lactoferrin and Epstein-Barr-Virus-Infections

Epstein-Barr virus (EBV) infection contributes to tumorigenesis of various human malignancies including nasopharyngeal carcinoma (NPC). EBV triggers innate immune and inflammatory responses partly through Toll-like receptor (TLR) signaling. Lactoferrin (LF), with its anti-inflammatory properties, is an important component of the innate immune system. We previously reported that LF protects human B lymphocytes from EBV infection by its ability to bind to the EBV receptor CD21, but whether LF can suppress EBV-induced inflammation is unclear. Here, we report that LF reduced synthesis of IL-8 and monocyte chemoattractant protein-1 (MCP-1) induced by EBV in macrophages via its suppression of NF-κB activity. LF interacted with TLR2 and interfered with EBV-triggered TLR2-NF-κB activation. LF inhibited the ability of TLR9 to recognize dsDNA by binding to its co-receptor CD14, which blocked the interaction between CD14 and TLR9. EBV-induced inflammation was thus aggravated in the presence of CD14. In addition, LF expression levels were significantly downregulated in NPC specimens, and correlated inversely with IL-8 and MCP-1 expression. These findings suggest that LF may suppress the EBV-induced inflammatory response through interfering with the activation of TLR2 and TLR9.

Topics: Chemokine CCL2; Epstein-Barr Virus Infections; Female; HEK293 Cells; Herpesvirus 4, Human; Host-Pathogen Interactions; Humans; Interleukin-8; Lactoferrin; Lipopolysaccharide Receptors; Macrophages; Male; Middle Aged; NF-kappa B; Toll-Like Receptor 2; Toll-Like Receptor 9; Up-Regulation

Lactoferrin (LF) is a multifunctional glycoprotein that plays an important role in native immune defense against infections, including human herpetic viruses, such as cytomegalovirus and herpes simplex virus types 1 and 2. However, its anti-Epstein-Barr virus (EBV, a γ-herpesvirus) function has not been reported in the literature. EBV is widespread in all human populations and is believed to be linked to tumorigenesis, such as lymphomas and nasopharyngeal carcinoma (NPC). We previously reported that LF expressed a significantly lower level in NPC tissues and was a likely tumor suppressor. Since EBV infection is a major carcinogen of NPC development, we investigated the effect of LF on EBV infection and found that LF could protect human primary B lymphocytes and nasopharyngeal epithelial cells from EBV infection, but had no effect on EBV genome DNA replication. LF prevented EBV infection of primary B cells mediated by its direct binding to the EBV receptor (CD21) on the B-cell surface. Tissue array immunohistochemistry revealed that LF expression was significantly downregulated in NPC specimens, in which high EBV viral capsid antigen-IgA levels were observed. These data suggest that LF may inhibit EBV infection and that its downregulation could contribute to NPC development.

Topics: Antigens, Viral; B-Lymphocytes; Capsid Proteins; Carcinoma; Cell Line, Tumor; Cells, Cultured; DNA Replication; DNA, Viral; Epithelial Cells; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Immunoglobulin A; Lactoferrin; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Nasopharynx; Virus Replication

Bacterial samples were obtained from the tonsillar surfaces of seven patients (four males, three females; median age 18 years, range 15 to 21 years) suffering from acute infectious mononucleosis with concomitant pharyngotonsillitis, and from five healthy controls. By using gold-labelled antiserum to human lysozyme and lactoferrin, micro-organisms on the tonsillar surfaces coated with these antibacterial substances could be identified by tracing the gold particles in the transmission electron microscope. In healthy individuals, most of the bacteria were coated with lysozyme and significantly more bacteria were coated with lysozyme than with lactoferrin (p < 0.01). In patients there was a non-significant reduction in lysozyme-coating of the bacteria, whereas lactoferrin-coating was significantly increased (p < 0.01). Changes in the lysozyme and/or lactoferrin coating of the tonsillar surface bacteria on the palatine tonsils during infectious mononucleosis cannot explain the tendency to immense local bacterial colonization with commensals and proneness to bacterial penetration into the epithelial cells.

Topics: Adolescent; Adult; Bacteria; Bacterial Infections; Epstein-Barr Virus Infections; Female; Humans; Immunohistochemistry; Lactoferrin; Male; Muramidase; Palatine Tonsil; Statistics, Nonparametric; Tonsillitis