Generally defined as an inflammatory response to infection, sepsis has a staggering 30-50 percent mortality rate and is responsible for 210,000 deaths annually in the United States. Despite the availability of antibiotics and other forms of therapy, the hospitalization of patients with severe sepsis (also known as septic shock) has increased 49 percent from 2003 to 2009, making the need for a targeted and effective therapy for this disease critical.
Guoyun Chen, PhD, MD, an assistant professor of Pediatrics Research at the University of Tennessee Health Science Center (UTHSC), has received a five-year grant of $380,000 per year from the National Institutes of Health to continue his research aimed at developing a sepsis therapy. In his project titled “Targeting Siglec-9/E for Therapy of Sepsis,” Dr. Chen and his team have observed a key interaction at the molecular level that may help inhibit the progression of sepsis if targeted properly.
Patients who survive the initial “cytokine storm”—the first phase of sepsis where the immune system over responds to infections—either recover or enter an immunosuppressive state. But with more than 30 clinical trials focused on the initial cytokine storm phase having shown no benefit, the identification of additional druggable targets are urgently needed to effectively treat sepsis.
Since many pathogens utilize ligands—or molecules that bind to other molecules—for several receptors known as toll-like receptors (TLRs), Dr. Chen states that is likely that these ligands can cooperate to activate multiple TLRs during sepsis. This presumably explains why antagonists, chemical agents that interfere with physiological responses, that only target a single TLR, have failed to restrain TLR signaling; signaling can still proceed downstream from those TLRs that are not specifically blocked by the antagonist. Given this, it became crucial to identify novel molecules which target many TLRs simultaneously to provide effective sepsis therapy.
Through the use of animal models, Dr. Chen and his research team have observed a noteworthy interaction between two types of receptors: TLRs and a family of 14 sialic acid-binding lectin receptors known as Siglecs. In their research, Dr. Chen discovered that the receptor Siglec-E and the TLR4 receptor could play a key role in the progression of sepsis.
“Recently, we discovered extensive and direct interactions between these receptors,” Chen said. “We observed that the cells from Siglec-E deficient mice demonstrated increased responses to all TLR ligands (produced high level of cytokines) and that Siglec-E negatively regulates the activation of the ligand TLR4 by controlling its movement throughout the body, suggesting that Siglec-E may play an important role in TLR-related sepsis development. Targeting Siglec-E holds great promise as therapy for treatment of sepsis.”
By controlling the TLRs through Siglecs, this therapy would then be able to inhibit the production of cytokines, providing a novel therapy to a devastating illness, with the potential of reducing sepsis patient hospitalization and mortality.