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.

KEYWORDS:

• Salmonella
• curli
• amyloid
• biofilm
• autoimmunity
• microbiome
• reactive arthritis

Acknowledgments

We would like to thank Dr. Roberto Caricchio, Dr. Marc Monestier and Dr. Bettina Buttaro for constructive discussions regarding the study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data are fully available without restriction.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2221813

Ethics statement

All animal experiments were performed in a BSL2 facility under protocols approved by AALAC-accredited Temple University Lewis Katz School of Medicine, Institutional Animal Care and Use Committee (IACUC #4868) in accordance with guidelines set forth by the USDA and PHS Policy on Humane Care and Use of Laboratory Animal Welfare. The institution has an Animal Welfare Assurance on file with the NIH Office for the Protection of Research Risks, Number A3594–01.

Additional information

Funding

C.T. is supported by NIH grants AI153325, AI151893, and AI148770. VT was supported by NIH grant AI168550. The work of A. J. P. K. was supported by the Histopathology Facility under NIH grant P30CA06927.