Identification of new genes that restrict TLR7 responses to self nucleic acids
Lupus is caused when a person’s immune system attacks the body’s own genetic material. In healthy people, the molecule Toll-like receptor 7 (TLR7) inside of cells recognizes the ribonucleic acid (RNA) from viruses and other pathogens that have invaded a person’s cells, while leaving a person’s own RNA untouched. In lupus patients, TLR7 mistakenly turns on an immune response against the body’s own RNA, which leads to lupus. In his previous research, Dr. Barton identified 20 genes in mice that, when disrupted, increase TLR7 responses to RNA. In this grant, Dr. Barton proposes to study how the genes he identified influence TLR7 responses and whether such increased responses lead to lupus. First, he will measure how the absence of these genes affects TLR7 in various immune cells. His research team will also generate mice lacking these genes to see if TLR7 responses to their own RNA lead to lupus.
What this study means for people with lupus
By finding new genes that control how the immune system responds to the body’s own genetic material, this work will further our understanding of lupus. This work will also potentially identify new targets for the treatment of lupus.
Activation of Toll-like receptor 7 (TLR7) by self RNA can lead to the development of lupus. The mechanisms that prevent such responses in most individuals remain incompletely understood. We have carried out a genome-wide CRISPR/Cas9 screen to identify genes that, when disrupted, increase TLR7 responses to RNA. The hits from this screen are remarkably enriched for genes involved in protein trafficking and give us critical molecular handles to identify and characterize novel regulatory mechanisms that influence TLR7 responses. This proposal will pursue three specific aims building on the initial results from this screen. First, we will validate hits from the screen and measure how loss of function alters TLR7 responses in macrophages and plasmacytoid dendritic cells. Second, we will examine how loss of function of genes identified in the screen alters TLR7 localization or receptor levels. Third, we will test the hypothesis that deletion of genes identified in the screen leads to TLR7-dependent SLE-like disease in mice. Overall, this work will identify novel genes and regulatory pathways that control inappropriate responses of TLR7 to self RNA, will improve our understanding of lupus, and will identify new targets for treatment of lupus.