Pathogenesis of liver involvement during dengue viral infections 學生 : 鄧喬方

The dengue virus can infect many cell types and cause diverse clinical and pathological effects. Both clinical and experimental observations suggest that there is liver involvement during dengue infection. Liver dysfunction could be a direct viral effect on liver cells or be an adverse consequence of dysregulated host immune responses against the virus. (Seneviratne et al., 2006)

To infect cells, dengue viruses need first to attach to host cell surfaces. DC-specific ICAM-3 grabbing non-integrin (DC-SIGN) was used by the virus to gain entry into monocyte-derived dendritic cells. (Navarro-Sanchez et al., 2003)

Heparan sulphate (HS) is involved in entry of all four dengue serotypes into HepG2 cells Several viruses are able to bind heparan sulphate (HS), a ubiquitous glycosaminoglycan found on the surface of cells. HS may act directly as a virus receptor or serve as a low-affinity virus-binding site, allowing the virus to accumulate before transfer to its high-affinity receptor. (Chen et al., 1997; Germi et al., 2002)

37-kilodalton/67-kilodalton high-affinity laminin receptor as a dengue virus serotype 1 receptor The DEN-1 virus used the 37/67 high-affinity laminin receptor to enter liver cells. Laminin receptor binding appeared to occur both directly or via HS-dependent interactions. (Thepparit and Smith, 2004)

GRP 78 (BiP) as a liver cell expressed receptor element for dengue virus serotype 2 Glucose regulated protein 78 (GRP78) was used by DEN-2 virus to gain entry into HepG2 cells. (Jindadamrongwech et al., 2004)

HepG2/Huh7 cell binding of DEN-1 and DEN-2 was found to be non-saturable There is a degree of cooperation in dengue virus binding onto liver cells. The binding of one virus to a liver cell serves to facilitate binding of further virus particles. It does this is by inducing conformational changes in cell surface binding molecules. (Suksanpaisan and Smith, 2003; Hilgard and Stockert, 2000)

Following dengue infection, cellular apoptosis in the liver has been seen both in vivo and in vitro. (Couvelard et al., 1999; Marianneau et al., 1996, 1997)

Correlation between DEN-2 infection and upregulated RANTES gene expression in liver cells has been shown in vitro RANTES (regulated upon activation, normal T cell expressed and secreted), a CC chemokine has chemotactic activity for T cells, monocytes, natural killer cells and eosinophils. (Lin et al., 2000)

Activation of the transcription factor NF-  B has been implicated in the induction of apoptosis NF-  B decoys were able to inhibit HepG2 apoptosis, further pointing to the important role played by the NF-  B pathway in this process. (Marianneau et al., 1997)

Dengue virus-induced TRAIL expression has been suggested to be partly responsible for causing apoptosis TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) DEN-2 infection was shown to cause TRAIL promotor activation, whereas a proteosome inhibitor and TRAIL antibody were able to inhibit DEN-2-induced apoptosis. (Matsuda et al., 2005)

Induction of apoptosis in liver cells is mediated by a non-p53 regulated pathway p53 may play a role in restricting the level of viral progeny to below a critical level at which apoptosis is triggered. 90% of Hep3B cells undergoing apoptosis compared to only 20% of HepG2 cells at day 5 post infection. Viral progeny released from the p53 null cell line (Hep3B) were nine-fold higher per attached cell than from the p53 wild type cell line (HepG2). (Thongtan et al., 2004)