Systemic exposure to bacterial amyloid curli alters the gut mucosal immune response and the microbiome, exacerbating Salmonella -induced arthritis

Abstract

The Salmonella biofilm-associated amyloid protein, curli, is a dominant instigator of systemic inflammation and autoimmune responses following Salmonella infection. Systemic curli injections or infection of mice with Salmonella Typhimurium induce the major features of reactive arthritis, an autoimmune disorder associated with Salmonella infection in humans. In this study, we investigated the link between inflammation and microbiota in exacerbating autoimmunity. We studied C57BL/6 mice from two sources, Taconic Farms and Jackson Labs. Mice from Taconic Farms have been reported to have higher basal levels of the inflammatory cytokine IL − 17 than do mice from Jackson Labs due to the differences in their microbiota. When we systemically injected mice with purified curli, we observed a significant increase in diversity in the microbiota of Jackson Labs mice but not in that of the Taconic mice. In Jackson Labs, mice, the most striking effect was the expansion of Prevotellaceae . Furthermore, there were increases in the relative abundance of the family Akkermansiaceae and decreases in families Clostridiaceae and Muribaculaceae in Jackson Labs mice. Curli treatment led to significantly aggravated immune responses in the Taconic mice compared to Jackson Labs counterparts. Expression and production of IL − 1β, a cytokine known to promote IL − 17 production, as well as expression of Tnfa increased in the gut mucosa of Taconic mice in the first 24 hours after curli injections, which correlated with significant increases in the number of neutrophils and macrophages in the mesenteric lymph nodes. A significant increase in the expression of Ccl3 in colon and cecum of Taconic mice injected with curli was detected. Taconic mice injected with curli also had elevated levels of inflammation in their knees. Overall, our data suggest that autoimmune responses to bacterial ligands, such as curli, are amplified in individuals with a microbiome that promote inflammation.

Pathways linking microbiota-gut-brain axis with neuroinflammatory mechanisms in Alzheimer’s pathophysiology

“…Curli possesses various mechanisms through which it may be disruptive to host health, such as TLR2/1-mediated microglia and astrocyte activation for the promotion of neuroinflammation and reduction of epithelial tight junction proteins [ 86 ] . As demonstrated via injection of Salmonella typhimurium -derived curli, the protein has the ability to alter gut microbiomes and enhance proinflammatory cytokines such as IL-1, which can have downstream consequences in peripheral and CNS inflammation, therefore influencing AD pathophysiology [ 94 ] . Curli may also aid in protecting bacteria from host antimicrobial activities and is variably produced in a strain-dependent manner [ 95 ] .…”

Serum Amyloid A3 Fuels a Feed-Forward Inflammatory Response to the Bacterial Amyloid Curli in the Enteric Nervous System

“…Microbial colonization and intraperitoneal curli injections were performed as previously described 36 , 37 in a biosafety level2 facility under protocols approved by AALAC-accredited Temple University Lewis Katz School of Medicine Institutional Animal Care and Use Committee (#4868) in accordance with guidelines set forth by the USDA and PHS Policy on the Humane Care and Use of Laboratory Animal Welfare. The institution has an Animal Welfare Assurance on file with the National Institutes of Health Office for the Protection of Research Risks, number A3594-01.…”

Amyloid, Crohn’s disease, and Alzheimer’s disease - are they linked?

“…However, under favorable conditions, it can also become pathogenic in these tissues (Sonthalia et al, 2016;Martıńez-Naharro et al, 2018;Pinto et al, 2021;Deng et al, 2022;Gurung and Li, 2022). Furthermore, previous studies have confirmed that human amyloid and bacterial amyloid share many common features, undoubtedly warranting a more in-depth analysis (Das et al, 2022;Bessho et al, 2023).…”