Cellular and molecular mechanisms of sepsis/septic shock
Sepsis, SIRS, septic shock and multi-organ failure are major clinical problems. Despite years of intensive research, there is still much that we do not know about the pathophysiology of these devastating diseases. Attempts at developing effective therapies for sepsis/septic shock and MODS have proven to be exceedingly difficult. This is due, in part, to our incomplete understanding of the cellular and mechanisms that mediate septic injury. We have made the novel observation that the macrophage class A scavenger receptor (SRA) plays a pivotal role in mediating the morbidity and mortality of sepsis/septic shock. This is a new, novel and previously unknown role for SRA. A successful completion to this research will substantially alter our understanding of the cellular and molecular mechanisms of sepsis. By way of example, it has been long postulated that the macrophage plays a prominent role in sepsis/septic shock, however, the precise mechanisms by which this occurs are still the subject of debate. The SRA receptor is found primarily on macrophages, therefore, our data will provide a mechanistic understanding of how a macrophage receptor, in this case SRA, mediates the pathophysiology of septic injury.
Innate immunity and myocardial dysfunction in sepsis
Myocardial dysfunction is a fatal complication of septic shock and is responsible for more than 20,000 deaths per year in the United States. It has been reported that 40% of patients with sepsis develop cardiac dysfunction and that in those patients with myocardial dysfunction, mortality ranges from 20% to 70%. Evidence points to a role for TLR mediated signaling in the regulation of cardiac function during sepsis/septic shock. Our data suggest that elements of innate immunity, i.e. TLR2 and TLR4, have opposing effects on cardiac function during CLP-induced sepsis. Importantly, we observed that either TLR2 priming or TLR4 deficiency activates the PI3K/Akt signaling pathway and that cardiac specific expression of caPI3K resulted in significant improvement of survival and attenuation of cardiac dysfunction in CLP sepsis, suggesting that the status of cardiac function during sepsis/septic shock determines the outcome of the disease. However, the cellular and molecular mechanisms associated with TLR modulation of cardiac function during sepsis/septic shock have not been elucidated. We are focused on defining the mechanisms by which TLRs differentially regulate cardiac function in response to sepsis. The results of this research will increase our basic science knowledge of how the innate immune response contributes to cardiac function in sepsis and, of potentially greater importance, how modulation of innate immunity induces cardioprotection during sepsis. The work proposed is also of practical significance because we have previously shown (Williams et al. J. Immunol. 172:449-454, 2004) that it is possible to pharmacologically up regulate PI3K/Akt activity in sepsis with subsequent amelioration of cardiac dysfunction and increased long term survival outcome.
Innate immune recognition and the fungal cell wall
Candida infections are among the most common fungal infections in ICU units. However, there is much that we do not know about the pathogenicity of Candida sepsis. We do know that fungal pathogens are recognized by the host innate immune system via genetically encoded receptors which interact with fungal cell wall macromolecules, such as glucan and mannan. Cell wall glucan is thought to be the primary fungal pathogen associated molecular pattern. Thus, the fungal cell wall plays a key role in the recognition and pathogenicity of fungal pathogens. Most of the current C. albicans cell wall models portray the cell wall as a relatively static barrier that does not substantially change. We have made the novel observation that the C. albicans cell wall is a highly adaptable and dynamic structure, which alters its structural and compositional phenotype in response to changing environmental conditions. We hypothesize that the C. albicans cell wall phenotype is critical to the recognition and response to the pathogen, and by extension its virulence. However, the precise phenotype(s) that are associated with pathogenicity have not been defined. To address this deficit in our knowledge we are defining which cell wall phenotypes are most characteristic of pathogenic Candida albicans.