Association of toll-like receptor 3 polymorphism with chronic hepatitis B

Abstract

Background: Previous studies in an experimental model of rabies showed neuronal process degeneration in association with severe clinical disease. Cultured adult rat dorsal root ganglion (DRG) neurons infected with CVS-11 strain of rabies virus (RABV) showed axonal swellings and immunostaining for 4-hydroxy-2-nonenal (4-HNE) indicating evidence of lipid peroxidation associated with oxidative stress and reduced axonal growth versus mock-infection. We have demonstrated that RABV induces alterations in a variety of mitochondrial parameters, including an increase in reactive oxygen species production after addition of substrates or inhibitors and increased activity of Complex I of the respiratory chain vs. mock infection. We have hypothesized that a RABV protein targets the mitochondria and triggers its dysfunction. Methods & Materials: We used immunocytochemistry, Western immunoblotting, immunoprecipation and proteomics methods to study RABV-and mock-infection of mouse neuroblastoma (MNA) cells. Results: Immunocytochemistry of CVS-infected cells after 72 h post-infection showed strong colocalization of mitochondria with the RABV phosphoprotein (P). Extracts of MNA cells from the mitochondrial subcellular fractionation were analyzed with a proteomics approach. We identified peptides belonging to the RABV P, glycoprotein (G), and nucleocapsid protein (N) with 67% of protein coverage at 95% confidence for P vs. N (8%) and G (6%). Our data show that the majority of viral peptides (79%) belong to P vs. N (13%) or G (8%), indicating that the extract was highly enriched with P. P was detected by immunoblotting in RABV-infected purified mitochondrial extracts and in Complex I immunoprecipitates from the extracts, but not in mock-infected extracts. A plasmid expressing P in cells produced an increase in Complex I activity, whereas expression of other RABV proteins did not. We have analyzed a variety of recombinant plasmids encoding various segments of the P gene. Expression of a peptide from amino acid 139 to 172 produced an increase in Complex I activity similar to expression of the entire P protein, whereas most peptides that did not contain this region did not produce increased activity of Complex I. Conclusion: The RABV phosphoprotein is present in mitochondria and may interact with Complex I causing mitochondrial dysfunction, oxidative stress, neuronal process degeneration, and severe clinical disease in experimental rabies.

Insights into the toll‐like receptors in sexually transmitted infections

“…Thus, it might have a protective role in reducing the risk of a CHB infection. 100 Chihab et al reported the role of TLR9 SNPs in the anti-viral immune response. SNP of TLT9 (rs5743836; AA, AG to GG) and rs187084 (AA) studied in CHB patients, and a significant association between HBV progression and TLR9 polymorphism rs187084 (AA) was found 101 (Table 2).…”

“…Another study reported that TLR3 SNP (1377CC and TT) increases a 2.4 fold higher risk of a CHB infection than (1377CT) polymorphism. Thus, it might have a protective role in reducing the risk of a CHB infection 100 . Chihab et al reported the role of TLR9 SNPs in the anti‐viral immune response.…”