In vitro and in vivo data now indicate that the EPS is a major virulence factor, capable of triggering the proinflammatory cytokine machinery and inducing mortality of fish. Streptococcus iniae EPS might therefore be considered to be responsible for sepsis and death just as lipopolysaccharide

is for Gram-negative pathogens. Current opinion perceives sepsis as the consequence of the excessive activation of the innate immune system through Toll-like receptors, ensuing in an uncontrolled release of multiple proinflammatory and anti-inflammatory cytokines that are largely responsible for the experimental and clinical symptoms of sepsis and septic shock (Bhakdi et al., 1991; Anderson et al., 1992; Bone, 1993; Cavaillon, 1995; Wenzel et al., 1996; Medzhitov & Janeway, 1997a, b; GSK126 solubility dmso Gao et al., 1999; Opal & Cohen, 1999; Sriskandan & Cohen, 1999; Ashare et al., 2005; Bozza et al., 2007). Although heterogeneous bacterial components [including bacterial wall components, peptidoglycan, lipoteichoic acid (LTA) and bacterial DNA (Heumann et al., 1994; Mattsson et al., 1994; de Kimpe et al., 1995; Timmerman et al., 1995; Vallejo et al., 1996; Sparwasser et al., 1997; Kengatharan et al., 1998; Gao et al., 1999; Opal & Cross, 1999)], commonly termed ‘pathogen-associated molecular pattern’ molecules (Medzhitov & Janeway, 1997a, b) have been implicated as initiating

these responses, it is widely accepted that, in Gram-negative bacterial sepsis, the pathophysiology basically involves an early and excessive release Trichostatin A purchase of lipopolysaccharide (LPS)-induced cytokines (Suffredini et al., 1989; Danner et al., 1991). It is also believed that, among the various cytokines, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 are the pivotal factors, mediating reactions associated with clinical deterioration, multiorgan system failure and death (Waage et al., 1991; Anderson et al., 1992; Beutler

& Grau, 1993; Bone, 1993, 1994; Casey et al., 1993; Muller-Alouf et al., 1994; Wenzel et al., 1996; Silverstein et al., 1997; Okusawa et al., 1998; Cohen & Abraham, 1999). Unlike the pathophysiology of shock caused by Gram-negative bacteria, which has been extensively investigated, comparatively little is known about the pathogenesis of the sepsis and shock induced by Gram-positive pathogens Pyruvate dehydrogenase lipoamide kinase isozyme 1 and, despite the fact that several Gram-positive bacterial components have been shown to trigger cytokine release by monocytes (Bone, 1993, 1994; Heumann et al., 1994; Mattsson et al., 1994; Timmerman et al., 1995; Vallejo et al., 1996; Kengatharan et al., 1998), a common pattern of bioactive molecules has not been defined. The conviction that LTA is the unequivocal counterpart of LPS in terms of pathogenesis of Gram-positive bacteria (Ginsburg, 2002) is also wavering (Nealon & Mattingly, 1985; Bhakdi et al., 1991; Vallejo et al., 1996; Han et al., 2003). In some instances (i.e.