Bacterial infections are a major contributor to morbidity and mortality in SLE. Infections trigger flares but they are often difficult to distinguish from the flare itself because biomarkers are lacking. Urinary tract infections (UTIs) such as those due to uropathogenic E. coli (UPEC), which are common in SLE patients, and especially in women, are characterized by the generation of a unique form of amyloid called curli. Curli contribute to the formation of bacterial biofilms, which are multicellular communities of bacteria that are protected from oxidative stress and antimicrobial agents. Curli-producing bacteria such as E. coli trigger the innate immune system through several TLRs and the inflammasome, therefore constituting a ?perfect storm? for individuals genetically predisposed to SLE. Indeed, our labs have recently discovered that curli complexed with DNA, is a powerful trigger of lupus disease in mouse models. Importantly, curli/DNA complexes triggered production of type I IFNs, important in the pathogenesis of lupus. Our preliminary data show that lupus patients have anti-curli/DNA Abs and their levels correlate with persistent bacteriuria, anti-dsDNA Abs and lupus flares. We also show that curli/DNA are able to trigger NETs, an important pathogenic mechanism in lupus. The goal of this application is to demonstrate that the autoimmune system in SLE patients is activated by curli/DNA from UPEC. Our long- term goal is to demonstrate that common curli-producing bacterial infections are a major environmental factor in human SLE that not only contributes to the development of lupus but also triggers flares and in turn accrual damage, which eventually leads to poor lupus outcome. We propose to investigate the role of infections in SLE with the following three AIMs.
Aim 1, we will investigate how PBMCs from lupus patients and healthy controls respond to bacterial curli and their biofilms. We will investigate 1) if curli/DNA activate the IFN Signature in SLE patients; 2) if they induce Neutrophil Extracellular Traps, a pathogenic mechanism in SLE; and 3) if autoreactive B cells from SLE patients are triggered by curli/DNA.
Aim 2; we will investigate if: 1) anti- curli/DNA antibodies predict the onset of Lupus; 2) if anti-curli correlate with gene expression profile signatures of inflammation, autoimmunity and chronic exposure to bacterial pathogens; and 3) We will follow prospectively lupus patients from our Temple Lupus Cohort and investigate if bacteriuria induces curli/DNA complexes to circulate in lupus patients and if they trigger flares and accrual damage.
In Aim 3 we will investigate if: 1) UPEC in lupus patients form biofilms that contain curli/DNA complexes and if they differ from healthy controls. 2) If the biofilms from lupus patients and controls are capable of activating innate and adaptive immunity. 3) We will investigate if biofilms from lupus patients are able to trigger lupus-like autoimmunity in animal models. The significance and innovation of our proposal lays in the demonstration that previously thought harmless common UTIs, are instead a constant trigger of a genetically predisposed autoimmune system. The discovery could lead to novel approaches to treat and even attempt to prevent this chronic and debilitating disease.
Current treatments for SLE patients can diminish active inflammation, but the persistence of the disease and occurrence of flares suggests that we are underestimating an important pathogenic player. We propose a role for recurrent common bacterial infections in triggering both lupus onset and flares, by providing the immune system with autoantigens in presence of bacterial stimuli, we propose to investigate common urinary tract infections frequent in SLE patients as the culprit for flares and continuous triggering of the lupus autoimmune system.
