Biology subjects

Smits, H. H.

Publications and source records attributed to Smits, H. H..

3 recordsLinked to original sources

bioRxiv2025

HpBoRB, a helminth-derived CCP domain protein which binds RELMβ

Helminth infections persist by influencing host immunity through the release of immunomodulatory proteins which prevent immune ejection. The intestinal nematode Heligmosomoides polygyrus bakeri (Hpb) secretes multiple families of immunomodulatory proteins, many of which are composed of consecutive Complement Control Protein (CCP) domains. We hypothesized that further CCP domain proteins are secreted by the parasite to interact with the host. We identified an unusually large number of CCP domain-containing proteins in the genome of Hpb, and cloned a range of these for screening in an Avidity-based Extracellular Interaction Screening (AVEXIS) assay, focussing on interactions with host immune proteins. This screen confirmed the binding of known immunomodulators (HpBARI, TGM1) for their targets (ST2, TGFBR2) and identified a new interaction between a 2 CCP domain Hpb protein and mouse resistin-like molecule beta (RELM{beta}), a host protein demonstrated to have anti-helminth properties. This protein was named Binder of RELM{beta} (HpBoRB). This interaction was confirmed in ELISA, competition assays, size exclusion chromatography and surface plasmon resonance experiments, identifying a subnanomolar affinity interaction between HpBoRB and RELM{beta}. These data may indicate that Hpb interferes with the potent anti-helminth host protein RELM{beta} and adds to our knowledge of the host-parasite interactions mediated by Hpb secreted proteins.

immunology↗

bioRxiv2022

Fasciola hepatica Fatty Acid Binding Protein 1 modulates T cell polarization by promoting dendritic cell thrombospondin-1 secretion without affecting metabolic homeostasis in obese mice

BackgroundThe parasitic trematode Fasciola hepatica evades host immune defenses through secretion of various immunomodulatory molecules. Fatty Acid Binding Proteins (fhFABPs) are among the main excreted/secreted proteins and have been shown to display anti-inflammatory properties. However, little is currently known regarding their impact on dendritic cells (DCs) and their subsequent capacity to prime specific CD4+ T cell subsets. Methodology/Principal FindingsThe immunomodulatory effects of both native F. hepatica extracts and recombinant fhFABPs were assessed on monocyte-derived human DCs (moDCs) and the underlying mechanism was next investigated using various approaches, including DC-allogenic T cell co-culture and DC phenotyping through transcriptomic, proteomic and FACS analyses. We mainly showed that fhFABP1 induced a tolerogenic-like phenotype in LPS-stimulated moDCs characterized by a dose-dependent increase in the cell-surface tolerogenic marker CD103 and IL-10 secretion, while DC co-stimulatory markers were not affected. A significant decrease in secretion of the pro-inflammatory cytokines IL-12p70 and IL-6 was also observed. In addition, these effects were associated with an increase in both Th2-on-Th1 ratio and IL-10 secretion by CD4+ T cells following DC-T cell co-culture. RNA sequencing and targeted proteomic analyses identified thrombospondin-1 (TSP-1) as a non-canonical factor highly expressed and secreted by fhFABP1-primed moDCs. The effect of fhFABP1 on T cell skewing was abolished when using a TSP-1 blocking antibody during DC-T cell co-culture. Immunomodulation by helminth molecules has been linked to improved metabolic homeostasis during obesity. Although fhFABP1 injection in high-fat diet-fed obese mice induced a potent Th2 immune response in adipose tissue, it did not improved insulin sensitivity or glucose homeostasis. Conclusions/SignificanceWe show that fhFABP1 modulates T cell polarization, notably by promoting DC TSP-1 secretion in vitro, without affecting metabolic homeostasis in a mouse model of type 2 diabetes.

immunology↗

bioRxiv2019

Defining mucosal immunity using mass cytometry following experimental human pneumococcal challenge

Streptococcus pneumoniae (Spn) is a common cause of respiratory infection, but also frequently colonises the nasopharynx in the absence of disease. We used mass cytometry to study immune cells from nasal biopsy samples, collected following experimental human pneumococcal challenge, in order to identify immunological changes that follow and control spn colonisation. Using 37 markers, we characterized 293 nasal immune cell clusters, of which 7 were associated with Spn colonisation. B cell and CD8+CD161+ T cell clusters were significantly higher in non-colonised than in colonised subjects. Spn colonization led to recirculation of not only Spn-specific but also aspecific nasal B cells. This associated with increased numbers of circulating plasmablasts and increased antibody levels against the unrelated bacterium Haemophilus influenzae. In addition, we demonstrated that baseline functionality of blood mucosal associated invariant T (MAIT) cells associated with protection against Spn. These results identify new host-pathogen interactions at the mucosa upon Spn colonisation.

immunology↗