Biology subjects

Meijer, A.

Publications and source records attributed to Meijer, A..

11 recordsLinked to original sources

bioRxiv2026

Emergence and antigenic characterisation of influenza A(H3N2) viruses with hemagglutinin substitutions N158K and K189R during the 2024/25 influenza season

BackgroundSeasonal human influenza viruses can escape from antibody-mediated neutralization when amino acid changes occur in the hemagglutinin protein. Routine surveillance identified circulation of an A(H3N2) virus variant in the Netherlands with amino acid substitutions at hemagglutinin positions 158 and 189. These amino acid positions were previously responsible for antigenic change of influenza A(H3N2) viruses and potentially lead to escape of this variant from vaccine-mediated immunity. AimTo characterize the emergence and antigenic properties of N158K and K189R double substitution virus variants. MethodsWe analyzed the geographical and temporal dynamics of the double-substitution variant using a phylogeographic approach and used hemagglutination inhibition assays and antigenic cartography methods to map its antigenic properties. ResultsA(H3N2) viruses carrying K189R were first detected in Guatemala in June 2024, before subsequently gaining the N158K substitution, which was intially detected in Colombia in November 2024, followed by detection in the Netherlands in December 2024. However, detections within Europe remained almost entirely confined to the Netherlands. The proportion of viruses carrying the N158K and K189R substitutions increased to 16% - 24% per collection week of sequenced Dutch viruses during the peak of the epidemic of the 2024-2025 respiratory season. Antigenic characterization of viruses with N158K and K189R substitutions indicated that these are antigenically distinct from the A(H3N2) components of 2025-2026 Northern Hemisphere vaccines, showing 8-192-fold reduction in hemagglutination inhibition titers with antisera against the vaccine strain compared to antisera against the homologous virus. ConclusionsInfluenza A(H3N2) viruses with N158K and K189R escaped recognition by antibodies raised against the 2024-2025 and 2025/2026 Northern Hemipshere vaccine strains in hemagglutination inhibition assays. These variants circulated widely in the Netherlands during the 2024-2025 influenza season, raising concerns about reduced vaccine-mediated protection if such variants would spread more broadly during 2025-2026 Northern Hemipshere season.

microbiology↗

bioRxiv2025

GBP1 drives lysosomal activity against cytosol-invading mycobacteria in macrophages

Guanylate-binding proteins (GBPs) are a family of interferon-inducible proteins playing diverse roles in the immunity to infections. By docking onto pathogens or pathogen-containing vesicles, GBPs can boost proinflammatory signaling. However, the interplay between GBPs and the phagolysosomal mechanisms mediating pathogen degradation remains largely unclear. Here, we elucidate the key role of GBP1 in driving lysosomal activity against mycobacterial infection in human macrophages. We show that phagosome damage induced by the mycobacterial ESX-1 secretion system triggers calcium release, and thereby the recruitment of GBP1, which resides in lysosomes upon interferon gamma activation. GBP1 targeting of mycobacteria-containing phagosomes leads to the recruitment of other GBPs but does not lead to the activation of membrane repair mechanisms or antimicrobial autophagy. Instead, GBP1 mediates lysosomal recruitment to intracellular mycobacteria, and promotes the maturation of phagolysosomes and their proteolytic activity required for the degradation of the mycobacterial cargo. Collectively, this work highlights the host-protective function of GBP1 in macrophages, where GBP1 acts as a key cellular sensor of mycobacterial infection and promotes the clearance activity of the host lysosomal system.

immunology↗

bioRxiv2025

Integrative Mapping of Pre-existing Immune Landscapes for Vaccine Response Prediction

Predicting individual vaccine responses remains a significant challenge due to the complexity and variability of immune processes. To address this gap, we developed immunaut, an open-source, data-driven framework implemented as an R package specifically designed for all systems vaccinologists seeking to analyze and predict immunological outcomes across diverse vaccination settings. Leveraging one of the most comprehensive live attenuated influenza vaccine (LAIV) datasets to date - 244 Gambian children enrolled in a phase 4 immunogenicity study - immunaut integrates humoral, mucosal, cellular, transcriptomic, and microbiological parameters collected before and after vaccination, providing an unprecedentedly holistic view of LAIV-induced immunity. Through advanced dimensionality reduction, clustering, and predictive modeling, immunaut identifies distinct immunophenotypic responder profiles and their underlying baseline determinants. In this study, immunaut delineated three immunophenotypes: (1) CD8 T-cell responders, marked by strong baseline mucosal immunity and extensive prior influenza virus exposure that boosts memory CD8 T-cell responses, without generating influenza virus-specific antibody responses; (2) Mucosal responders, characterized by pre-existing systemic influenza A virus immunity (specifically to H3N2) and stable epithelial integrity, leading to potent mucosal IgA expansions and subsequent seroconversion to influenza B virus; and (3) Systemic, broad influenza A virus responders, who start with relatively naive immunity and leverage greater initial viral replication to drive broad systemic antibody responses against multiple influenza A virus variants beyond those included in the LAIV vaccine. By integrating pathway-level analysis, model-derived contribution scores, and hierarchical decision rules, immunaut elucidates how distinct immunological landscapes shape each response trajectory and how key baseline features, including pre-existing immunity, mucosal preparedness, and cellular support, dictate vaccine outcomes. Collectively, these findings emphasize the power of integrative, predictive frameworks to advance precision vaccinology, and highlight immunaut as a versatile, community-available resource for optimizing immunization strategies across diverse populations and vaccine platforms. One-Sentence SummaryUsing one of the most comprehensive LAIV datasets compiled to date, immunaut, an integrative machine learning framework, identifies distinct immunophenotypic responder groups shaped by baseline immune landscapes, advancing precision vaccinology and guiding more effective, personalized immunization strategies. Graphical abstractImmunaut, an automated framework for mapping and predicting vaccine response immunotypes. Step 1 outlines the identification of vaccine response outcomes using pre- and post-vaccination data integration across immune features, including antibodies, flu-specific T-cells, and immunophenotyping at mucosal and systemic sites. Clustering methods define the vaccine response landscape, stability, and validation through t-SNE-based visualization. Step 2 leverages an automated machine learning modeling approach, to enhance the accuracy and interpretability of vaccine response predictions, enabling stratification and targeted intervention strategies for personalized vaccine immunogenicity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/634302v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@62276corg.highwire.dtl.DTLVardef@a5f25org.highwire.dtl.DTLVardef@eca34borg.highwire.dtl.DTLVardef@1d4999b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Pathology and immunity after SARS-CoV-2 infection in male ferrets is affected by age and inoculation route

Improving COVID-19 intervention strategies partly relies on animal models to study SARS-CoV-2 disease and immunity. In our pursuit to establish a model for severe COVID-19, we inoculated young and adult male ferrets intranasally or intratracheally with SARS-CoV-2. Intranasal inoculation established an infection in all ferrets, with viral dissemination into the brain and gut. Upon intratracheal inoculation only adult ferrets became infected. However, neither inoculation route induced observable COVID-19 symptoms. Despite this, a persistent inflammation in the nose was prominent in especially young ferrets and follicular hyperplasia in the bronchi developed 21 days post infection. These effects -if sustained- might resemble long-COVID. Respiratory and systemic cellular responses and antibody responses were induced only in animals with an established infection. We conclude that intranasally-infected ferrets resemble asymptomatic COVID-19 and possibly aspects of long-COVID. Combined with the increasing portfolio to measure adaptive immunity, ferrets are a relevant model for SARS-CoV-2 vaccine research.

microbiology↗

bioRxiv2020

Rapid SARS-CoV-2 whole genome sequencing for informed public health decision making in the Netherlands

SARS-CoV-2 is a novel coronavirus that has rapidly spread across the globe. In the Netherlands, the first case of SARS-CoV-2 has been notified on the 27th of February. Here, we describe the first three weeks of the SARS-CoV-2 outbreak in the Netherlands, which started with several different introductory events from Italy, Austria, Germany and France followed by local amplification in, and later also, outside the South of the Netherlands. The timely generation of whole genome sequences combined with epidemiological investigations facilitated early decision making in an attempt to control local transmission of SARS-CoV-2 in the Netherlands.

genomics↗

bioRxiv2020

Comparison of commercial RT-PCR diagnostic kits for COVID-19

The final months of 2019 witnessed the emergence of a novel coronavirus in the human population. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has since spread across the globe and is posing a major burden on society. Measures taken to reduce its spread critically depend on timely and accurate identification of virus-infected individuals by the most sensitive and specific method available, i.e. real-time reverse transcriptase PCR (RT-PCR). Many commercial kits have recently become available, but their performance has not yet been independently assessed. The aim of this study was to compare basic analytical and clinical performance of selected RT-PCR kits from seven different manufacturers (Altona Diagnostics, BGI, CerTest Biotec, KH Medical, PrimerDesign, R-Biopharm AG, and Seegene). We used serial dilutions of viral RNA to establish PCR efficiency and estimate the 95% limit of detection (LOD95%). Furthermore, we ran a panel of SARS-CoV-2-positive clinical samples (n=16) for a preliminary evaluation of clinical sensitivity. Finally, we used clinical samples positive for non-coronavirus respiratory viral infections (n=6) and a panel of RNA from related human coronaviruses to evaluate assay specificity. PCR efficiency was [≥]96% for all assays and the estimated LOD95% varied within a 6-fold range. Using clinical samples, we observed some variations in detection rate between kits. Importantly, none of the assays showed cross-reactivity with other respiratory (corona)viruses, except as expected for the SARS-CoV-1 E-gene. We conclude that all RT-PCR kits assessed in this study may be used for routine diagnostics of COVID-19 in patients by experienced molecular diagnostic laboratories.

microbiology↗

bioRxiv2019

The Consequences of Egg Adaptation in the H3N2 Component to the Immunogenicity of Live Attenuated Influenza Vaccine

Adaptation in egg-passaged vaccine strains may cause reduced vaccine effectiveness due to altered antigenicity of the influenza haemagglutinin. We tested whether egg adaptation modified serum and mucosal antibody responses to the A(H3N2) component in the Live Attenuated Influenza Vaccine (LAIV). Twice as many children seroconverted to an egg-adapted H3N2 than the equivalent wildtype strain. Seroconversion to the wildtype strain was greater in children seronegative pre-LAIV, whereas higher mucosal IgA responses to wildtype antigen were observed if seropositive prior to vaccination. Sequencing of virus from nasopharyngeal swabs from 7 days post-LAIV showed low sequence diversity and no reversion of egg-adaptive mutations.

immunology↗

bioRxiv2019

Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

Neutrophilic inflammation with prolonged neutrophil survival is common to many inflammatory conditions, including chronic obstructive pulmonary disease (COPD). There are few specific therapies that reverse neutrophilic inflammation, but uncovering mechanisms regulating neutrophil survival is likely to identify novel therapeutic targets. Screening of 367 kinase inhibitors in human neutrophils and a zebrafish tail fin injury model identified ErbBs as common targets of compounds that accelerated inflammation resolution. The ErbB inhibitors gefitinib, CP-724714, erbstatin and tyrphostin AG825 significantly accelerated apoptosis of human neutrophils, including neutrophils from people with COPD. Neutrophil apoptosis was also increased in Tyrphostin AG825 treated-zebrafish in vivo. Tyrphostin AG825 decreased peritoneal inflammation in zymosan-treated mice, and increased lung neutrophil apoptosis and macrophage efferocytosis in a murine acute lung injury model. Tyrphostin AG825 and knockdown of egfra and erbb2 by CRISPR/Cas9 reduced inflammation in zebrafish. Our work shows that inhibitors of ErbB kinases have therapeutic potential in neutrophilic inflammatory disease.

immunology↗

bioRxiv2019

Deficiency in the autophagy modulator Dram1 exacerbates pyroptotic cell death of Mycobacteria-infected macrophages

DNA Damage Regulated Autophagy Modulator 1 (DRAM1) is a stress-inducible regulator of autophagy and cell death. DRAM1 has been implicated in cancer, myocardial infarction, and infectious diseases, but the molecular and cellular functions of this transmembrane protein remain poorly understood. Previously, we have proposed DRAM1 as a host resistance factor for tuberculosis (TB) and a potential target for host-directed anti-infective therapies. In this study, we generated a zebrafish dram1 mutant and investigated its loss-of-function effects during Mycobacterium marinum (Mm) infection, a widely used model in TB research. In agreement with previous knockdown analysis, dram1 mutation increased the susceptibility of zebrafish larvae to Mm infection. RNA sequencing revealed major effects of Dram1 deficiency on metabolic, immune response, and cell death pathways during Mm infection, whereas only minor effects on proteinase and metabolic pathways were found under uninfected conditions. Furthermore, unchallenged dram1 mutants did not display overt autophagic defects, but autophagic targeting of Mm was reduced in absence of Dram1. The phagocytic ability of macrophages in dram1 mutants was unaffected, but acidification of Mm-containing vesicles was strongly reduced, indicating that Dram1 is required for phagosome maturation. By in vivo imaging we observed that Dram1-deficient macrophages fail to restrict Mm during early stages of infection. The resulting increase in bacterial burden could be reverted by knockdown of inflammatory caspase a (caspa) and gasdermin Eb (gsdmeb), demonstrating pyroptosis as the mechanism underlying premature cell death of Mm-infected macrophages in dram1 mutants. Collectively, these data demonstrate that dissemination of mycobacterial infection in zebrafish larvae is promoted in absence of Dram1 due to reduced maturation of mycobacteria-containing vesicles, failed intracellular containment, and consequent pyroptotic cell death of infected macrophages. These results provide new evidence that Dram1 plays a central role in host resistance to intracellular infection, acting at the crossroad of autophagy and cell death.

immunology↗

bioRxiv2019

Modular actin nano-architecture enables podosome protrusion and mechanosensing

Basement membrane transmigration during embryonal development, tissue homeostasis and tumor invasion relies on invadosomes, a collective term for invadopodia and podosomes. An adequate structural framework for this process is still missing. Here, we reveal the modular actin nano-architecture that enables podosome protrusion and mechanosensing. The podosome protrusive core contains a central branched actin module encased by a linear actin module, each harboring specific actin interactors and actin isoforms. From the core, two actin modules radiate: ventral filaments bound by vinculin and connected to the plasma membrane and dorsal interpodosomal filaments crosslinked by myosin IIA. On stiff substrates, the actin modules mediate long-range substrate exploration, associated with degradative behavior. On compliant substrates, the vinculin-bound ventral actin filaments shorten, resulting in short-range connectivity and a focally protrusive, non-degradative state. Our findings redefine podosome nanoscale architecture and reveal a paradigm for how actin modularity drives invadosome mechanosensing in cells that breach tissue boundaries.

cell biology↗

bioRxiv2019

Use of a pandemic H1N1 strain with updated haemagglutinin and neuraminidase results in increased nasopharyngeal shedding and improved immunogenicity to Russian-backbone live attenuated influenza vaccine among children aged 2 - 4 years old: an open label, prospective, observational, phase 4 study in The Gambia.

BackgroundPoor efficacy and effectiveness of the pandemic H1N1 (pH1N1) component in intranasal live attenuated influenza vaccine (LAIV) has been demonstrated in several studies. The reasons for this are unclear, but may be due to impaired replicative fitness of pH1N1 A/California/07/2009-like (Cal09) LAIV strains. MethodsIn an open-label, prospective, observational, phase 4 study, we evaluated the impact of updating the pH1N1 component in the Russian-backbone trivalent LAIV from Cal09 in 2016-17 (n=118) to an A/Michigan/45/2015-like strain (A/17/New York/15/5364, NY15) in 2017-18 (n=126), on shedding and immunogenicity in Gambian children aged 2-4 years old. The study was nested within a larger randomised controlled trial investigating LAIV-microbiome interactions (ClinicalTrials.gov NCT02972957). FindingsCal09 showed impaired nasopharyngeal shedding compared to H3N2 and influenza B, along with sub-optimal serum antibody and T-cell responses. Following the switch to NY15, a significant increase in pH1N1 shedding was seen, along with improvements in seroconversion and influenza-specific CD4+ T-cell responses. Viral kinetics in vitro mirrored these findings, with NY15 showing greater replicative ability than Cal09 in human nasal epithelial cells. Persistent shedding to day 7 was independently associated with both seroconversion and CD4+ T cell response in multivariable logistic regression. InterpretationOur results suggest that the pH1N1 component switch in LAIV may have overcome problems in prior formulations. LAIV effectiveness against pH1N1 should therefore improve in upcoming influenza seasons. Our data also highlight the importance of evaluating replicative fitness, in addition to antigenicity, when selecting annual LAIV components and design of potentially more effective vaccines. FundingThe Wellcome Trust.

clinical trials↗