Pediatric Liver Organoids Accumulate More Omicron RNA and Mount Stronger Innate Immune Responses

Liver organoids grown from pediatric donors accumulate more Omicron viral RNA and switch on a stronger innate immune transcriptional program than organoids derived from adults, according to a laboratory study published in Frontiers in Public Health. The work, led by researchers at Sun Yat-sen University's First Affiliated Hospital and the Guangdong Provincial Center for Disease Control and Prevention, set out to probe why children have appeared unusually susceptible to severe acute hepatitis of unknown origin since early 2022. Clinicians worldwide have reported clusters of this condition in children, no definitive cause has been established, and some evidence has pointed toward a possible association with SARS-CoV-2 infection, particularly during periods when the Omicron variant predominated.

What remained unclear was whether hepatocytes themselves—the functional cells of the liver—differ in their permissiveness to the virus or in the immune programs they deploy once infected. To address that question, the team used non-tumorous, tumor-adjacent liver organoids from both pediatric and adult donors and first profiled the basal expression of genes known to facilitate viral entry. Pediatric hepatocytes expressed significantly higher levels of several entry-related factors than adult cells, including ASGR1, KREMEN1, CTSB, CTSL and VIM.

Two SARS-CoV-2 entry-related receptors, ACE2 and TMPRSS4, also remained consistently higher in pediatric organoids across all viral strains tested. Both pediatric and adult liver organoids proved permissive to infection with the wildtype virus and with Omicron BA.1 and BA.2, but the viral burden differed in two important ways. First, Omicron BA.1 and BA.2 produced higher intracellular viral RNA levels than the wildtype virus in both age groups.

Second, pediatric organoids carried a notably higher intracellular viral RNA burden than adult organoids, so the combination of pediatric tissue and Omicron produced the heaviest load. RNA sequencing then revealed what the infected cells were doing transcriptionally. In pediatric organoids, Omicron infection induced a more pronounced innate-immune-associated response than wildtype infection, engaging interferon signalling as well as the RIG-I-like receptor and Toll-like receptor pathways—the canonical sensing circuits cells use to detect viral RNA.

At the same time, transcripts belonging to adaptive immune pathways were relatively downregulated. In adult organoids, the transcriptomic divergence between Omicron and wildtype infection was far less pronounced, suggesting that the variant-specific immune signature is largely a pediatric phenomenon in this model. Direct comparisons between age groups reinforced the pattern: Omicron-infected pediatric organoids upregulated interferon-γ signalling and other innate immune-associated transcriptional programs relative to infected adult organoids, while downregulating adaptive immune-pathway transcripts.

Taken together with the elevated entry-factor expression and higher viral RNA burden, the data sketch a coherent picture in which pediatric liver cells appear intrinsically more equipped for viral entry, accumulate more Omicron RNA once infected, and respond with a transcriptional program that leans heavily on innate antiviral signalling while adaptive components recede within the organoid cells themselves. The authors are careful about what these findings can and cannot support. The study is an in vitro organoid experiment, not a clinical investigation.

It did not include tissue or samples from children with acute hepatitis of unknown origin, and it cannot establish a causal or epidemiological link between SARS-CoV-2 infection and the pediatric hepatitis cases reported since 2022. What the model provides is a hypothesis-generating observation: the age-dependent differences in viral RNA accumulation and immune response, correlated with elevated expression of viral entry factors, lead the authors to conclude that SARS-CoV-2—particularly Omicron—could contribute to hepatocyte injury in children. Whether that contribution accounts for any fraction of the acute hepatitis cases of unknown origin is a question the organoid model was not designed to answer on its own.

Subject of Research: Age-dependent differences in SARS-CoV-2 entry-factor expression and innate immune responses between pediatric and adult liver organoids

Article Title: Age-dependent differences in SARS-CoV-2 entry-factor expression and innate immune responses between pediatric and adult liver organoids

Article References: Xue, T., Hu, J., Liu, Z., Zhu, L., Zhao, Y., Ren, X., Xu, L., Li, X., Lu, J., & Wang, L. (2026). Age-dependent differences in SARS-CoV-2 entry-factor expression and innate immune responses between pediatric and adult liver organoids. Frontiers in Public Health, 14, Article 1951670. https://doi.org/10.3389/fpubh.2026.1951670

Image Credits: AI Generated

DOI: 10.3389/fpubh.2026.1951670

Keywords: SARS-CoV-2, Omicron, liver organoids, pediatric hepatitis, viral entry factors, innate immunity, interferon signalling, ACE2, TMPRSS4, RNA sequencing, hepatocytes, Age-dependent