Bacterial amyloid curli acts as a carrier for DNA to elicit an autoimmune response via TLR2 and TLR9
| Autor: | Michael H. Lee, Çagla Tükel, Nicole J. Medeiros, Lauren K. Nicastro, Bettina A. Buttaro, Ronald Paul Wilson, Gerard C. L. Wong, Stefania Gallucci, Sarah A. Tursi, Ernest Y. Lee |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Bacterial Diseases Salmonella typhimurium Physiology Autoimmunity Pathology and Laboratory Medicine Biochemistry Immune Receptors Immune tolerance White Blood Cells Mice 0302 clinical medicine Animal Cells Salmonella Immune Physiology Medicine and Health Sciences Internalization lcsh:QH301-705.5 Toll-like Receptors media_common Immune System Proteins Organic Compounds Acquired immune system Immune complex 3. Good health Bacterial Pathogens Chemistry Infectious Diseases Medical Microbiology Physical Sciences Interferon Type I Salmonella Infections Cellular Types Pathogens Research Article Signal Transduction lcsh:Immunologic diseases. Allergy DNA Bacterial Amyloid media_common.quotation_subject Immune Cells Immunology Biology Microbiology Antibodies 03 medical and health sciences Immune system Enterobacteriaceae Bacterial Proteins Virology Genetics Animals Humans Cellulose Molecular Biology Microbial Pathogens Autoantibodies Innate immune system Blood Cells Bacteria Macrophages Organic Chemistry Organisms Chemical Compounds Biology and Life Sciences Proteins Bacteriology Cell Biology Toll-Like Receptor 2 Toll-Like Receptor 9 Mice Inbred C57BL TLR2 030104 developmental biology lcsh:Biology (General) Biofilms Parasitology Interferons lcsh:RC581-607 Bacterial Biofilms 030215 immunology |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 13, Iss 4, p e1006315 (2017) |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | Bacterial biofilms are associated with numerous human infections. The predominant protein expressed in enteric biofilms is the amyloid curli, which forms highly immunogenic complexes with DNA. Infection with curli-expressing bacteria or systemic exposure to purified curli-DNA complexes triggers autoimmunity via the generation of type I interferons (IFNs) and anti-double-stranded DNA antibodies. Here, we show that DNA complexed with amyloid curli powerfully stimulates Toll-like receptor 9 (TLR9) through a two-step mechanism. First, the cross beta-sheet structure of curli is bound by cell-surface Toll-like receptor 2 (TLR2), enabling internalization of the complex into endosomes. After internalization, the curli-DNA immune complex binds strongly to endosomal TLR9, inducing production of type I IFNs. Analysis of wild-type and TLR2-deficient macrophages showed that TLR2 is the major receptor that drives the internalization of curli-DNA complexes. Suppression of TLR2 internalization via endocytosis inhibitors led to a significant decrease in Ifnβ expression. Confocal microscopy analysis confirmed that the TLR2-bound curli was required for shuttling of DNA to endosomal TLR9. Structural analysis using small-angle X-ray scattering revealed that incorporation of DNA into curli fibrils resulted in the formation of ordered curli-DNA immune complexes. Curli organizes parallel, double-stranded DNA rods at an inter-DNA spacing that matches up well with the steric size of TLR9. We also found that production of anti-double-stranded DNA autoantibodies in response to curli-DNA was attenuated in TLR2- and TLR9-deficient mice and in mice deficient in both TLR2 and TLR9 compared to wild-type mice, suggesting that both innate immune receptors are critical for shaping the autoimmune adaptive immune response. We also detected significantly lower levels of interferon-stimulated gene expression in response to purified curli-DNA in TLR2 and TLR9 deficient mice compared to wild-type mice, confirming that TLR2 and TLR9 are required for the induction of type I IFNs. Finally, we showed that curli-DNA complexes, but not cellulose, were responsible elicitation of the immune responses to bacterial biofilms. This study defines the series of events that lead to the severe pro-autoimmune effects of amyloid-expressing bacteria and suggest a mechanism by which amyloid curli acts as a carrier to break immune tolerance to DNA, leading to the activation of TLR9, production of type I IFNs, and subsequent production of autoantibodies. Author summary Bacterial amyloids are conserved proteins expressed by many bacteria in biofilms. Bacterial amyloid curli and DNA form highly immunogenic complexes that stimulate autoimmunity and accelerate the progression of systemic lupus erythematosus. Here, we show that the innate immune receptors TLR2 and TLR9 are critical for shaping the autoimmune adaptive immune response to curli-DNA complexes. Mice deficient in these receptors show attenuated production of anti-double-stranded DNA autoantibodies and type I IFNs. The cross beta-sheet structure of curli is recognized by TLR2, leading to endosomal internalization of the curli-DNA complex and subsequent binding to TLR9. Synchrotron diffraction studies suggest that curli-DNA immune complexes present double-stranded DNA rods at an inter-DNA spacing that matches well to the steric size of TLR9, thus promote multivalent amplification of binding and TLR9 activation. Overall, our results identify a novel series of events pivotal to induction of autoimmunity by amyloid-expressing bacteria. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|