Hepatotropic viruses naturally have narrow host and tissue tropisms, challenging the development of robust experimental models. The advent of organoid technology provides a unique opportunity for moving the field forward. Here, we demonstrate that three-dimensional cultured organoids from fetal and adult human liver with cholangiocyte or hepatocyte phenotype support hepatitis E virus (HEV) replication. Inoculation with infectious HEV particles demonstrates that human liver–derived organoids support the full life cycle of HEV infection. By directing organoids toward polarized monolayers in a transwell system, we observed predominantly apical secretion of HEV particles. Genome-wide transcriptomic and tRNAome analyses revealed robust host responses triggered by viral replication. Drug screening in organoids identified brequinar and homoharringtonine as potent HEV inhibitors, which are also effective against the ribavirin resistance variant harboring G1634R mutation. Thus, successful recapitulation of HEV infection in liver-derived organoids shall facilitate the study of virus-host interactions and development of antiviral therapies.

Nirmatrelvir is the main component of Paxlovid, an oral antiviral drug approved for the treatment of COVID-19 caused by SARS-COV-2 infection. Nirmatrelvir targets the main protease (M^pro), which is substantially conserved among different coronaviruses. Here, our molecular docking analysis indicates comparable affinity of nirmatrelvir binding to the M^pro enzymes of SARS-CoV-2 and three seasonal coronaviruses (OC43, 229E and NL63). However, in cell culture models, we found that nirmatrelvir potently inhibited SARS-CoV-2, OC43 and 229E, but not NL63. The insensitivity of NL63 to nirmatrelvir treatment was demonstrated at both viral replication and infectious titer levels. The antiviral activity of nirmatrelvir against OC43 and 229E was further confirmed in human airway organoids. The combination of nirmatrelvir and molnupiravir exerted differential patterns of antiviral response against OC43 and 229E. These results revealed disparities in the ability of nirmatrelvir to inhibit different coronaviruses, and caution against repurposing of nirmatrelvir as a pan-coronavirus treatment.

The pathogenesis of enteric viral infections is attributed to both viral replication and the resultant immune-inflammatory response. To recapitulate this complex pathophysiology, we engineer macrophage-augmented organoids (MaugOs) by integrating human macrophages into primary intestinal organoids. Echovirus 1, echovirus 6, rotavirus, seasonal coronavirus OC43 and SARS-CoV-2— known to directly invade the intestine— are used as disease modalities. We demonstrate that these viruses efficiently propagate in MaugOs and stimulate the host antiviral response. However, rotavirus, coronavirus OC43 and SARS-CoV-2, but not the two echoviruses, trigger inflammatory responses. Acetate, a microbial metabolite abundantly present in the intestine, potently inhibits virus-induced inflammatory responses in MaugOs, while differentially affecting viral replication in macrophages and organoids. Furthermore, we provide a proof-of-concept of combining antiviral agent with either anti-inflammatory regimen or acetate to simultaneously inhibit viral infection and inflammatory response in MaugOs. Collectively, these findings demonstrate that MaugOs are innovative tools for studying the complex virus-host interactions and advancing therapeutic development.

Background: Steatotic liver disease (SLD) affects ~30% of adults worldwide. The global population is continuously threatened by epidemic and endemic viral diseases. This study aims to thoroughly examine the interaction between SLD and major viral diseases. Methods: We systematically searched databases from inception to April 2, 2024, for observational studies recording viral-infected adult patients with eligible data on the presence of hepatic steatosis. Results: Six hundred thirty-six eligible studies were included in the analysis of SLD prevalence. Among patients with monoinfections, the highest SLD prevalence was observed in those infected with HCV at 49% (95% CI: 47%–51%), followed by SARS-CoV-2 (39%, 95% CI [34%–44%]), HIV (39%, 95% CI [33%–44%]), and HBV (36%, 95% CI [32%–40%]). Additionally, co-infections, such as HCV-HIV and HBV-HCV, exhibit even higher SLD prevalence. The prevalence of steatohepatitis is particularly high in HIV-infected (24%, 95% CI: 17%–30%) and HCV-infected (18%, 95% CI: 13%–24%) populations. The co-existence of SLD with viral infections was associated not only with the progression of liver disease but also with more severe outcomes of the infections and poorer responses to antiviral treatment. The combination of cardiometabolic risk factors and viral-associated and host factors contributes to the higher risk of SLD in viral-infected populations. Conclusions: SLD is highly prevalent in viral-infected populations, and the reciprocal interactions between SLD and viral diseases exacerbate both conditions, leading to poorer patient outcomes in general.