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Fulminant hepatic failure (FHF) is a lethal manifestation of hepatitis A virus (HAV) infection, whose underlying mechanisms are poorly understood. We aimed to evaluate the importance of the modulation of the RANTES‐chemokine receptor type 5 (CCR5) signaling axis and its immunomodulatory effects in directing hepatitis A disease pathogenesis using an in silico, in vitro and patient cohort‐based approach. In silico interaction studies were performed using computation approaches with suitable software. Differential expression of relevant cytokines and immune cell markers were studied using real‐time quantitative reverse transcription PCR (qRT‐PCR), enzyme‐linked immunosorbent assay, and flow‐cytometry‐based methods. In the HepG2 cell line, we studied inflammatory responses and susceptibility to HAV infection following RANTES stimulation and antibody blockade of CCR5. The HAV‐VP3 region exhibited high interaction in CCR5: HAV complexes. RANTES levels were significantly increased in FHF cases. Reduced monocyte and T‐cell activation were observed in FHF cases. RANTES expression inversely correlated with viremia but positively correlated with proinflammatory responses. Hyper Th1‐biased immune responses, marked by high interleukin (IL)‐12/IL‐10 ratio were observed in FHF cases, which were also characterized by upregulated tumor necrosis factor‐alpha (TNF‐α) expression and reduced interferon‐gamma expression. In vitro, RANTES was protective against HAV infection but resulted in upregulated TNF‐α expression. Although viral load increased upon the regulation of inflammatory responses by CCR5 blocking, it was still significantly lower compared to control HAV‐infected cells. Our study suggests the importance of RANTES‐CCR5 signaling and linked‐immunomodulation in HAV disease pathogenesis, as well as highlights the utility of CCR5 antagonists as a risk‐reduction strategy in FHF patients. Our findings, therefore, have important implications for the management of high‐risk HAV infections. Highlights: Hepatitis A virus infection mediated significant RANTES expression in patients.Fulminant patients exhibited altered RANTES‐linked Th1‐biased immunomodulation.Supportive correlations were observed between immunomodulation and outcome.Immune responses were studied in RANTES‐stimulated, HAV‐infected HepG2 cell line.Inflammatory outcomes of protective RANTES could be regulated by CCR5 blocking. [ABSTRACT FROM AUTHOR]

[Display omitted] • The germline variants analysis from alcohol metabolism pathway genes obtained a significant variant in the ALDH1L2 gene (rs199841702) found to associate with alcoholic liver disease. • Most of the available online in-silico Pathogenicity prediction tools predicted ALDH1L2 (c.337C > G, p.Pro113Ala) gene variant as 'deleterious' and 'pathogenic'. • The presence of the GC genotype in ALDH1L2 (rs19984170)polymorphism may indicate an increased risk of developing ALD. The pathogenetic events of liver disease are seemingly determined by factors linked to ethanol metabolism. The variations in genes encoding enzymes of the ethanol metabolic pathway can influence exposure to alcohol and thus may act as risk factors for the development of liver disease. The present study aimed to understand the genetic aspect of germline variations in ethanol metabolic pathway genes in two major categories of liver disease i.e. ALD and NAFLD. Targeted Re-sequencing was performed in the two disease categories along with healthy control followed by an assessment and evaluation of the variants in a case vs control manner. The pathogenicity prediction was evaluated using SIFT, PolyPhen, PROVEN, LRT, CADD, FATHMM, EIGEN, REVEL and VarSome, while MD simulation of a novel significant variant was performed using the GROMACS 5.1.4 package. The annotation of targeted re-sequencing results revealed 2172 variants in different locations of the genes. Upon recurrent assessment predominantly focusing on exonic missense variants from these genes of the alcohol metabolism pathway, the ALDH1L2 [c.337C > G, p.Pro113Ala, (rs199841702)] variant was found highly significant with comprehensive results. The amino acid substitution tool that predicted protein stability due to a point mutation showed a decrease in stability. The genotyping distribution of the identified novel variant in the population revealed that heterozygosity is significantly distributed in ALD patients. However, the predominant association between the inherited variant and the cause of developing disease needs further robust study. [ABSTRACT FROM AUTHOR]