Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections

Inflammasomes are multi-protein complexes integrating pathogen-triggered signaling leading to the generation of pro-inflammatory cytokines including interleukin-18 (IL-18). Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections are associated with elevated IL-18, suggesting inflammasome activation. However, there is marked person-to-person variation in the inflammasome response to HCV and HIV. We hypothesized that host genetics may explain this variation. To test this, we analyzed the associations of plasma IL-18 levels and polymorphisms in 10 genes in the inflammasome cascade. About 1538 participants with active HIV and/or HCV infection in three ancestry groups are included. Samples were genotyped using the Illumina Omni 1-quad and Omni 2.5 arrays. Linear regression analyses were performed to test the association of variants with log IL-18 including HCV and HIV infection status, and HIV RNA in each ancestry group and then meta-analyzed. Eleven highly correlated single-nucleotide polymorphisms (r²=0.98–1) in the IL-18-BCO2 region were significantly associated with log IL-18; each T allele of rs80011693 confers a decrease of 0.06 log pg ml⁻¹ of IL-18 after adjusting for covariates (rs80011693; rs111311302 β=−0.06, P-value=2.7 × 10⁻⁴). In conclusion, genetic variation in IL-18 is associated with IL-18 production in response to HIV and HCV infection, and may explain variability in the inflammatory outcomes of chronic viral infections

Phenolic content and antioxidant activity in Lentinula edodes grown on eucalyptus biomass

Objective. To determine whether Lentinula edodes (L edodes) cultured on eucalyptus chips in the Ecuadorian highland generates antioxidant metabolites and anti-inflammatory effects.Methods. Total phenolic content was determined by the Folin-Ciocalteu reaction, the in vitro antioxidant activity of L edodes extracts was evaluated by the DPPH method and the in vivo anti-inflammatory activity was studied in mice. The chemical composition was studied by phytochemical screening and gas chromatography/mass spectrometry (GC/MS).Results. Total phenols were higher in extracts with increasingly high-water content. The antioxidant activity was robust and significantly strong in these extracts, suggesting the active metabolites are water-soluble. The anti-inflammation activity was significant in aqueous extracts only. Phytochemical screening indicated an overall similar composition to the literature reported earlier. GC/MS detected galactitol, trehalose, xylitol, phosphoric acid and octadecanoic acid among the most abundant metabolites.Conclusions. Cultivation on eucalyptus biomass at the Ecuadorian highlands retains the overall chemical composition, the phenolic content, antioxidant levels, and the in vivo anti-inflammatory activity of L edodes. The 11.3% content of trehalose observed is interesting for its capacity to control cellular stress damage.Key Words: inflammation, antioxidants, phenols, shiitake, Lentinula, phytotherapeutic

Asymptomatic HLA-A*02:01-Restricted Epitopes from Herpes Simplex Virus Glycoprotein B Preferentially Recall Polyfunctional CD8+ T Cells from Seropositive Asymptomatic Individuals and Protect HLA Transgenic Mice against Ocular Herpes

Evidence from C57BL/6 mice suggests that CD8(+) T cells, specific to the immunodominant HSV-1 glycoprotein B (gB) H-2(b)–restricted epitope (gB(498–505)), protect against ocular herpes infection and disease. However, the possible role of CD8(+) T cells, specific to HLA-restricted gB epitopes, in protective immunity seen in HSV-1–seropositive asymptomatic (ASYMP) healthy individuals (who have never had clinical herpes) remains to be determined. In this study, we used multiple prediction algorithms to identify 10 potential HLA-A*02:01–restricted CD8(+) T cell epitopes from the HSV-1 gB amino acid sequence. Six of these epitopes exhibited high-affinity binding to HLA-A*02:01 molecules. In 10 sequentially studied HLA-A*02:01–positive, HSV-1–seropositive ASYMP individuals, the most frequent, robust, and polyfunctional CD8(+) T cell responses, as assessed by a combination of tetramer, IFN-γ-ELISPOT, CFSE proliferation, CD107a/b cytotoxic degranulation, and multiplex cytokine assays, were directed mainly against epitopes gB(342–350) and gB(561–569). In contrast, in 10 HLA-A*02:01–positive, HSV-1–seropositive symptomatic (SYMP) individuals (with a history of numerous episodes of recurrent clinical herpes disease) frequent, but less robust, CD8(+) T cell responses were directed mainly against nonoverlapping epitopes (gB(183–191) and gB(441–449)). ASYMP individuals had a significantly higher proportion of HSV-gB–specific CD8(+) T cells expressing CD107a/b degranulation marker and producing effector cytokines IL-2, IFN-γ, and TNF-α than did SYMP individuals. Moreover, immunization of a novel herpes-susceptible HLA-A*02:01 transgenic mouse model with ASYMP epitopes, but not with SYMP epitopes, induced strong CD8(+) T cell–dependent protective immunity against ocular herpes infection and disease. These findings should guide the development of a safe and effective T cell–based herpes vaccine