Florian Krammer, Ron A. M. Fouchier, Maryna C. Eichelberger
et al.
ABSTRACTNeuraminidase is one of the two surface glycoproteins of influenza A and B viruses. It has enzymatic activity that cleaves terminal sialic acid from glycans, and that activity is essential at several points in the virus life cycle. While neuraminidase is a major target for influenza antivirals, it is largely ignored in vaccine development. Current inactivated influenza virus vaccines might contain neuraminidase, but the antigen quantity and quality are varied and not standardized. While there are data that show a protective role of anti-neuraminidase immunity, many questions remain unanswered. These questions, among others, concern the targeted epitopes or antigenic sites, the potential for antigenic drift, and, connected to that, the breadth of protection, differences in induction of immune responses by vaccination versus infection, mechanisms of protection, the role of mucosal antineuraminidase antibodies, stability, and the immunogenicity of neuraminidase in vaccine formulations. Reagents for analysis of neuraminidase-based immunity are scarce, and assays are not widely used for clinical studies evaluating vaccines. However, efforts to better understand neuraminidase-based immunity have been made recently. A neuraminidase focus group, NAction!, was formed at a Centers of Excellence for Influenza Research and Surveillance meeting at the National Institutes of Health in Bethesda, MD, to promote research that helps to understand neuraminidase-based immunity and how it can contribute to the design of better and broadly protective influenza virus vaccines. Here, we review open questions and knowledge gaps that have been identified by this group and discuss how the gaps can be addressed, with the ultimate goal of designing better influenza virus vaccines.
Jillian C. Carmichael, Christian S. Stevens, Kristina E. Atanasoff
et al.
Human cytomegalovirus (HCMV) genetic manipulation traditionally relies on bacterial artificial chromosome (BAC) recombineering, necessitated by its large ~236 kb genome. This approach is limited by the scarcity of HCMV strains engineered into BACs and often requires the deletion of ‘non-essential’ genes to accommodate the BAC cassette. We developed a novel approach using temperature-sensitive Sendai virus (SeV) vectors to deliver CRISPR/Cas9 for targeted HCMV genome editing without these constraints. This system achieves high editing efficiency (80–90%) in fibroblasts, epithelial cells and endothelial cells without BAC intermediates. As proof of principle, we targeted the HCMV (TB40/E strain) pentamer complex (PC) genes UL128 and UL130, crucial for viral entry into non-fibroblast cells. Edited viruses showed significantly reduced infectivity in epithelial cells, confirming functional disruption of the PC. Plaque purification yielded isogenic clones with phenotypes comparable to AD169, a naturally PC-deficient strain. Furthermore, multiplexed editing created precise 663 bp deletions in over 60% of viral genomes. Importantly, this method enables HCMV editing in physiologically relevant cell types without fibroblast passaging, which typically introduces mutations. This SeV-Cas9 system represents a significant advancement for studying HCMV biology in diverse cell types.
ObjectiveThe prognostic role of the hemoglobin, albumin, lymphocyte, and platelet (HALP) score in non-small cell lung cancer (NSCLC) has been widely reported, but the results remain controversial. Therefore, we aim to evaluate the prognostic and clinicopathological value of the HALP score in NSCLC through a pooled analysis.MethodsWe conducted a comprehensive literature search of PubMed, Embase, Web of Science, Cochrane Library, and the ClinicalTrials.gov databases in December 2024 to identify studies evaluating the relationship between the pretreatment HALP score and outcomes in NSCLC patients. Eligible studies included patients treated with surgical resection, chemotherapy, or immunotherapy. The HALP score was calculated using peripheral blood levels of hemoglobin, albumin, lymphocytes, and platelets measured before treatment. Data were extracted and analyzed to determine the association of the HALP score with overall survival (OS), disease/progression/recurrence-free survival (DFS/PFS/RFS), and clinicopathological characteristics. Subgroup and sensitivity analyses were performed to ensure the robustness and reliability of the results.ResultsA total of 10 studies involving 7024 patients were included. The results demonstrated that patients with lower pretreatment HALP score had worse OS (hazard ratio [HR] = 1.73, 95% confidence interval [95% CI]: 1.27-2.34, p < 0.001) and DFS/PFS/RFS (HR = 1.86, 95% CI: 1.30-2.64, p < 0.001). The results remained consistent across subgroup analyses based on study characteristics and sensitivity analyses. Additionally, a lower HALP score was significantly associated with age (odds ratio [OR] = 1.43, 95% CI: 1.15-1.78, p = 0.001) and tumor size (OR = 0.54, 95% CI: 0.38-0.76, p < 0.001).ConclusionsThe HALP score is a valuable prognostic biomarker for predicting survival outcomes in NSCLC patients. Its ability to integrate multiple aspects of systemic inflammation and nutritional status makes it a promising tool for improving risk stratification and guiding treatment decisions. Future studies should continue to validate this finding in prospective, multicentre trials.
IntroductionMyasthenia Gravis (MG) is an autoimmune disorder characterized by impaired neuromuscular junction (NMJ) transmission. Current treatments for MG include steroids and nonsteroidal immunosuppressive therapies (NSISTs). However, approximately 20% of patients show a poor response to these therapies, which are often associated with significant side effects. Telitacicept, a novel recombinant fusion protein targeting the BAFF/APRIL pathway, has shown promise in treating autoimmune diseases, including MG.MethodsThis retrospective study compared the efficacy of telitacicept monotherapy (10 patients) to NSISTs (16 patients) and sequential therapy (6 patients) in managing Myasthenia Gravis (MG) at The First Affiliated Hospital of Wenzhou Medical University (July 2020-November 2024). The primary endpoint was the time to achieve minimal symptom expression (MSE), and secondary endpoint was the change in the mean daily prednisone dosage from baseline to month 4.ResultsAmong telitacicept-treated patients, 80% achieved MSE within 4 months, with a significant reduction in mean daily dose of prednisone (from 45.00 mg to 6.25 mg, P < 0.001). In contrast, only 12.5% of the NSISTs group achieved MSE, with no significant change in mean daily dose of prednisone (P = 0.091). The sequential therapy group (efgartigimod followed by telitacicept) maintained stable disease conditions.ConclusionTelitacicept is effective in inducing MSE rapidly and offers a steroid-sparing effect, making it a promising alternative to traditional NSISTs with fewer side effects in MG patients.
Obstructive sleep apnea (OSA) drives immune dysregulation through its hallmark stressors—intermittent hypoxia (IH) and sleep fragmentation (SF). Beyond impaired sleep, OSA acts as a systemic inflammatory trigger that disrupts immune homeostasis and reshapes both innate and adaptive responses. Recent evidence shows that OSA activates hypoxia-inducible factor-1α (HIF-1α), NF-κB signaling, and the NLRP3 inflammasome, promoting chronic inflammation and immune-cell dysfunction. These alterations mechanistically contribute to OSA-associated cardiovascular disease, metabolic disorders, cognitive impairment, and tumor progression. Reframing OSA as an immune-modulating disorder highlights the need for diagnostics and therapies guided by immunology rather than airway management alone.
ObjectiveThe objective of this meta-analysis is to assess the all-cause and cause-specific mortality in patients with psoriasis.MethodIn accordance with PRISMA guidelines, a systematic search of PubMed, EMBASE, and the Cochrane Library (from inception to March 2025) was conducted. Eligible studies comprised English-language cohort studies comparing mortality risk (HR/OR/RR) in adults with psoriasis versus healthy/non-psoriasis controls. Two reviewers independently screened studies, extracted data, and assessed study quality using the Newcastle-Ottawa Scale. Hazard ratios (HRs) were synthesized using random-effects models in Stata 14.0. Sensitivity analyses, subgroup analyses, and assessments of publication bias (via funnel plots and Egger’s test) were also performed.ResultA total of 20 studies involving 8825989 participants were included. Psoriasis patients demonstrated significantly increased risks of all-cause mortality [HR=1.19, 95% CI (1.11–1.28), P=0.000], cardiovascular mortality [HR = 1.32, 95% CI (1.11–1.58), P = 0.002], infection-related mortality [HR=1.24, 95% CI (1.13–1.36), P=0.000], and suicide mortality [HR=1.50, 95% CI (1.03–2.19), P=0.034]. The risk of mortality due to neoplasms was marginally elevated but not statistically significant [HR=1.05, 95% CI (0.98–1.12), P=0.151]. No significant associations were found for neurological disease mortality [HR=0.96, 95%CI (0.83–1.11), P=0.976] or accident-related mortality [HR=0.91, 95% CI (0.81–1.02), P=0.629]. Sensitivity analysis supports the findings. Subgroup analyses revealed higher all-cause mortality risks in Europe (HR=1.11) and Asia (HR=1.23), as well as an increased risk with greater disease severity (moderate-to-severe: HR=1.44; severe: HR=1.54). No publication bias was detected.ConclusionPsoriasis is associated with an increased risk of all-cause, cardiovascular, infection-related, and suicide mortality, highlighting the need for enhanced monitoring and targeted interventions to prevent adverse outcomes particularly for individuals with severe psoriasis.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251017192, identifier CRD420251017192.
Abstract The diagnostic assays currently used to detect Shigella spp . (Shigella) and enterotoxigenic Escherichia coli (ETEC) are complex or elaborate which make them difficult to apply in resource poor settings where these diseases are endemic. The simple and rapid nucleic acid amplification-based assay "Rapid LAMP-based Diagnostic Test (RLDT)" was evaluated to detect Shigella spp (Shigella) and enterotoxigenic Escherichia coli (ETEC) and determine the epidemiology of these pathogens in Kolkata, India. Stool samples (n = 405) from children under five years old with diarrhea seeking care at the hospitals were tested, and 85(21%) and 68(17%) by RLDT, 91(23%) and 58(14%) by quantitative PCR (qPCR) and 35(9%) and 15(4%) by culture, were positive for Shigella and ETEC, respectively. The RLDT showed almost perfect agreement with qPCR, Kappa 0.96 and 0.89; sensitivity 93% and 98%; specificity 100% and 97% for Shigella and ETEC, respectively. While RLDT detected additional 12% Shigella and 13% ETEC than culture, all culture positives for Shigella and ETEC except one each were also positive by the RLDT, sensitivity 97% and 93% respectively. RLDT is a simple, sensitive, and rapid assay that could be implemented with minimum training in the endemic regions to strengthen the disease surveillance system and rapid outbreak detection.
Acadia M. Thielking, Kieran P. Fitzmaurice, Ronel Sewpaul
et al.
Abstract Introduction As access to effective antiretroviral therapy (ART) has improved globally, tobacco‐related illnesses, including cardiovascular disease, cancer and chronic respiratory conditions, account for a growing proportion of deaths among people with HIV (PWH). We estimated the impact of tobacco smoking and smoking cessation on life expectancy among PWH in South Africa. Methods In a microsimulation model, we simulated 18 cohorts of PWH with virologic suppression, each homogenous by sex, initial age (35y/45y/55y) and smoking status (current/former/never). Input parameters were from data sources published between 2008 and 2022. We used South African data to estimate age‐stratified mortality hazard ratios: 1.2−2.3 (females)/1.1−1.9 (males) for people with current versus never smoking status; and 1.0−1.3 (females)/1.0−1.5 (males) for people with former versus never smoking status, depending on age at cessation. We assumed smoking status remains unchanged during the simulation; people who formerly smoked quit at model start. Simulated PWH face a monthly probability of disengagement from care and virologic non‐suppression. In sensitivity analysis, we varied smoking‐associated and HIV‐associated mortality risks. Additionally, we estimated the total life‐years gained if a proportion of all virologically suppressed PWH stopped smoking. Results Forty‐five‐year‐old females/males with HIV with virologic suppression who smoke lose 5.3/3.7 life‐years compared to PWH who never smoke. Smoking cessation at age 45y adds 3.4/2.4 life‐years. Simulated PWH who continue smoking lose more life‐years from smoking than from HIV (females, 5.3 vs. 3.0 life‐years; males, 3.7 vs. 2.6 life‐years). The impact of smoking and smoking cessation increase as smoking‐associated mortality risks increase and HIV‐associated mortality risks, including disengagement from care, decrease. Model results are most sensitive to the smoking‐associated mortality hazard ratio; varying this parameter results in 1.0−5.1 life‐years gained from cessation at age 45y. If 10−25% of virologically suppressed PWH aged 30−59y in South Africa stopped smoking now, 190,000−460,000 life‐years would be gained. Conclusions Among virologically suppressed PWH in South Africa, tobacco smoking decreases life expectancy more than HIV. Integrating tobacco cessation interventions into HIV care, as endorsed by the World Health Organization, could substantially improve life expectancy.
Jiansheng Jiang, Daniel K. Taylor, Ellen J. Kim
et al.
Abstract Loading of MHC-I molecules with peptide by the catalytic chaperone tapasin in the peptide loading complex plays a critical role in antigen presentation and immune recognition. Mechanistic insight has been hampered by the lack of detailed structural information concerning tapasin–MHC-I. We present here crystal structures of human tapasin complexed with the MHC-I molecule HLA-B*44:05, and with each of two anti-tapasin antibodies. The tapasin-stabilized peptide-receptive state of HLA-B*44:05 is characterized by distortion of the peptide binding groove and destabilization of the β 2 -microglobulin interaction, leading to release of peptide. Movements of the membrane proximal Ig-like domains of tapasin, HLA-B*44:05, and β 2 -microglobulin accompany the transition to a peptide-receptive state. Together this ensemble of crystal structures provides insights into a distinct mechanism of tapasin-mediated peptide exchange.
Tzvi Y. Pollock, Víctor R. Vázquez Marrero, Igor E. Brodsky
et al.
The inflammatory cytokine tumor necrosis factor (TNF) is necessary for host defense against many intracellular pathogens, including Legionella pneumophila. Legionella causes the severe pneumonia Legionnaires’ disease and predominantly affects individuals with a suppressed immune system, including those receiving therapeutic TNF blockade to treat autoinflammatory disorders. TNF induces pro-inflammatory gene expression, cellular proliferation, and survival signals in certain contexts, but can also trigger programmed cell death in others. It remains unclear, however, which of the pleiotropic functions of TNF mediate control of intracellular bacterial pathogens like Legionella. In this study, we demonstrate that TNF signaling licenses macrophages to die rapidly in response to Legionella infection. We find that TNF-licensed cells undergo rapid gasdermin-dependent, pyroptotic death downstream of inflammasome activation. We also find that TNF signaling upregulates components of the inflammasome response, and that the caspase-11-mediated non-canonical inflammasome is the first inflammasome to be activated, with caspase-1 and caspase-8 mediating delayed pyroptotic death. We find that all three caspases are collectively required for optimal TNF-mediated restriction of bacterial replication in macrophages. Furthermore, caspase-8 is required for control of pulmonary Legionella infection. These findings reveal a TNF-dependent mechanism in macrophages for activating rapid cell death that is collectively mediated by caspases-1, -8, and -11 and subsequent restriction of Legionella infection.
Abdullah Alqarihi, Teclegiorgis Gebremariam, Yiyou Gu
et al.
Mucormycosis caused by Rhizopus species is a fungal infection with often fatal prognosis. Inhalation of spores is the major route of entry, with nasal and alveolar epithelial cells among the first cells that encounter the fungi. In patients with hematologic malignancies or those undergoing cytotoxic chemotherapy, Rhizopus causes pulmonary infections. On the other hand, DKA patients predominantly suffer from rhinoorbital/cerebral mucormycosis. The reason for such disparity in disease types by the same fungus is not known. Here, we show that the unique susceptibility of DKA subjects to rhinoorbital/cerebral mucormycosis is likely due to specific interaction between nasal epithelial cell GRP78 and fungal CotH3, the expression of which increases in the presence of host factors present in DKA. In contrast, pulmonary mucormycosis is initiated via interaction of inhaled spores expressing CotH7 with integrin β1 receptor, which activates EGFR to induce fungal invasion of host cells. These results introduce a plausible explanation for disparate disease manifestations in DKA versus those in hematologic malignancy patients and provide a foundation for development of therapeutic interventions against these lethal forms of mucormycosis.
Leandro do Nascimento Camargo, Leandro do Nascimento Camargo, Renato Fraga Righetti
et al.
BackgroundIL-17 is a modulator of the inflammatory response and is implicated in lung remodeling in both asthma and chronic obstructive pulmonary disease (COPD). Well as and probably in patients with asthma–COPD overlap (ACO).MethodsIn this study, we evaluated the response of the airways and alveolar septa to anti-IL-17 treatment in an ACO model. Fifty-six male BALB/c mice were sensitized with ovalbumin (OVA group), received porcine pancreatic elastase (PPE group), or both (ACO group). Mice were then treated with either anti-IL-17 monoclonal antibody or saline. We evaluated hyperresponsiveness, bronchoalveolar lavage fluid (BALF) cell counts, and mean alveolar diameter. We quantified inflammatory, response, extracellular matrix remodeling, oxidative stress markers, and signaling pathway markers.ResultsAnti-IL-17 treatment in the ACO anti-IL-17 group reduced the maximum response of respiratory system Rrs, Ers, Raw, Gtis, this when compared to the ACO group (p<0.05). There was a reduction in the total number of inflammatory cells, neutrophils, and macrophages in the BALF in the ACO anti-IL-17 group compared to the ACO group (p<0.05). There was attenuated dendritic cells, CD4+, CD8+, FOXP3, IL-1β, IL-2, IL-6, IL-13, IL-17, IL-33 in ACO anti-IL-17 group in airway and alveolar septum compared to the ACO group (p<0.05). We observed a reduction of MMP-9, MMP-12, TIMP-1, TGF-β, collagen type I in ACO anti-IL-17 group in airway and alveolar septum compared to the ACO group (p < 0.05). We also observed a reduction of iNOS and 8-iso-PGF2α in the airways and in the alveolar septum was reduced in the ACO anti-IL-17group compared to the ACO group (p < 0.05). Regarding the signaling pathways, NF-kB, ROCK-1, and ROCK-2 in the airway and alveolar septum were attenuated in the ACO anti-IL-17 group when compared to the ACO group (p<0.05).ConclusionsOur results suggest that inhibiting IL-17 modulates cell-associated cytokine production in lung tissue, extracellular matrix remodeling, and oxidative stress in ACO through the modulation of NF-kB and FOXP3.
Amanda Rangert, Amanda Rangert, Carin Oldin
et al.
BackgroundRotavirus infection is a potential trigger of type 1 diabetes (T1D) and rotavirus vaccination is hypothesized to decrease the incidence of T1D. In Sweden, rotavirus vaccination was introduced in 2014 in two regions and from 2019, nationwide. This study aims to investigate the association between rotavirus vaccination and incidence of T1D in Swedish children and whether rotavirus vaccination is associated with a change in clinical manifestation at diabetes onset.MethodsA nationwide register-based study with all Swedish children <15 years of age, diagnosed with T1D 2009-2019 was conducted. 7893 children were retrieved. Nationwide vaccine coverage was collected from Child Health Services. Three vaccine groups were created: I: Vaccination start 2014; II: Gradual vaccination start 2016-2018; III: No vaccination. Incidence rates of T1D before (2009-2014) and after (2014-2019) introduction of rotavirus vaccine were compared.FindingsThe mean incidence of T1D in children <15 years was 42·61 per 100 000 during the observed period. When comparing the years before and after 2014 the incidence rate ratio (IRR) for children <5 years was 0·86 in group I (p=0·10), 0·85 (p=0·05) in group II and 0·87 (p=0·06) in group III. A similar IRR reduction was also seen among older children who received no vaccine. Children developing or not developing T1D were vaccinated to the same extent. No differences regarding clinical manifestation at onset associated with rotavirus vaccination were seen.InterpretationThere is no association between rotavirus vaccination in children and incidence or clinical manifestation of T1D.
There have been many attempts to identify common biophysical properties which differentiate allergens from their non-immunogenic counterparts. This review will focus on recent studies which examine two such factors: abundance and stability. Anecdotal accounts have speculated that the elevated abundance of potential allergens would increase the likelihood of human exposure and thus the probability of sensitization. Similarly, the stability of potential allergens dictates its ability to remain a viable immunogen during the transfer from the source to humans. This stability could also increase the resilience of potential allergens to both gastric and endosomal degradation, further skewing the immune system toward allergy. Statistical analyses confirm both abundance and stability as common properties of allergens, while epidemiological surveys show a correlation between exposure levels (abundance) and allergic disease. Additional studies show that changes in protein stability can predictably alter gastric/endosomal processing and immunogenicity, providing a mechanistic link between stability and allergenicity. However, notable exceptions exist to both hypotheses which highlight the multifaceted nature of immunological sensitization, and further inform our understanding of some of these other factors and their contribution to allergic disease.
Lina M. Montoya, Michael R. Kosorok, Elvin H. Geng
et al.
Abstract Personalized intervention strategies, in particular those that modify treatment based on a participant's own response, are a core component of precision medicine approaches. Sequential multiple assignment randomized trials (SMARTs) are growing in popularity and are specifically designed to facilitate the evaluation of sequential adaptive strategies, in particular those embedded within the SMART. Advances in efficient estimation approaches that are able to incorporate machine learning while retaining valid inference can allow for more precise estimates of the effectiveness of these embedded regimes. However, to the best of our knowledge, such approaches have not yet been applied as the primary analysis in SMART trials. In this paper, we present a robust and efficient approach using targeted maximum likelihood estimation (TMLE) for estimating and contrasting expected outcomes under the dynamic regimes embedded in a SMART, together with generating simultaneous confidence intervals for the resulting estimates. We contrast this method with two alternatives (G-computation and inverse probability weighting estimators). The precision gains and robust inference achievable through the use of TMLE to evaluate the effects of embedded regimes are illustrated using both outcome-blind simulations and a real-data analysis from the Adaptive Strategies for Preventing and Treating Lapses of Retention in Human Immunodeficiency Virus (HIV) Care (ADAPT-R) trial (NCT02338739), a SMART with a primary aim of identifying strategies to improve retention in HIV care among people living with HIV in sub-Saharan Africa.