According to the most recent CDC report, the incidence of sepsis in the United States is over 1.7 million each year, resulting in about 270,000 deaths and over $20 billion in healthcare costs. Sepsis results from infection of any microorganisms with bacteria being the most common. Pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharides (LPS) activate innate immune cells, macrophages in particular, as well as tissue resident cells such as vascular endothelial cells and cardiomyocytes through Toll-like receptors (TLRs). The activated macrophages engulf and kill the microbes. On the one hand, this process may reduce microbial load and limit the infection. On the other hand, these activated macrophages may elicit a stronger than desirable inflammatory response by secreting excess amounts of cytokines and oxidative molecules, acting on tissue resident cells and leading to tissue damage. Moreover, the damaged tissues release endogenous damage-associated molecular patterns (DAMPs), which further escalate the inflammatory cascade through binding to TLRs, particularly TLR2 and TLR4, on immune cells and tissue resident cells. This vicious cycle rapidly leads to multi-organ injury, and eventually death. The quick evolution and the complexity of the pathology of bacterial sepsis make it extremely difficult to treat. Current management still relies on source control, antibiotics, and organ support. Although inflammation plays a key detrimental role in the pathogenesis of septic shock, no anti-inflammatory approaches have been proved successful due to various reasons. In the past 10 years, we and collaborators 1) isolated a new single compound from Chinese herbs, determined its structure, and named it Sparstolonin B (SsnB); 2) characterized SsnB as a dual TLR2 and TLR4 antagonist; 3) discovered that SsnB antagonizes TLR2/4 by disrupting the interaction between TIRAP and MyD88, a unique key event in TLR2/4 signaling; 4) demonstrated that SsnB effectively inhibits inflammatory responses of multiple cell lines and primary cell types to both exogenous and endogenous TLR2/4 ligands; 5) showed that SsnB inhibits the hypoxia-induced cardiomyocyte inflammatory response and apoptosis in cell culture and in live heart slices; 6) reported that intraperitoneal administration of SsnB effectively reduced the death of LPS endotoxemic mice; and 7) in most recent preliminary study demonstrated that SsnB prolonged survival of male CD-1 mice using a cecal ligation and puncture (CLP) model. On the basis on these achievements, we are in a unique position to develop SsnB as a novel therapy for bacterial sepsis. Toward this goal, we propose in this STTR phase I project to establish the feasibility of clinical development. We propose two specific aims: SA1. To establish the effectiveness of SsnB in various mouse strains using the CLP model of bacterial sepsis; and SA2. To optimize the therapeutic regimen of SsnB to treat CLP-induced sepsis. We believe this safe and effective natural compound has the potential to reduce the mortality of bacterial sepsis and reduce healthcare and related costs tremendously.
Bacterial sepsis is a devastating condition that results in high mortality and huge healthcare cost. In the past 10 years, we discovered and mechanistically characterized a Chinese herb-derived compound, Sparstolonin B that selectively antagonize toll-like receptors 2 and 4 signaling. We propose in this STTR phase I project to establish the feasibility of clinical development of Sparstolonin B as a novel therapy for bacterial sepsis.