Sepsis has a prevalence of 750,000 cases and claims more than 200,000 lives each year. Cardiovascular collapse induced by cardiac depression and profound vasodilatation represents a main feature of septic shock and contributes to its high mortality. While the current critical care therapy offers survival benefit, the septic mortality due to cardiac dysfunction remains high. Therefore, a better understanding of the molecular mechanisms that lead to cardiac dysfunction during septic shock is needed to further improve the care of patients with severe sepsis. Innate immune signaling such as those via Toll-like receptors (TLRs) and their signaling molecules MyD88 and Trif represents the first line of defense against microbial infection and play a role in sepsis, but their role in cardiac dysfunction and the underlying mechanisms during sepsis remain poorly defined. We have recently demonstrated that activation of TLR2 signaling inhibits cardiomyocyte (CM) function and that animals deficient in TLR2 have markedly improved cardiac function and survival in polymicrobial peritonitis sepsis. MyD88, but not Trif, is essential in polymicrobial sepsis-induced cardiac dysfunction and mortality. The complement system is also a part of innate immunity but its interaction with TLRs during sepsis is poorly understood. Our preliminary data have clearly demonstrated that TLR stimulation in vitro or polymicrobial sepsis in vivo specifically induces a robust complement factor B (cfB) expression in the heart, a key component of alternative pathway. Moreover, mice deficient in cfB have a significantly improved cardiac function and survival compared with wild-type (WT) mice during sepsis. The proposal is based on the following three hypotheses: 1) TLR2/4-MyD88 signaling, an important determinant in sepsis-induced cardiac dysfunction, mediates the specific myocardial cfB expression in sepsis, 2) cfB contributes to the sepsis-induced cardiac dysfunction via distinct intracellular mechanisms including impaired Ca2+ handling, mitochondrial dysfunction, and oxidative stress, and 3) genetic deletion or pharmacological inhibition of cfB can lead to improved cardiac function and better survival during polymicrobial sepsis.
In Specific Aim 1, we will determine the role of TLR2 and TLR4 in mediating cardiac cfB expression in sepsis.
In Specific Aim 2, we will delineate the role of MyD88 signaling in cfB expression and cardiac dysfunction in sepsis.
In Specific Aim 3, we will define the role of cfB in the pathogenesis of cardiac dysfunction in polymicrobial sepsis.
In Specific Aim 4, we will determine the efficacy of pharmacological cfB inhibition to protect against sepsis-induced cardiac dysfunction. Together these aims will further our understanding of 1) the complex interaction between TLR signaling and the complement system in the heart during sepsis, 2) the role of MyD88 signaling in septic cardiac dysfunction, 3) the critical role of cfB and alternative pathway in polymicrobial sepsis, and 4) the therapeutic efficacy of an anti-cfB antibody in a clinically relevant model of polymicrobial sepsis. We believe that such insights will serve as a foundation for the future development of novel therapeutic approaches to the clinical management of severe sepsis.

Public Health Relevance

Sepsis has a prevalence of 750,000 cases each year in the United States and claims more than 210,000 of lives. Myocardial dysfunction represents a main feature of severe sepsis and contributes to the high mortality. The current proposal is aimed to investigate role of the innate immune system in sepsis-induced cardiac dysfunction. This type of study may provide potential molecular targets for intervention in the clinical management of sepsis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Gong, Yu; Zou, Lin; Feng, Yan et al. (2014) Importance of Toll-like receptor 2 in mitochondrial dysfunction during polymicrobial sepsis. Anesthesiology 121:1236-47
Chen, Chan; Feng, Yan; Zou, Lin et al. (2014) Role of extracellular RNA and TLR3-Trif signaling in myocardial ischemia-reperfusion injury. J Am Heart Assoc 3:e000683
Zhang, Ming; Zou, Lin; Feng, Yan et al. (2014) Toll-like receptor 4 is essential to preserving cardiac function and survival in low-grade polymicrobial sepsis. Anesthesiology 121:1270-80
Feng, Yan; Zou, Lin; Chen, Chan et al. (2014) Role of cardiac- and myeloid-MyD88 signaling in endotoxin shock: a study with tissue-specific deletion models. Anesthesiology 121:1258-69
Zou, Lin; Feng, Yan; Li, Yan et al. (2013) Complement factor B is the downstream effector of TLRs and plays an important role in a mouse model of severe sepsis. J Immunol 191:5625-35