Cell Wall-Mediated Neuronal Damage in Early Sepsis

Abstract

Neuronal dysfunction can occur in the course of sepsis without meningitis. Sepsis-associated neuronal damage (SAND) was observed in the hippocampus within hours in experimental pneumococcal bacteremia. Intravascular challenge with purified bacterial cell wall recapitulated SAND. SAND persisted in PAFr ؊/؊ mice but was partially mitigated in mice lacking cell wall recognition proteins TLR2 and Nod2 and in mice overexpressing interleukin-10 (IL-10) in macrophages. Thus, cell wall drives SAND through IL-10-repressible inflammatory events. Treatment with CDP-choline ameliorated SAND, suggesting that it may be an effective adjunctive therapy to increase survival and reduce organ damage in sepsis.During sepsis, organ dysfunction occurs independently of invasion of the organ by circulating bacteria. In the case of early encephalopathy, which occurs in up to 70% of septic patients in intensive care units (42), the pathogenesis is unclear, as it precedes peripheral organ dysfunction and bacterial invasion of the central nervous system (CNS). It is assumed that intravascular inflammation deleteriously affects neuronal function at a distance (i.e., across the blood-brain barrier) since the vascular compartment and the CNS communicate bidirectionally during infection (38). For example, production of the late mediator of sepsis HMGB1 is inhibited by acetylcholine released from the vagus nerve in response to systemic lipopolysaccharide (LPS) (51). Conversely, intraperitoneal lipopolysaccharide induces intracerebral expression of TLR2 (21), interleukin-6 (IL-6) (50), and IL-1␤ (49); activates microglia in the dentate gyrus; decreases hippocampal neurogenesis (29); and causes alteration of neuronal function (18). Greater understanding of how these effects are related to neurological damage is required for the design of therapeutic interventions.Streptococcus pneumoniae is a gram-positive bacterium reported to have the highest case fatality rate (14.5%) of all organisms causing pediatric sepsis (52). Patients are noted for devastating neurological sequelae even in the absence of meningitis (39). However, the mechanism of neuronal injury has been studied only in the context of meningitis, where the presence of a threshold of Ͼ10 5 pneumococci/ml in the subarachnoid space induces strong inflammation, a response that is recapitulated by purified pneumococcal cell wall (47, 48). Neuronal damage during meningitis arises from a combination of direct cytotoxicity of bacterial components and activation of the host response (3,19,20,25,35). Apoptosis of neurons in the dentate gyrus of the hippocampus is particularly prominent both in animal models (3-5, 43) and at human autopsy (31), and detailed analysis has indicated that it arises by both caspase-dependent and -independent pathways. However, the effect of pneumococcal bacteremia on neurons remains unknown. While studying the development of meningitis during sepsis in mice, we observed that neuronal damage was evident prior to entry of bacteria into the subarachnoid space. Although the...

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

“…Accordingly, engagement of additional TLR2-independent pattern-recognition receptor pathways, such as NOD-like receptors, β-integrins, C-type lectins, inflammasomes, or other innate pathways [46][47][48][49], may contribute to S. epidermidis bacteremia-induced brain injury, especially at high concentrations of bacteria, and should be characterized in future studies. Consistent with these observations, Streptococcus pneumoniae induced neuronal injury within hours of bacteremia in adult mice, preceding detectable CNS penetration that was only partially mitigated in TLR2-deficient animals [9].…”

“…In summary, our study provides the first direct evidence that the consequences of transient bacteremia due to S. epidermidis, and possibly other bacterial pathogens [9], in early life may be substantially more severe than commonly appreciated and may include both TLR2-dependent and TLR2-independent brain inflammation and injury. These observations may indicate novel approaches to reduce bacteremia-associated brain injury in early life, including development of targeted antiinfective/ antiinflammatory agents designed to accompany conventional antibiotics, thereby potentially enhancing bacterial clearance while reducing brain injury.…”

“…However, several steps in this process remain to be further characterized in future studies, including the cellular source of inflammatory mediators in the brain, such as CCL2, and whether dead bacteria or bacterial products, such as the TLR2 agonist bacterial lipopeptides, spill into the CNS. Notably, it has been previously shown that S. pneumoniae bacterial cell wall debris can trigger preterm brain injury [9].…”

“…In animal models, inflammation, such as that caused by systemic administration of lipopolysaccharide, induces cerebral white-matter injury similar to that seen in preterm human infants [3,7,8]. Fewer studies have addressed the ability of live bacteria to induce brain injury [9], and to our knowledge none of these have modeled this in newborn animals that express distinct immune function and susceptibility to brain injury [2,10].…”

Sepsis-Associated Encephalopathy: A Magnetic Resonance Imaging and Spectroscopy Study

“…Creatine levels are also valuable because they are related to cerebral energy metabolism (Sibtain et al, 2007), which would be expected to be perturbed because of the mitochondrial dysfunction in sepsis (d 'Avila et al, 2008). Finally, NAA is recognized as a marker of neuronal damage (Ross and Bluml, 2001) and decreases of its levels have been associated with neuronal loss (Birken and Oldendorf, 1989;Moffett et al, 2007;Vuori et al, 2004) in various pathologies including sepsis (Orihuela et al, 2006).…”