosis infection (LTBI) and subsequent TB preventive treatment (TPT). Major TPT regimens require ≥3 months of drug exposure and demonstrate suboptimal safety profiles, significantly compromising treatment completion rates. The development of shorter, safer chemoprophylaxis strategies therefore represents a critical need in global TB control. Among close contacts, school-aged children and adolescents constitute the most vulnerable demographic subgroup, warranting prioritized intervention efforts. Method An investigator-initialed prospective, multicenter, open-label, non-inferiority, cluster randomized controlled clinical trial is being implemented under the auspices of the national TB control program in China. Close contacts of school pulmonary TB index cases regardless of diagnostic types are actively screened with symptoms, interferon-gamma release assay (IGRA) test, chest imaging, and sputum molecular diagnostic testing to detect TB infection and exclude active TB. Eligible LTBI cases will be randomized at a 1:1 cluster ratio to receive either a standard 3HR regimen (3-month daily isoniazid plus rifampicin) or a novel 1H3P3 ultra-short regimen (one-month isoniazid plus rifapentine three times a week) for TPT with subsequent follow-up to two years for disease progression. The primary composite endpoint includes microbiologically confirmed TB (sputum culture or molecular diagnostic testing) or clinically diagnosed TB. With 80% power to detect non-inferiority (20% margin), the study requires 1,760 participants per arm, accounting for cluster design effects. Discussion Shortening treatment duration is a key to improve adherence to TPT, thus achieving optimal protective efficacy. This trial evaluates a promising ultra-short, well-tolerated TPT regimen with an active control. Cluster randomization was adopted to reduce interference in school-setting, potential limitations include implementation challenges by enlarged sample size, complicated cluster assignment and limited generalizability by school-based population. If successful, this ultra-short, well-tolerated regimen could optimize TPT delivery, particularly in congregate settings. Integrating with active screening, our findings may inform scalable TB control strategies, advancing progress toward global TB elimination goals. Trial Registration ClinicalTrials.gov NCT06022146. https://clinicaltrials.gov/study/NCT06022146

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare clinical syndrome that is characterized by selective vulnerability to intracellular pathogens. Deficiency in IL12RB1 is the most common type of MSMD but the heterogeneity of its clinical Manifestation Makes precise diagnosis difficult. Here, we report a previously healthy 29 year-old woman who had suffered from disseminated infection with Mycobacterium tilburgii, which is a rare, unculturable environmental mycobacteria, for over 2 years. We used whole exome sequencing to detect a novel compound heterozygous variant in the IL12RB1 gene. Immunological analysis of the patient’s peripheral lymphocytes showed a barely detectable level of IL-12Rβ1, a reduced population of follicular helper T (Tfh) cells and impaired production of IFN-γ in response to IL-12/IL-23 stimulation. Metagenomic next-generation sequencing was used to identify the causative pathogen and to analyze drug susceptibility. The infection was contained by a combination of anti-mycobacterial drugs and IFN-γ supplementary treatment. An RNA-seq analysis, using follow-up blood samples, revealed the limited success of these treatments over 6 months. Our findings support the screening for inherited immunological problems in patients with difficult-to-treat mycobacterial infections. The suboptimal response to prolonged anti-mycobacterial drugs and IFN-γ supplementation warrants the development of novel therapeutic strategies for MSMD patients.

Objectives: Our objective was to investigate the clinical characteristics, complications, and treatment outcomes of Epstein–Barr virus (EBV)-related infectious mononucleosis (IM) in children and to identify risk factors associated with prolonged fever and abnormal liver function. Methods: This retrospective study included 3006 children admitted to Shenzhen Children’s Hospital from May 2009 to April 2024 with suspected EBV-related IM. After excluding cases without etiological evidence and those with underlying diseases, 2660 cases were analyzed. Data on demographics, clinical manifestations, laboratory findings, complications, and treatment outcomes were collected. Logistic regression was used to identify risk factors for prolonged fever and abnormal liver function. Results: Among the 2660 confirmed cases, patients ranged from 8 months to 17 years of age, with a median age of 4 years and a male-to-female ratio of 1.46:1. Co-infections were identified in 369 (13.9%) patients, predominantly with Group A Streptococcus. Complications occurred in 560 (24.46%) of the 2289 patients without co-infections, with bronchitis being the most common (42.68%). Elevated ferritin and atypical lymphocyte percentage were associated with prolonged fever (p < 0.001), while elevated lactate dehydrogenase (LDH) and a lower CD4% predicted abnormal liver function (p < 0.001). Antiviral therapy did not shorten fever duration or hospital stay but prolonged both when combined with corticosteroids or intravenous immunoglobulin (IVIG) (p < 0.001). Conclusions: Specific laboratory markers such as ferritin, atypical lymphocyte percentage, LDH, and CD4% are important predictors of prolonged fever or liver dysfunction in EBV-IM. Our findings suggest that antiviral therapy may not be beneficial in uncomplicated cases and highlight the need for tailored treatment strategies to optimize patient outcomes.