The systemic inflammatory response induced by gram-positive bacteria is associated with considerable morbidity and mortality attributable to refractory hypotension, cardiac dysfunction and multiorgan failure. Despite the potentially important role that TNF-a, lL-1b and NO may play in producing cardiac decompensation in human septic shock, little is known with regard to mechanism(s) by which bacterial pathogens induce their expression in the heart. A major advance in the understanding of the early events in gram-positive bacterial signaling has been the identification of Toll-like receptors (TLRs). Recent studies suggest that TLR2 may be a pattern recognition receptor that binds gram-positive bacteria and their cell wall components. In addition, TLR2 is an effective signaling molecule that activates NF-kB, leading to cytokine production. The long-term objectives of this research initiative are not only to delineate the molecular pathogenesis of gram-positive septic shock, but also to develop strategies to prevent or attenuate the untoward effects of sepsis in the heart. Toward this end, the immediate specific objective of this application will be to delineate the role of TLR2 in the pathogenesis of myocardial dysfunction associated with gram-positive septic shock. Two closely interrelated hypotheses will be tested: first, signaling via TLR-2 is responsible, at least in part, for the induction of proinflammatory mediators associated with myocardial inflammation following infection with the gram-positive bacterium Staphylococcus aureus; second, TLR2 is responsible, at least in part, for the development of or S. aureus-induced left ventricular contractile dysfunction. These hypotheses will be tested in three Specific Aims.
Specific Aim 1 will determine whether TLR2 mediates the inflammatory response induced by gram-positive bacteria in the heart.
Specific Aim 2 will determine whether TLR2 mediates the cardiac response following infection with S. aureus.
Specific Aim 3 will determine whether immunotherapeutic interventions designed to interdict signaling via TLR2 prevent and/or modify left ventricular dysfunction in gram-positive septic shock. These studies will provide definitive new information with respect to the mechanisms responsible for the deleterious effects of gram-positive sepsis on cardiac function and structure.
|Dong, Jian-Wen; Vallejo, Jesus G; Tzeng, Huei-Ping et al. (2010) Innate immunity mediates myocardial preconditioning through Toll-like receptor 2 and TIRAP-dependent signaling pathways. Am J Physiol Heart Circ Physiol 298:H1079-87
|Tzeng, Huei-Ping; Fan, Jinping; Vallejo, Jesus G et al. (2008) Negative inotropic effects of high-mobility group box 1 protein in isolated contracting cardiac myocytes. Am J Physiol Heart Circ Physiol 294:H1490-6
|Hardarson, Hordur S; Baker, J Scott; Yang, Zhao et al. (2007) Toll-like receptor 3 is an essential component of the innate stress response in virus-induced cardiac injury. Am J Physiol Heart Circ Physiol 292:H251-8
|Sakata, Yasushi; Dong, Jian-Wen; Vallejo, Jesus G et al. (2007) Toll-like receptor 2 modulates left ventricular function following ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 292:H503-9
|Vallejo, Jesus G; Nemoto, Shintaro; Ishiyama, Masakuni et al. (2005) Functional significance of inflammatory mediators in a murine model of resuscitated hemorrhagic shock. Am J Physiol Heart Circ Physiol 288:H1272-7
|Knuefermann, Pascal; Sakata, Yasushi; Baker, J Scott et al. (2004) Toll-like receptor 2 mediates Staphylococcus aureus-induced myocardial dysfunction and cytokine production in the heart. Circulation 110:3693-8
|Nemoto, Shintaro; Vallejo, Jesus G; Knuefermann, Pascal et al. (2002) Escherichia coli LPS-induced LV dysfunction: role of toll-like receptor-4 in the adult heart. Am J Physiol Heart Circ Physiol 282:H2316-23