Biology subjects

Visser, R.

Publications and source records attributed to Visser, R..

15 recordsLinked to original sources

bioRxiv2026

Disentangling maternal pregnancy and fetal-specific plasma signatures through integrated proteomics and site-specific N-glycoproteomics

During pregnancy, mother and fetus co-exist albeit as two physiologically distinct individuals, connected through the placenta and the umbilical cord. This connection allows for the exchange of vital substances, while individual blood homeostasis remains intact. We hypothesized that comparing maternal and cord plasma (N-glyco)proteomes would provide insights into the biological communication and unique physiological state of each individual. As comparing only matched maternal and umbilical cord blood plasma misses a crucial identifier in determining whether observed changes are related to infancy, pregnancy or both, we designed a triad study by adding a non-pregnant women control group. This allowed us to distinguish pregnancy-specific proteins and their potentially altered N-glycosylation from those in infancy. We found that the fetus and mother have distinct proteomes, N-glycoproteoforms and alternative complement regulation. Moreover, we observed that pregnancy in women led to specific N-glycosylation changes on a select set of primarily HDL-associated and acute-phase proteins. Lastly, our data provide evidence for an early fetal development of the humoral immune system as especially fetal IgM displayed distinctive N-glycosylation signatures.

developmental biology↗

bioRxiv2026

Patient-derived monoclonal anti-HPA-1a can induce platelet activation through FcγRIIa

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a pregnancy-associated disorder caused by maternal alloantibodies targeting paternally inherited human platelet antigens (HPAs). These antibodies traverse the placenta and bind to fetal platelets, causing thrombocytopenia and potentially severe complications including intracranial hemorrhage (ICH). Beyond platelets, antibodies may also target other fetal cells such as endothelial cells and placental trophoblasts thereby exacerbating disease severity. Anti-HPA-1a antibodies, the primary cause of FNAIT, display functional heterogeneity due to differences in epitope specificity, glycosylation, which complicate disease severity prediction. Here, we report the structural and functional characterization of two novel anti-HPA-1a antibodies, D-204 and M-204, derived from a mother with a severe FNAIT case. In comparison to D-204 and other existing anti-HPA-1a antibodies such as B2G1 and 26.4, M-204 bound IIb{beta}3 with different kinetics, reaching only half-maximal binding, as determined by flow cytometry. Notably, only M-204 induced platelet aggregation. To investigate the underlying mechanism behind this aggregation, various antibody formats were generated (Fab, Fab2, bispecific, and IgG-Fc dead). Aggregation required both Fab-arms to engage HPA-1a and intact binding to Fc{gamma}RIIa. Structural models and crystal structures suggest the dual engagement of both Fab-arms is required for Fc{gamma}RIIA-engagement which is a unique feature of M-204 among known HPA-1 monoclonals. Our findings highlight the functional diversity of anti-HPA-1a antibodies and provide new insights into their pathogenic mechanisms.

immunology↗

bioRxiv2026

Targeting neutrophil signaling networks in immune complex-mediated autoimmune disease

Fragment crystallizable gamma receptor (Fc{gamma}R)-induced signaling is a crucial process that determines the cellular response to immune complexes (IC) in autoimmune diseases. In several diseases including pemphigoid diseases (PD), such as epidermolysis bullosa acquisita (EBA), or rheumatoid arthritis (RA), neutrophils are prominently involved as effector cells, while others such as immune thrombocytopenia (ITP) are independent of neutrophils. At the same time, most diseases are commonly treated by broad-range immunosuppression accompanied by severe risk for adverse effects. Signal transduction inhibitors (STIs) have been successfully applied in cancer therapy. However, their use in autoimmune diseases is an emerging, but so far understudied potential treatment avenue. Therefore, we screened a target-selective compound library consisting of 155 STIs in a neutrophil-based assay and conducted a multiplex kinase activity profiling with IC-stimulated neutrophils. Thus, we found novel potential therapeutic targets that were validated both in vitro in functional neutrophil assays and in vivo in murine models of EBA Here, we demonstrate that both systemic and topical treatment with several individual STIs is effective in a prophylactic approach in these models. Furthermore, therapeutic treatment with the BTK inhibitor ibrutinib in the immunization-induced EBA model reduced disease severity by approximately 85 % and showed efficacy in additional experimental models of EBA, arthritis, and ITP. Together, the present study contributes to the elucidation of Fc{gamma}R-dependent signaling in neutrophils and identifies multiple novel promising treatment options including inhibition of PLC, PDK-1, PKC, p38, DNA-PK, KSP, c-Met, TBK-1 and BTK for IC-mediated autoimmune diseases.

immunology↗

bioRxiv2025

CDK7, CDK9, or CDK11 Inhibition Reduces Neutrophil-Driven Inflammation and Tissue Damage in Experimental Autoimmune Models

BackgroundCyclin-dependent kinases (CDKs) are involved in basic cellular processes like regulation of cell-cycle progression and transcription. However, recent data also indicate a specific role in terminally differentiated neutrophils by promoting reactive oxygen species (ROS) release, degranulation, neutrophil extracellular trap formation, or apoptosis. Since these mechanisms are implicated in multiple autoimmune diseases, we aimed to delineate the role of CDKs in IC-mediated autoimmune diseases both in vitro and in vivo. MethodsWe analyzed CDK gene expression in unstimulated and immune complex (IC)-stimulated neutrophils. Subsequently, we investigated the effect of pharmacological CDK inhibition on IC-activated neutrophil functions. To analyze the inhibitors in a more translational approach, we proceeded with the systemic and topical application of the effective inhibitors in a murine antibody transfer-induced local epidermolysis bullosa acquisita (EBA) model. The most efficient inhibitor, MC180295, was validated in two other IC-mediated models of autoimmune disease: Serum-transfer arthritis (STA), which also, but not exclusively, depends on neutrophils and immune thrombocytopenia (ITP), which is considered less neutrophil-dependent. ResultsWe found 14 CDKs expressed in unstimulated cells, while the IC-stimulation showed an upregulation of CDK2 and CDK4 expression. Inhibitors selectively targeting CDK1, CDK2, CDK4/6, CDK7, CDK9, CDK11, and CDK12 showed effects on different neutrophil functions (surface activation marker expression, ROS release, adhesion, apoptosis) in vitro. In the predominantly neutrophil-driven EBA model, we observed a reduction of disease severity upon treatment with CDK7, CDK9, or CDK11 inhibitors. Inhibiting these CDKs with topical THZ2, MC180295, or OTS964, respectively, also improved the clinical phenotype. In line with our hypothesis, MC180295 impaired the development of STA, but not ITP. ConclusionsCDK7, CDK11, and especially CDK9 inhibition show therapeutic potential in IC-driven neutrophil-mediated diseases such as rheumatoid arthritis and EBA.

immunology↗

bioRxiv2025

ERK5 is required for neutrophil-mediated ROS release and essential in epidermolysis bullosa acquisita

Neutrophils are key effector cells in antibody-mediated autoimmune diseases, contributing to inflammation via the release of reactive oxygen species (ROS). Extracellular signal-regulated kinase 5 (ERK5), a member of the MAPK family, is expressed in neutrophils but its role in autoimmune disease pathogenesis remains unclear. We investigated the functional relevance of ERK5 in antibody-mediated autoimmune diseases by comparing neutrophil-dependent (epidermolysis bullosa acquisita, EBA; serum transfer arthritis, STA) and neutrophil-independent (immune thrombocytopenia, ITP) murine models using the small-molecule ERK5 inhibitor XMD8-92. In vitro, pharmacological ERK5 inhibition specifically reduced neutrophil ROS release and CD62L shedding without affecting adhesion, chemotaxis, or CD18 expression. No major effects on viability were observed. In vivo, ERK5 inhibition with XMD8-92 significantly ameliorated antibody transfer-induced EBA, supporting a critical role of neutrophil-derived ROS in disease pathogenesis. In STA and ITP, ERK5 inhibition did not affect clinical outcomes. Together, these findings highlight ERK5 as a regulator of neutrophil ROS release and a potential therapeutic target in ROS-driven autoimmune diseases such as EBA.

immunology↗

bioRxiv2024

Potato cultivars use different root physiological and molecular mechanisms to acclimate to salt stress

O_LISoil salinity induces osmotic stress and ion toxicity in plants, detrimentally affecting their growth and development. Potato (Solanum tuberosum) faces yield reductions due to salt stress. The mechanisms of salt stress resilience, especially in adventitious roots, remain unknown. C_LIO_LIWe investigated the resilience of three potato cultivars - Desiree, Innovator, and Mozart - by studying their physiological and transcriptomic responses to salt stress. C_LIO_LIOur findings reveal that under salt stress, the growth of stolons and stolon node roots is similarly reduced unlike tubers, even though they are physically connected. Surprisingly, tubers accumulate Cl- but not Na+ under salt stress, suggesting an active Na+ exclusion mechanism. Innovator showed the lowest suberin and lignin deposition before salt stress and higher K+ leakage, leading to a stronger initial stress response with high ABA content and a distinct transcriptomic pattern. Nevertheless, Innovator was the most resilient, displaying lower growth, salt-tolerance index and tuber yield reduction. Transcriptomic analysis revealed several K+/Na+ channel genes which might regulate ions homeostasis during salt stress, in particular in Innovator. C_LIO_LIAltogether, we conclude that acclimation ability, rather than initial protection of roots against salt, prevails in long term salt-stress resilience of potato. C_LI

plant biology↗

bioRxiv2023

Stacking of PRRs in potato to achieve enhanced resistance against Phytophthora infestans

Plants employ pattern recognition receptors (PRRs) to sense pathogen-associated molecular patterns (PAMPs) or apoplastic effectors at the plant cell surface, as well as nucleotide-binding domain leucine-rich-repeat-containing receptors (NLRs) to sense effectors inside the plant cell. Breeding for potato resistance to P. infestans has focused on the use of NLRs, however, these genes are typically quickly overcome since the matching avirulence genes evolve exceptionally quickly. Here, we stacked two PRRs, PERU and RLP23, that recognize the rather conserved Phytophthora PAMPs Pep-13/25 and nlp20, respectively, in the potato cultivar Atlantic, and evaluated their effect on P. infestans resistance. We found that PERU and RLP23 cooperate for the early immune responses like the accumulation of reactive oxygen species (ROS) and production of ethylene by recognizing their corresponding PAMPs. Furthermore, we show that potato plants overexpressing these two PRRs are slightly less affected by P. infestans compared to the single transformants. Together, our data suggest that pyramiding of surface receptors can provide additional enhanced resistance against pathogens, however, more effective or synergistic combinations that may include intracellular NLR receptors should be explored.

plant biology↗

bioRxiv2022

DNA primase large subunit is an essential plant gene for geminiviruses, putatively priming viral ss-DNA replication

The family of Geminiviridae consists of more than 500 circular single-stranded (ss) DNA viral species that can infect numerous dicot and monocot plants. Geminiviruses replicate their genome in the nucleus of a plant cell, taking advantage of the hosts DNA replication machinery. For converting their DNA into double-stranded DNA, and subsequent replication, these viruses rely on host DNA polymerases. However, the priming of the very first step of this process, i.e. the conversion of incoming circular ssDNA into a dsDNA molecule, has remained elusive for almost 30 years. In this study, sequencing of melon (Cucumis melo) accession K18 carrying the Tomato leaf curl New Delhi virus (ToLCNDV) recessive resistance quantitative trait locus (QTL) in chromosome 11, and analyses of DNA sequence data from 100 melon genomes, showed a conservation of a shared mutation in the DNA Primase Large subunit (PRiL) of all accessions that exhibited resistance upon a challenge with ToLCNDV. Silencing of (native) Nicotiana benthamiana PriL and subsequent challenging with three different geminiviruses showed a severe reduction in titers of all three viruses, altogether emphasizing an important role of PRiL in geminiviral replication. A model is presented explaining the role of PriL during initiation of geminiviral DNA replication, i.e. as a regulatory subunit of primase that generates an RNA primer at the onset of DNA replication in analogy to DNA Primase-mediated initiation of DNA replication in all living organisms.

plant biology↗

bioRxiv2022

The BNT162b2 mRNA SARS-CoV-2 vaccine induces transient afucosylatedIgG1 in naive but not antigen-experienced vaccinees

The onset of severe SARS-CoV-2 infection is characterized by the presence of afucosylated IgG1 responses against the viral spike (S) protein, which can trigger exacerbated inflammatory responses. Here, we studied IgG glycosylation after BNT162b2 SARS-CoV-2 mRNA vaccination to explore whether vaccine-induced S protein expression on host cells also generates afucosylated IgG1 responses. SARS-CoV-2 naive individuals initially showed a transient afucosylated anti-S IgG1 response after the first dose, albeit to a lower extent than severely ill COVID-19 patients. In contrast, previously infected, antigen-experienced individuals had low afucosylation levels, which slightly increased after immunization. Afucosylation levels after the first dose correlated with low fucosyltransferase 8 (FUT8) expression levels in a defined plasma cell subset. Remarkably, IgG afucosylation levels after primary vaccination correlated significantly with IgG levels after the second dose. Further studies are needed to assess efficacy, inflammatory potential, and protective capacity of afucosylated IgG responses. One sentence summaryA transient afucosylated IgG response to the BNT162b2 mRNA vaccine was observed in naive but not in antigen-experienced individuals, which predicted antibody titers upon the second dose.

immunology↗

bioRxiv2020

Allelic variants of the NLR protein Rpi-chc1 differentially recognise members of the Phytophthora infestans PexRD12/31 effector superfamily through the leucine-rich repeat domain

O_LIPhytophthora infestans is a pathogenic oomycete that causes the infamous potato late blight disease. Resistance (R) genes from diverse Solanum species encode intracellular receptors that recognize P. infestans RXLR effector proteins and provide effective defence responses. To deploy these R genes in a durable fashion in agriculture, we need to understand the mechanism of effector recognition and the way the pathogen evades recognition. C_LIO_LIWe cloned sixteen allelic variants of the Rpi-chc1 gene from Solanum chacoense and other Solanum species, and identified the cognate P. infestans RXLR effectors. These tools were used to study receptor-ligand interactions and co-evolution. C_LIO_LIFunctional and non-functional alleles of Rpi-chc1 encode Coiled-Coil-Nucleotide Binding-Leucine-Rich-Repeat (CNL) proteins. Rpi-chc1.1 recognised multiple PexRD12 (AVRchc1.1) proteins while Rpi-chc1.2 recognised multiple PexRD31 (AVRchc1.2) proteins, both from the PexRD12/31 superfamily. Domain swaps between Rpi-chc1.1 and Rpi-chc1.2 revealed that overlapping subdomains in the LRR were responsible for the difference in effector recognition. C_LIO_LIThis study showed that Rpi-chc1.1 and Rpi-chc1.2, evolved to recognize distinct members of the same PexRD12/31 effector family via the LRR domain. The biased distribution of polymorphisms suggests that exchange of LRRs during host-pathogen co-evolution can lead to novel recognition specificities. These insights will help future strategies to breed for durable resistant varieties. C_LI

plant biology↗

bioRxiv2020

The Rpi-mcq1 resistance gene family recognizes Avr2 of Phytophthora infestans but is distinct from R2

Potato late blight, which is caused by the destructive oomycete pathogen Phytophthora infestans, is a major threat to global food security. Several nucleotide binding, leucine-rich repeat (NLR) Resistance to P. infestans (Rpi) genes have been introgressed into potato cultivars from wild Solanum species that are native to Mexico, but these were quickly defeated. Positional cloning in Solanum mochiquense, combined with allele mining in Solanum huancabambense, were used to identify a new family of Rpi genes from Peruvian Solanum species. Rpi-mcq1, Rpi-hcb1.1 and Rpi-hcb1.2 confer race-specific resistance to a panel of P. infestans isolates. Effector assays showed that the Rpi-mcq1 family mediates a hypersensitive response upon recognition of the RXLR effector AVR2, which had previously been found to be exclusively recognized by the family of R2 resistance proteins. The Rpi-mcq1 and R2 genes are distinct and reside on chromosome IX and IV, respectively. This is the first report of two unrelated R protein families that recognize the same AVR protein. We anticipate that this likely is a consequence of a geographically separated dynamic co-evolution of R gene families of Solanum with an important effector gene of P. infestans. Author summaryPotato is the largest non-grain staple crop and essential for food security world-wide. However, potato plants are continuously threatened by the notorious oomycete pathogen Phytophthora infestans that causes late blight. This devastating disease has led to the Irish famine more then 150 years ago, and is still a major threat for potato. Resistance against P. infestans can be found in wild relatives of potato, which carry resistance genes that belong to the nucleotide binding site-leucine-rich repeat (NLR) class. Known NLR proteins typically recognize a matching effector from Phytophthora, which leads to a hypersensitive resistance response (HR). For example, R2 from Mexican Solanum species recognizes AVR2 from P. infestans. So far, these R genes exclusively match to one Avr gene. Here, we identified a new class of NLR proteins that are different from R2, but also recognize the same effector AVR2. This new family of NLR occurs in South American Solanum species, and we anticipate that it is likely a product of a geographically separated co-evolution with AVR2. This is the first report of two unrelated R protein families that recognize the same AVR protein.

plant biology↗

bioRxiv2020

ELR is a true pattern recognition receptor that associates with elicitins from diverse Phytophthora species

The first layer of plant immunity against pathogens is mediated by cell surface pattern recognition receptors (PRRs) that recognize pathogen molecules in the apoplast. Several pairs of PRRs and their matching extracellular ligands have been described but, in many cases, actual evidence for ligand binding by the PRR is lacking. The receptor-like protein ELR from Solanum microdontum, which triggers cell death upon co-expression with elicitins of various Phytophthora species and enhances resistance to late blight caused by Phytophthora infestans, was previously identified as the elicitin receptor by forward genetic screenings employing the INF1 elicitin of P. infestans. In this study, we investigated whether ELR associates with INF1 and other elicitins that are secreted by diverse Phytophthora spp. We performed in planta and in vitro co-immunoprecipitation of ELR with several affinity-tagged elicitins, as well as in planta transient co-expression assays. We found that ELR physically interacts with the class I elicitins INF1 and ParA1, from P. infestans and Phytophthora parasitica, respectively, which is in line with their ability to cause cell death when co-expressed with ELR in potato. Together, we demonstrate that ELR is a genuine PRR that binds elicitins of Phytophthora species.

plant biology↗

bioRxiv2020

Afucosylated immunoglobulin G responses are a hallmark of enveloped virus infections and show an exacerbated phenotype in COVID-19

IgG antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc-tail, essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anti-cancer therapeutic antibodies for their elevated binding and killing activity through Fc receptors (Fc{gamma}RIIIa). Here, we report that afucosylated IgG which are of minor abundance in humans ([~]6% of total IgG) are specifically formed against surface epitopes of enveloped viruses after natural infections or immunization with attenuated viruses, while protein subunit immunization does not elicit this low fucose response. This can give beneficial strong responses, but can also go awry, resulting in a cytokine-storm and immune-mediated pathologies. In the case of COVID-19, the critically ill show aggravated afucosylated-IgG responses against the viral spike protein. In contrast, those clearing the infection unaided show higher fucosylation levels of the anti-spike protein IgG. Our findings indicate antibody glycosylation as a potential factor in inflammation and protection in enveloped virus infections including COVID-19.

immunology↗

bioRxiv2020

RLP/K enrichment sequencing; a novel method to identify receptor-like protein (RLP) and receptor-like kinase (RLK) genes

O_LIThe identification of immune receptors in crop plants is time-consuming but important for disease control. Previously, resistance gene enrichment sequencing (RenSeq) was developed to accelerate mapping of nucleotide-binding domain and leucine-rich repeat containing (NLR) genes. However, resistances mediated by pattern recognition receptors (PRRs) remain less utilised. C_LIO_LIHere, our pipeline shows accelerated mapping of PRRs. Effectoromics leads to precise identification of plants with target PRRs, and subsequent RLP/K enrichment sequencing (RLP/KSeq) leads to detection of informative SNPs that are linked to the trait. C_LIO_LIUsing Phytophthora infestans as a model, we identified Solanum microdontum plants that recognize the apoplastic effectors INF1 or SCR74. RLP/KSeq in a segregating Solanum population confirmed the localization of the INF1 receptor on chromosome 12, and lead to the rapid mapping of the response to SCR74 to chromosome 9. By using markers obtained from RLP/KSeq in conjunction with additional markers, we fine-mapped the SCR74 receptor to a 43-kbp G-LecRK locus. C_LIO_LIOur findings show that RLP/KSeq enables rapid mapping of PRRs and is especially beneficial for crop plants with large and complex genomes. This work will enable the elucidation and characterisation of the non-NLR plant immune receptors and ultimately facilitate informed resistance breeding. C_LI

plant biology↗

bioRxiv2019

The Synchytrium endobioticum AvrSen1 triggers a Hypersensitive Response in Sen1 potatoes while natural variants evade detection

Synchytrium endobioticum is an obligate biotrophic fungus of the phylum Chytridiomycota. It causes potato wart disease, has a world-wide quarantine status and is included on the HHS and USDA Select Agent list. S. endobioticum isolates are grouped in pathotypes based on their ability to evade host-resistance in a set of differential potato varieties. So far, thirty-nine pathotypes are reported. A single dominant gene (Sen1) governs pathotype 1 resistance and we anticipated that the underlying molecular model would involve a pathogen effector (AvrSen1) that is recognized by the host. The S. endobioticum specific secretome of fourteen isolates representing six different pathotypes was screened for effectors specifically present in pathotype 1(D1) isolates but absent in others. We identified a single AvrSen1 candidate. Expression of this candidate in potato Sen1 plants showed a specific hypersensitive response, which co-segregated with the Sen1 resistance in potato populations. No HR was obtained with truncated genes found in pathotypes that evaded recognition by Sen1. These findings established that our candidate gene was indeed Avrsen1. The S. endobioticum AvrSen1 is a single copy gene and encodes a 376 amino acid protein without predicted function or functional domains, and is the first effector gene identified in Chytridiomycota, an extremely diverse yet underrepresented basal lineage of fungi.\n\nAuthor SummaryPlant pathogens can have a great social and economic impact, and are a continuous threat to food security. A clear example is Synchytrium endobioticum, the fungus causing potato wart disease. The impact of the pathogen, lack of effective chemical control agents and the longevity of resting spores produced by the pathogen led to a world-wide quarantine status for S. endobioticum. Strict phytosanitary measures and the use of resistance potato varieties are currently the only way to prevent the spread of the disease. The emergence of new pathotypes that overcome resistance urged to study the underlying molecular mechanisms of S. endobioticum recognition by the plant. Here we describe the identification of the first effector (AvrSen1) of S. endobioticum that is recognized by the Sen1 resistance gene product. Also, we report the loss of AvrSen1 in other pathotypes thus avoiding recognition by the plant and triggering immune responses. AvrSen1 represents the first effector to be identified in the basal fungal lineage Chytridiomycota. The discovery of AvrSen1 provides an important tool to manage potato wart disease. Moreover, knowledge about Chytridiomycota effectors will shed light on other (pathogenic) interactions and the co-evolution of Chytridiomycota species with their hosts.

plant biology↗