Tukel, C. | bioRxiv Science

bioRxiv2026

A Novel Biofilm Amyloid Ligand for Caspase-11 Drives Hyperactivation in Dendritic Cells

Bacterial biofilms drive persistent infection and chronic inflammation, yet host sensing of biofilm-derived ligands remains poorly understood. Here we identify curli amyloid, an integral component of Enterobacteriaceae biofilms, as a novel activator of the non-canonical inflammasome in human and mouse dendritic cells (DCs). Curli both primes and activates the inflammasome, directly binding caspase-11 to engage NLRP3 and drive robust IL-1{beta} maturation without pyroptosis, establishing curli as a previously unrecognized trigger of DC hyperactivation. Mechanistically, this non-lytic signaling is marked by limited gasdermin D oligomerization without mitochondrial localization and NINJ1-dependent membrane rupture. Functionally, curli-hyperactivated DCs show enhanced migration to the draining lymph nodes in vivo, suggesting consequent augmented adaptive immunity. Finally, curli-containing biofilms also elicit IL-1{beta} secretion without cell death, identifying bacterial amyloid as a central driver of non-lytic inflammasome activation during immune recognition of biofilms.

immunology↗

bioRxiv2025

Commensal Escherichia coli colonization triggers Peyer's patch development

The gut microbiota plays a pivotal role in shaping mucosal immunity, yet the specific microbes contributing to lymphoid tissue development remain poorly defined. Here, we identify Escherichia coli, a pioneer commensal bacterium, as a key driver of naive B cell accumulation in gut Peyers patches and lamina propria via a CXCR2-dependent mechanism. We show that E. coli promotes B cell recruitment through the production of curli amyloid fibers, which signal via Toll-like receptor 2 (TLR2). Notably, this effect extends beyond the neonatal period, revealing a broader temporal window for microbial modulation of mucosal immune development. These findings reveal a previously unrecognized role for a defined gut commensal bacterium and its molecular products in orchestrating the formation of gut-associated lymphoid tissue and B cell recruitment.

microbiology↗

bioRxiv2022

Enteric glia adopt an activated pro-inflammatory state in response to human and bacterial amyloids

Mounting evidence suggests a role for the microbiome-gut-brain axis in amyloid-associated neurodegeneration, but the pathogenic changes induced by amyloids in the gastro-intestinal tract remain elusive. To scrutinize the early response to amyloids of human and bacterial origin, we challenged primary murine myenteric networks with A{beta}1-42 (vs a scrambled version of A{beta}1-42) and curli (vs culture medium), respectively, and performed shotgun RNA sequencing. Both amyloid types induced a transcriptional signature of DNA damage and cell cycle dysregulation. Using in vitro neurosphere-derived cultures and in vivo amyloid injections we found that enteric glia and smooth muscle cells were the most responsive cell types, showing increased proliferation, {gamma}H2AX burden and SOD2 levels after amyloid challenge. Consistent with this activated state, we identified a pro-inflammatory hub in the transcriptional profile of amyloid-stimulated myenteric networks. Enteric glia were the principal source of the associated cytokines, and in vivo, this was accompanied by an influx of immune cells. Together, these results shed new light on the intrinsic vulnerability of ENS cells to both amyloid species and position enteric glial cell activation as an early driver of neurodegenerative disease progression. Significance statementThe increasing socio-economic impact of Alzheimers disease (AD), long sub-clinical disease progression window, and failure of drug candidates demand mechanistic insight into the early stages of disease development. Epidemiological associations and experimental studies in rodents suggest that the gut may be vulnerable to amyloids and mediate their transfer to the brain. However, whether and how amyloids induce local pathology in the gastro-intestinal wall is not known. We identified a pathogenic program that becomes activated in the gastro-intestinal tract after exposure to amyloid {beta} and curli (the main bacterial amyloid), and show that enteric glia are responsible for creating an amyloid-induced pro-inflammatory environment. This insight of an early response in a distant, more accessible organ than the brain, may have important implications for both disease diagnosis and therapy.

neuroscience↗