Seasonal coronaviruses widely circulate in the global population, and severe complications can occur in specific vulnerable populations. Little is known on their pathogenic mechanisms and no approved treatment is available. Here, we present anecdotal evidence that the level of IL-1β, a hallmark of inflammasome activation, appears elevated in a subset of seasonal coronavirus infected patients. We found that cultured human macrophages support the full life cycle of three cultivatable seasonal coronaviruses. Their infections effectively activate NLRP3 inflammasome activation through TLR4 ligation and NF-κB activation. This activation can be attenuated by specific pharmacological inhibitors and clinically used medications including dexamethasone and flufenamic acid. Interestingly, combination of antiviral and anti-inflammatory drugs simultaneously inhibit seasonal coronavirus-triggered inflammatory response and viral replication. Collectively, these findings show that the TLR4/NF-κB/NLRP3 axis drives seasonal coronavirus triggered-inflammatory response, which in turn represents a viable therapeutic target.

Hepatitis E virus (HEV) infection can cause severe acute hepatitis in pregnant women and chronic infection in immunocompromised patients, promoting the development of effective antiviral therapies. In this study, we identified niclosamide, a widely used anthelmintic drug, as a potent inhibitor of HEV replication in a range of subgenomic and full-length HEV models, which are based on human cell lines and liver organoids harbouring genotype 1 and 3 HEV strains. Niclosamide is known to have multiple cellular targets including the inhibition of STAT3 and NFκB signaling pathways. Although HEV activates STAT3, we excluded its involvement in the anti-HEV activity of niclosamide. Interestingly, HEV infection activated NFκB and activation of NFκB promoted viral replication. Consistently, stable silencing of NFκB by lentiviral RNAi inhibited HEV replication. By targeting NFκB signaling, we further revealed its role in mediating the anti-HEV action of niclosamide. These results demonstrated that niclosamide potently inhibits HEV replication by inhibiting NFκB signaling but independent of STAT3. Our findings support the potential of repurposing niclosamide for treating HEV infection.

Background & aims: Hepatitis E virus (HEV) infection is the most common cause of liver inflammation, but the pathogenic mechanisms remain largely unclear. We aim to explore whether HEV infection activates inflammasomes, the crosstalk with antiviral interferon response and potential of therapeutic targeting. Approach & results: We measured IL-1β secretion, the hallmark of inflammasome activation, in serum of HEV-infected patients and rabbits, and in cultured macrophage cell lines and primary monocyte-derived macrophages. We found that genotypes 3 and 4 HEV infection in rabbits elevated IL-1β production. A profound increase of IL-1β secretion was further observed in HEV-infected patients (1733 pg/mL ± 1234; n = 70) compared with healthy individuals (731 pg/mL ± 701; n = 70). As macrophages are the drivers of inflammatory response, we found inoculation with infectious HEV particles robustly triggered NLRP3 inflammasome activation in primary macrophages and macrophage cell lines. We further revealed that the ORF2 capsid protein and the formed integral viral particles are responsible for activating inflammasome response. We also identified NF-κB signaling activation as a key upstream event of HEV-induced NLRP3 inflammasome response. Interestingly, inflammasome activation antagonizes interferon response to facilitate viral replication in macrophages. Pharmacological inhibitors and clinically used steroids can effectively target inflammasome activation. Combining steroids with ribavirin simultaneously inhibit HEV and inflammasome response without cross-interference. Conclusions: HEV infection strongly activates NLRP3 inflammasome activation in macrophages, which regulates host innate defense and pathogenesis. Therapeutic targeting NLRP3, in particular when combined with antiviral agents, represents a viable option for treating severe HEV infection.

Background & Aims Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new terminology updated from non-alcoholic fatty liver disease (NAFLD). In this study, we aim to estimate the global prevalence of MAFLD specifically in overweight and obese adults from the general population by performing a systematic review and meta-analysis through mining the existing epidemiological data on fatty liver disease. Methods We searched Medline, Embase, Web of Science, Cochrane and google scholar database from inception to November, 2020. DerSimonian-Laired random-effects model with Logit transformation was performed for data analysis. Sensitivity analysis and meta-regression were used to explore predictors of MAFLD prevalence in pooled statistics with high heterogeneity. Results We identified 116 relevant studies comprised of 2667052 participants in general population with an estimated global MAFLD prevalence as 50.7% (95% CI 46.9-54.4) among overweight/obese adults regardless of diagnostic techniques. Ultrasound was the most commonly used diagnostic technique generating prevalence rate of 51.3% (95% CI 49.1-53.4). Male (59.0%, 95% CI 52.0-65.6) had a significantly higher MAFLD prevalence than female (47.5%, 95% CI 40.7-54.5). Interestingly, MAFLD prevalence rates are comparable based on classical NAFLD and non-NAFLD studies in general population. The pooled estimate prevalence of comorbidities such as type 2 diabetes and metabolic syndrome was 19.7% (95% CI 12.8-29.0) and 57.5% (95% CI 49.9-64.8), respectively. Conclusion MAFLD has an astonishingly high prevalence rate in overweight and obese adults. This calls for attention and dedicated action from primary care physicians, specialists, health policy makers and the general public alike.