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Sanford-Burnham researchers identify key functions of immune system response
LA JOLLA, Calif.— Scientists at the Sanford-Burnham Medical Research Institute have shown in a genome-wide study how key immune sensors arrive at the "front lines" of infection. According to lead author Dr. Sumit Chanda, this knowledge may be exploited to develop new therapies for infectious and autoimmune diseases with significant unmet medical need like lupus and inflammatory bowel disease (IBD).
In a study published March 14 in Cell Host & Microbe, Chanda and his colleagues identified 190 genes that are crucial to the function of two toll-like receptors (TLRs), TLR7 and TLR9, which recognize pathogens and trigger immune responses. TLRs have been widely studied and research into these pathways even garnered a Nobel Prize in 2011; many pathogens—including HIV, Group A streptococcus and the influenza virus—elicit a response from TLR7 or TLR9 in the endosomes of cells.
The study is actually the third time that Chanda's laboratory has used a systems-based approach to dissect host/pathogen interactions, one that focuses on genome-wide RNAi analysis. The team previously used this method to study how cells respond to influenza and HIV infections.
"Essentially, we knocked down every gene in the genome, one at a time, and asked the question, 'how does the cell respond to a viral infection?'" says Chanda, who is an associate professor in the Infectious and Inflammatory Disease Center at Sanford-Burnham. "What we're interested in studying now is what the host cell requirements are for replication, how the cell senses these viruses and responds to different types of microbial infection, then triggers autoimmunity."
The risk inherent in autoimmunity, of course, is the immune system mistaking some part of the body as a pathogen and attacking its own cells. TLR7 and TLR9 can end up mistakenly triggering an immune response against the host, instead of the invader, if there are breakdowns in this first-responder network.
"Our hypothesis was that there was not much known about these pathways, and we have to do a bit more work to understand how things are fine-tuned to preserve that balance," Chanda says.
To act on this hypothesis, Chanda's laboratory used an RNAi screen to identify 190 genes that cells rely upon to coordinate a response to a pathogen that has breached the endosome. Then, using advanced computational methods, they were able to reconstruct a molecular blueprint that revealed the intricate wiring of this critical immune defense network. Next, they drilled down and looked at one gene from the RNAi screen called hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) that plays a fundamental role in localizing these receptors to the endosomes. HRS is part of a larger complex that recognizes and sorts other proteins into various internal vesicles, including endosomes.
Previous research has shown that proper functioning of the immune system depends on these critical receptors getting to the endosome. If TLR7 and TLR9 are sent to the wrong place, the host is not only susceptible to infection, but also to autoimmune diseases. Chanda's team found that without this HRS protein, TLR9 cannot do its job because it is not delivered to the right location.
Chanda—who once worked in drug discovery at Novartis—is now leading his team in the search for chemical compounds that might shut down errant signaling in the TLR7 and TLR9 system. If scientists are able to find such compounds that also demonstrate a strong safety profile, treatments may be developed for several autoimmune diseases, including lupus, Crohn's disease, diabetes and IBD.
"We have an amazingly rich set of data that gives us a set of potential targets, but now we need to go on and start assessing what would be the best target for the treatment of disease and move into more of a lead optimization type of analysis," he says. "Our challenge now is to find something that can be chronically inhibited without inducing long-term toxicity to the patient. But what this study does is open up the field for finding these potential candidates, and figuring out what will give you the best efficacy, but also a very reasonable safety profile."
The Sanford-Burnham study, "Cofactors Required for TLR7- and TLR9-Dependent Innate Immune Responses," was funded by the U.S. Department of Defense, the Alliance for Lupus Research, the National Institute of Allergy and Infectious Diseases and the National Institute of General Medical Sciences at the National Institutes of Health and the Irvington Institute Fellowship Program of the Cancer Research Institute. Chanda's co- authors included Chih-yuan Chiang, Amanda M. Opaluch, Paul D. De Jesus and Quy T. Nguyen from Sanford-Burnham; Alex Engel and Gregory M. Barton from the University of California, Berkeley; Irene Ramos, Ana M. Maestre and Ana Fernandez-Sesma from the Mount Sinai School of Medicine; Ismael Secundino and Victor Nizet from the University of California, San Diego; and Genevieve Welch, Ghislain M.C. Bonamy, Loren J. Miraglia, Anthony P. Orth and Yingyao Zhou from the Genomics Institute of the Novartis Research Foundation.
Both photos are courtesy of: Sanford-Burnham Medical Research Institute
Dr. Sumit Chanda, associate professor in the Infectious and Inflammatory Disease Center at Sanford-Burnham Medical Research Institute and senior author of the study.
Mutant TLR9 (green) fails to traffic to endosomes (orange), a problem that can lead to autoimmune disease or increase susceptibility to infection.