Biological and Clinical Significance of Endotoxemia in the Course of Hepatitis C Virus Infection

Abstract

Endotoxins or lipopolysaccharides (LPS), major components of the cell wall of Gram-negative bacteria, once released from the bacterial outer membrane bind to specific receptors and, in particular, to a membrane-bound receptor, the CD14 (mCD14) and the toll-like receptor 4 present on monocytes/ macrophages. In turn, LPS-activated monocytes/ macrophages release in the host tissue an array of so-called proinflammatory cytokines and, among them, Tumor Necrosis Factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8 and IL-12 are the major mediators. Before therapy (To) and at the end of 6-month interferon (IFN)-alpha/Ribavirin (RIB) treatment (T6), circulating endotoxin levels were measured in responder and non responder HCV+ patients. At T0, 57% of the non responders were endotoxin-positive and had, on average, 54 pg/ml of plasma LPS while in 50% of the responder patients endotoxin were found with an average of 29 pg/ml. At T6, in responders LPS were no longer detectable, while in 42% of the non responders LPS were found (average levels 45 pg/ml). In terms of serum cytokine concentration, at T6 IFN-gamma levels when compared to those detected at T0 were increased in both endotoxin-positive and endotoxin-negative patients. However, at T6 IL-10 concentration was significantly increased only in the group of endotoxin-negative subjects (responder patients), in comparison to T0 values. The origin of endotoxemia in HCV+ patients seems to be multifactorial, likely depending on impaired phagocytic functions and reduced T-cell mediated antibacterial activity. In these patients, however, one cannot exclude the passage of LPS from the gut flora to the blood stream, owing a condition of altered intestinal permeability. At the same time, a less efficient detoxification of enteric bacterial antigens at the hepatic level should be taken into consideration. Finally, novel therapeutic attempts aimed to neutralize LPS in the host are discussed.

Viral and Host Factors Induce Macrophage Activation and Loss of Toll-Like Receptor Tolerance in Chronic HCV Infection

“…Here we showed that HCV core protein, a TLR2 ligand (6,7), activated and induced tolerance in normal but not in cHCV monocytes. We also identified increased levels of endotoxin, a TLR4 ligand, in plasma of patients with cHCV infection, which is in agreement with previous reports (26). It is noteworthy that cHCV patients included in our study did not exhibit liver cirrhosis, yet low levels of endotoxemia occurred in patients with cHCV without advanced liver disease.…”

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

“…Indeed, LPS has been shown to accelerate liver fibrosis through TLR-4 signaling on Kupffer cells following membrane binding via LPS binding protein (LBP) and CD14 (121). These events lead to the generation of superoxide and the release of proinflammatory and profibrogenic cytokines such as TNF-␣, IL-1, IL-6, and IL-12, all of which induce liver damage (122,123). Consistent with these findings, microbial translocation has been shown to contribute to liver disease in several clinical settings, such as alcoholic liver disease (124,125) and other enteric processes (126)(127)(128).…”

HIV infection and the gastrointestinal immune system

“…93 Indeed, damage to the GI tract has been observed to result in the luminal translocation of microbial products such as lipopolysaccharide (LPS), peptidoglycan, bacterial CpG DNA, flagellae, and viral genomes: molecules that can directly stimulate the innate immune system through Toll-like receptors. This process, termed microbial translocation, has been observed in numerous diseases, including ulcerative colitis and Crohn's disease, 94 graft-versus-host disease, 95 and hepatitis 96 as well as after abdominal surgeries 97 and in pancreatitis. 98 Importantly, in many of these situations the microbial translocation is associated not only with local inflammation of the gut microenvironment but also with systemic immune activation.…”