Chronic hepatitis C virus (HCV) infection is a leading cause of liver disease. Liver inflammation underlies infection-induced fibrosis, cirrhosis and liver cancer but the processes that promote hepatic inflammation by HCV are not defined. We provide a systems biology analysis with multiple lines of evidence to indicate that interleukin-1β (IL-1β) production by intrahepatic macrophages confers liver inflammation through HCV-induced inflammasome signaling. Chronic hepatitis C patients exhibited elevated levels of serum IL-1β compared to healthy controls. Immunohistochemical analysis of healthy control and chronic hepatitis C liver sections revealed that Kupffer cells, resident hepatic macrophages, are the primary cellular source of hepatic IL-1β during HCV infection. Accordingly, we found that both blood monocyte-derived primary human macrophages, and Kupffer cells recovered from normal donor liver, produce IL-1β after HCV exposure. Using the THP-1 macrophage cell-culture model, we found that HCV drives a rapid but transient caspase-1 activation to stimulate IL-1β secretion. HCV can enter macrophages through non-CD81 mediated phagocytic uptake that is independent of productive infection. Viral RNA triggers MyD88-mediated TLR7 signaling to induce IL-1β mRNA expression. HCV uptake concomitantly induces a potassium efflux that activates the NLRP3 inflammasome for IL-1β processing and secretion. RNA sequencing analysis comparing THP1 cells and chronic hepatitis C patient liver demonstrates that viral engagement of the NLRP3 inflammasome stimulates IL-1β production to drive proinflammatory cytokine, chemokine, and immune-regulatory gene expression networks linked with HCV disease severity. These studies identify intrahepatic IL-1β production as a central feature of liver inflammation during HCV infection. Thus, strategies to suppress NLRP3 or IL-1β activity could offer therapeutic actions to reduce hepatic inflammation and mitigate disease.

Please cite this paper as: Papic et al. (2011) Liver involvement during influenza infection: perspective on the 2009 influenza pandemic. Influenza and Other Respiratory Viruses 6(3), e2–e5.Elevation of liver transaminase levels is a frequent observation during systemic infections. The aim of our study was to investigate liver damage during pandemic 2009 influenza A/H1N1 infection in comparison with seasonal influenza. Serum levels of aspartate aminotransferase, alanine aminotransferase, and gamma‐glutamyl transpeptidase (GGT) were significantly higher in patients with pandemic influenza compared to seasonal influenza, which was strongly correlated with hypoxia. Moreover, a positive correlation between C‐reactive protein and serum GGT, alkaline phosphatase, and lactate dehydrogenase was noticed. Our findings support the hypothesis that the pandemic 2009 influenza A/H1N1 is an illness with a significant immune response to infection leading to hepatocellular injury.

We describe the first report of RNA sequencing of 5' capped (Pol II) RNAs isolated from acutely hepatitis C virus (HCV) infected Huh 7.5 cells that provides a general approach to identifying differentially expressed annotated and unannotated genes that participate in viral-host interactions. We identified 100, 684, and 1,844 significantly differentially expressed annotated genes in acutely infected proliferative Huh 7.5 cells at 6, 48, and 72 hours, respectively (fold change ≥ 1.5 and Bonferroni adjusted p-values < 0.05). Most of the differentially expressed genes (>80%) and biological pathways (such as adipocytokine, Notch, Hedgehog and NOD-like receptor signaling) were not identified by previous gene array studies. These genes are critical components of host immune, inflammatory and oncogenic pathways and provide new information regarding changes that may benefit the virus or mediate HCV induced pathology. RNAi knockdown studies of newly identified highly upregulated FUT1 and KLHDC7B genes provide evidence that their gene products regulate and facilitate HCV replication in hepatocytes. Our approach also identified novel Pol II unannotated transcripts that were upregulated. Results further identify new pathways that regulate HCV replication in hepatocytes and suggest that our approach will have general applications in studying viral-host interactions in model systems and clinical biospecimens.

Background Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease associated with systemic changes in immune response which might be associated with COVID-19 severity. The aim of this study was to investigate the impact of NAFLD on COVID-19 severity and outcomes. Methods A prospective observational study included consecutively hospitalized adult patients with severe COVID-19 between March and June 2021. Patients were screened for fatty liver by ultrasound and subsequently diagnosed with NAFLD. Patients were daily followed until discharge, and demographic, clinical and laboratory data were collected and correlated to clinical outcomes. Results Of the 216 patients included, 120 (55.5%) had NAFLD. NAFLD group had higher C-reactive protein (84.7 mg/L, IQR 38.6-129.8 vs 66.9, 32.2-97.3, p=0.0340), Interleukin-6 (49.19 ng/L, IQR 22.66-92.04 vs 13.22, IQR 5.29-39.75, p&lt;0.0001), aspartate aminotransferase (58 IU/L, IQR 40-81 vs 46, IQR 29-82, p=0.0123), alanine aminotransferase (51 IU/L, IQR 32-73 vs 40, IQR 23-69, p=0.0345) and lactate dehydrogenase (391 IU/L, IQR 285-483 vs 324, IQR 247-411, p= 0.0027). The patients with NAFLD had higher disease severity assessed by seven-category ordinal scale, more frequently required HFNC or NIV (26, 21.66% vs 10, 10.42%, p=0.0289), had longer duration of hospitalization (10, IQR 8-15 vs. 9, IQR 6-12 days, p=0.0018) and pulmonary thromboembolism (26.66% vs. 13.54%, p=0.0191). On multivariable analyses, NAFLD was negatively associated with time to recovery (HR 0.64, 95%CI 0.48-0.86) and was identified as a risk factor for pulmonary thrombosis (OR 2.15, 95%CI 1.04-4.46). Conclusions NAFLD is associated with higher COVID-19 severity, adverse outcomes and pulmonary thrombosis.