Amyloid-DNA Composites of Bacterial Biofilms Stimulate Autoimmunity

Abstract

SUMMARY Research on the human microbiome has established that commensal and pathogenic bacteria can influence obesity, cancer, and autoimmunity through mechanisms mostly unknown. We found that a component of bacterial biofilms, the amyloid protein curli, irreversibly formed fibers with bacterial DNA during biofilm formation. This interaction accelerated amyloid polymerization and created potent immunogenic complexes that activated immune cells, including dendritic cells, to produce cytokines such as Type I interferons, which are pathogenic in systemic lupus erythematosus (SLE). When given systemically, curli-DNA composites triggered immune activation and production of autoantibodies in lupus-prone and wild-type mice. We also found that the infection of lupus-prone mice with curli-producing bacteria triggered higher autoantibody titers compared to curli-deficient bacteria. These data provide a mechanism by which the microbiome and biofilm-producing enteric infections may contribute to the progression of SLE and point to a potential molecular target for treatment of autoimmunity.

Amyloid Structures as Biofilm Matrix Scaffolds

“…Some recent information pointed out that DNA might also play this role. Direct interaction of DNA with two major bacterial amyloids, curli and PSMs, reveals its role as a nucleator of amyloid polymerization (80). In the case of curli fibers, Gallo et al (80) showed that Salmonella curli fibers bind tightly to extracellular DNA (eDNA), protecting it from degradation by DNases.…”

“…In the case of curli fibers, Gallo et al (80) showed that Salmonella curli fibers bind tightly to extracellular DNA (eDNA), protecting it from degradation by DNases. Furthermore, addition of three different types of nucleic acids (synthetic oligonucleotide, Salmonella genomic DNA, or eukaryotic DNA) indistinctly reduced the lag phase for curli fiber polymerization, suggesting a mechanism by which DNA molecules trigger the assembly of CsgA monomers into highly stable complexes that would provide stability to Salmonella enterica serovar Typhimurium biofilms (80).…”

“…Curli fibers are able to stimulate the innate immune system by recognizing the Toll-like receptor 2 (TLR2)-TLR1 heterocomplex (83)(84)(85). Interestingly, a very recent study highlights the role of curli-DNA complexes in the stimulation of the innate and adaptive immune systems and suggests that these complexes can accelerate autoimmunity contributing to systemic lupus erythematosus pathogenesis (80). In an indirect manner, the strong innate immune response activated by bacterial amyloids could stimulate neuropathogenic signals that promote amyloid aggregation and inflammatory degeneration characteristic of age-related neurological diseases such as Alzheimer's disease.…”

Salmonella Extracellular Matrix Components Influence Biofilm Formation and Gallbladder Colonization

“…Salmonella biofilm ECM components have been determined and include proteins (curli fimbriae and BapA), polysaccharides (extracellular DNA, cellulose, O-antigen capsule, colanic acid [in nontyphoidal serovars], and Vi antigen [ViAg] [in serovars Typhi, Dublin, and Paratyphi C]) (7,(13)(14)(15)(16)(17). Individual mutations in these ECM factors have been tested by various groups for their roles in biofilm formation, and some have also been examined for phenotypes in vertebrate models of infection (18)(19)(20)(21)(22)(23)(24). However, combinations of mutations and direct comparisons in vitro or in vivo have not been made.…”

Biofilms 2015: Multidisciplinary Approaches Shed Light into Microbial Life on Surfaces

“…At least 40% of bacterial species produce amyloid-like proteins that share a quaternary structure, as well as physical and immunological properties, with human amyloids associated with complex diseases such as Alzheimer's disease, prion diseases, and type II diabetes. Hence, bacterial amyloids present in the biofilm extracellular matrix, where they can bind extracellular DNA (eDNA), could induce inflammation and production of anti-double-stranded DNA (anti-dsDNA) as well as antichromatin antibodies, potentially contributing to the progression of autoimmunity (30). In his work, Steven Goodman (Nationwide Children's Hospital, Columbus, OH) has found that targeting the DNABII family of proteins required for the maintenance of eDNA structure can prevent biofilm formation by nontypeable Haemophilus influenzae, P. aeruginosa, S. aureus, and Burkholderia cenocepacia.…”