Dr. Roberto Caricchio is studying whether usually harmless, common bacterial infections, such as urinary tract infections, might be an environmental trigger of lupus onset and flares in genetically at-risk individuals. Normally, a bacterial infection sets off the immune system to make antibodies and take other actions to fight off the invading bacteria. Dr. Caricchio’s theory is that in people who are susceptible to lupus, those infections also cause the immune system to make antibodies that recognize and attack a person’s own body.

What this study means to people with lupus

Dr. Caricchio will look specifically at urinary tract infections (UTIs) in people with and without lupus. Some bacteria that cause UTIs produce a protein called “curli” that can bind to DNA and form a compound that triggers lupus in mouse models. Preliminary evidence shows that individuals with lupus have antibodies against this curli/DNA compound. Dr. Caricchio will investigate whether curli/DNA antibodies can predict lupus in at-risk people and if UTIs in people who have lupus create curli/DNA compounds in their blood that cause flares. This exciting research could open a new avenue of approaches to treat and even prevent lupus.

Bacterial infections are a major contributor to morbidity and mortality in SLE. Urinary tract infections (UTIs) such as those due to uropathogenic E. coli (UPEC), which are common in SLE patients, 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. Our labs have recently discovered that curli complexed with DNA, is a powerful trigger of lupus disease in mouse models. 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. Our data also show that curli/DNA can trigger NETs, an important pathogenic mechanism in lupus. The goal here 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. 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; 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 can activate innate and adaptive immunity. 3) We will investigate if biofilms from lupus patients can 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.