Biology subjects

Seeger, A.

Publications and source records attributed to Seeger, A..

6 recordsLinked to original sources

bioRxiv2026

Swimming motility in the gut microbiota is diverse and increased in inflammation.

Swimming motility has long been studied as a virulence mechanism of enteric pathogens, while the resident microbiota's motility has only been inferred from proxies or explored through a few model species. This study presents a direct, functional analysis of gut bacterial motility in health and inflammation. Using phase-contrast microscopy and high-throughput 3D tracking, we quantified motile bacteria and characterized their swimming behaviours directly in diluted fresh gut content. In healthy mice, fewer than 3% of bacteria were motile along the digestive tract, and their swimming patterns were dominated not by the run-tumble behavior of model gut species but by diverse behaviours rich in reverses. In five mouse models with intestinal inflammation (spanning chemical, genetic, dietary and infectious etiologies) the motile fraction rose by at least 4-fold, correlating with elevated Lipocalin-2 where measured. Reverse-rich patterns remained prevalent in these inflamed conditions, with the notable exception of Salmonella infection. Paired metagenomics and metatranscriptomics showed enrichment of flagellar genes, while communities transferred into cecal water from inflamed mice raised their motile fraction within an hour, indicating that the rise reflects both enrichment of motile taxa and rapid modulation within existing populations. In vitro assays with human-derived isolates confirmed motility across several phyla, with variability down to strain level, and identified oxygen and viscosity as key modulators. These findings support increased motility as a hallmark of the inflamed gut and challenge established assumptions about gut bacterial motility.

microbiology↗

bioRxiv2025

Synergistic non-neutralizing plasma antibodies to PfRH5 drive potent malaria parasite growth inhibition

An effective blood-stage vaccine is needed to protect against malaria pre-erythrocytic stage breakthrough. P. falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as a promising blood-stage vaccine antigen candidate, reducing parasite growth in humans during malaria challenge and showing field efficacy in children. Here, we characterize the human plasma IgG response to the RH5.1 vaccine candidate at monoclonal resolution, revealing that plasma repertoires are dominated by abundant, non-neutralizing antibodies. Using oligoclonal reconstitution experiments, in which defined pools of recombinant plasma mAbs are reassembled and functionally tested, we map how individual antibody interactions shape parasite growth inhibition activity. This approach allows us to discern which antibodies, within a polyclonal setting, act additively or synergistically, thereby revealing the emergent properties of anti-PfRH5 IgG. We further show that IgG lineages targeting linear epitopes lack neutralizing activity, while non-neutralizing IgG lineages that bind conformational epitopes can exhibit potent, interdependent synergy with each other and with neutralizing mAbs. These synergistic antibodies were identified in the plasma IgG compartments of five volunteers and highlight non-neutralizing PfRH5 epitopes that are critical for polyclonal-mediated growth inhibition. Our findings have broad implications for PfRH5 vaccine immunogen engineering and the role of non-neutralizing antibodies in infectious disease immunity.

immunology↗

bioRxiv2025

The adhesion molecules β7 integrin and L-selectin contribute to cholestatic liver disease in male mice

Background & AimsPrimary sclerosing cholangitis (PSC) is a long-term progressive disease, often occurring in conjunction with inflammatory bowel disease (IBD). Dysregulated immune cell migration and gut microbiota alterations are implicated in disease progression. Livers of PSC patients show upregulation of the endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1). Here we examined the role of the leukocytic adhesion molecules (AM) {beta}7 integrin and L-selectin, both binding partners of MAdCAM-1, in an experimental mouse model resembling aspects of human PSC. MethodsWild type (WT), {beta}7 integrin-deficient ({beta}7-/-), L-selectin-deficient (L-sel-/-), and L-selectin/{beta}7 integrin double-deficient (L-sel-/-/{beta}7-/-) male mice were compared in the model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced cholangiopathy. The extent of pathology was evaluated by serum parameters, histology, flow cytometry, and expression of inflammatory mediators. Fecal microbiota changes were assessed by 16S rRNA amplicon sequencing and intestinal permeability was measured by FITC-dextran assay. ResultsAM-deficient mice were markedly protected from DDC-induced cholangiopathy. Hepatic immune cell populations of AM-deficient mice differed significantly from those of WT mice. Adoptively transferred {beta}7-/- CD8+ T cells caused significantly less liver damage than CD8+ WT T cells in DDC-treated {beta}7-/- mice. DDC-feeding caused substantial changes in fecal microbiota profiles, which differed between the mouse strains, and a strong increase in intestinal permeability that was significantly lower in {beta}7-/- than WT mice. Conclusions{beta}7 integrin and L-selectin contribute to DDC-induced cholangiopathy with {beta}7 integrin-expressing CD8+ T cells playing a crucial role in promoting pathogenesis. In addition, AM-expressing immune cells may contribute to the inflammatory process by causing unfavorable gut microbiota shifts and destabilizing the gut barrier. Synopsis{beta}7 integrin- and/or L-selectin-deficient mice are less susceptible to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced experimental cholangiopathy. {beta}7 integrin-expressing CD8+ T cells contribute to DDC-induced pathogenesis. {beta}7 integrin promotes DDC-induced gut barrier dysfunction and microbiota shifts, potentially exacerbating hepatic injury.

immunology↗

bioRxiv2025

Intercellular adhesion molecule-1 protects against adipose tissue inflammation and insulin resistance but promotes liver inflammation and hepatic fibrosis in mice

Metabolic dysfunction associated steatotic liver disease (MASLD) presents a growing global health problem with a range of manifestations, including steatosis, steatohepatitis, and cirrhosis. It is strongly associated with obesity, disease progression being promoted not only by hepatic leukocyte accumulation but also by inflammatory signals from adipose tissue and an altered gut microbiome. To determine the contribution of intercellular adhesion molecule-1 (ICAM-1) to MASLD pathogenesis, mice with an ICAM-1 mutation (Icam1tmBay) were compared to wild type (WT) mice in a Western-style diet (WD) model. WD-induced MASLD was accompanied by increased ICAM-1 expression in liver, epididymal white adipose tissue (EWAT), and intestine in WT mice. WD-fed Icam1tmBay mice exhibited increased circulating neutrophils, higher frequencies of inflammatory leukocytes in EWAT, and a worsened glucose tolerance when compared to WT mice. In contrast, the mutation resulted in reduced WD-induced liver damage and less accumulation of intrahepatic leukocytes. WD-feeding caused substantial changes in fecal microbiota with decreased microbial diversity that differed between the mouse strains. In conclusion, ICAM-1 positively regulates adipose tissue homeostasis and protects from insulin resistance but promotes liver damage in diet-induced obesity. This points to various organ-specific roles for ICAM-1 and the potential of liver-specific targeting of ICAM-1 for treatment of MASLD.

immunology↗

bioRxiv2024

Hybrid immunity to SARS-CoV-2 arises from serological recall of IgG antibodies distinctly imprinted by infection or vaccination

We used plasma IgG proteomics to study the molecular composition and temporal durability of polyclonal IgG antibodies triggered by ancestral SARS-CoV-2 infection, vaccination, or their combination ("hybrid immunity"). Infection, whether primary or post-vaccination, mainly triggered an anti-spike antibody response to the S2 domain, while vaccination predominantly induced anti-RBD antibodies. Immunological imprinting persisted after a secondary (hybrid) exposure, with >60% of the ensuing serological response originating from the initial antibodies generated during the first exposure. We highlight one instance where hybrid immunity arising from breakthrough infection resulted in a marked increase in the breadth and affinity of a highly abundant vaccination-elicited plasma IgG antibody, SC27. With an intrinsic binding affinity surpassing a theoretical maximum (KD < 5 pM), SC27 demonstrated potent neutralization of various SARS-CoV-2 variants and SARS-like zoonotic viruses (IC50 [~]0.1-1.75 nM) and provided robust protection in vivo. Cryo-EM structural analysis unveiled that SC27 binds to the RBD class 1/4 epitope, with both VH and VL significantly contributing to the binding interface. These findings suggest that exceptionally broad and potent antibodies can be prevalent in plasma and can largely dictate the nature of serological neutralization. HIGHLIGHTS{blacksquare} Infection and vaccination elicit unique IgG antibody profiles at the molecular level {blacksquare}Immunological imprinting varies between infection (S2/NTD) and vaccination (RBD) {blacksquare}Hybrid immunity maintains the imprint of first infection or first vaccination {blacksquare}Hybrid immune IgG plasma mAbs have superior neutralization potency and breadth

immunology↗

bioRxiv2023

Altered neutrophil extracellular traps in response to Mycobacterium tuberculosis in persons living with HIV with no previous TB and negative TST and IGRA

Persons living with HIV (PLWH) have an increased risk for tuberculosis (TB). After prolonged and repeated exposure, some PLWH never develop TB and test persistently negative in tests of immune sensitization tuberculin skin test (TST) and interferon gamma release assays (IGRA) for Mycobacterium tuberculosis (Mtb). This group has been identified and defined as HIV+ persistently TB, tuberculin and IGRA negative (HITTIN). To investigate potential innate mechanisms unique to individuals with the HITTIN phenotype we compared their neutrophil Mtb infection response to that of PLWH, with no TB history, but who test persistently IGRA positive, and tuberculin positive (HIT). Neutrophil samples from 17 HITTIN (PMNHITTIN) and 11 HIT (PMNHIT) were isolated and infected with Mtb H37Rv for 1h and 6h. RNA was extracted and used for RNAseq analysis. At 1h of Mtb infection, PMNHITTIN displayed 151 significantly upregulated and 40 significantly downregulated differentially expressed genes (DEGs) and PMNHIT 98 significantly upregulated and 11 significantly downregulated DEGs. At the 6h timepoint, PMNHITTIN displayed 3106 significantly upregulated and 3548 significantly downregulated DEGs while PMNHIT had 3816 significantly up- and 3794 significantly downregulated DEGs. There was no significant differential transcriptional response at 1h between infected PMNHITTIN and PMNHIT. However, when contrasting the log2FC 6h infection response to Mtb from PMNHITTIN against PMNHIT, 2285 genes showed significant differential response between the two groups. Apoptosis and NETosis were key pathways linked to the enrichment of genes in PMNHITTIN when contrasted to PMNHIT after 6h infection with Mtb. Fluorescence microscopy revealed relatively lower neutrophil extracellular trap formation and cell loss in PMNHITTIN compared to PMNHIT, showing that PMNHITTIN have a distinct response to Mtb.

genetics↗