# Human liver-derived organoids recapitulate Oropouche virus infection and manifestation, enabling antiviral drug discovery

## TL;DR

This study uses human liver organoids to model Oropouche virus infection and identifies molnupiravir and interferon-alpha as potential treatments.

## Contribution

The study introduces a novel liver organoid model for OROV and identifies effective antiviral drug combinations.

## Key findings

- OROV infects liver organoids and causes cellular damage and interferon response.
- Molnupiravir significantly inhibits OROV replication and reduces cell damage.
- Combining molnupiravir with interferon-alpha shows synergistic antiviral effects.

## Abstract

Oropouche virus (OROV) is a neglected, re-emerging arbovirus that typically causes self-limiting febrile illness but can also lead to severe complications. With no approved vaccines or treatments available, we integrate clinical data with human liver-derived organoids to assess liver involvement in OROV infection and identify antiviral candidates through drug repurposing. Patient blood tests show elevated liver enzymes, indicating OROV-associated hepatic dysfunction. OROV isolates productively infect liver organoids and induce severe cellular damage. Transcriptomic profiling reveals strong virus-host interactions, including activation of interferon-stimulated genes and cell death pathways. Pharmacological inhibition of the interferon pathway enhances OROV replication, whereas treatment with therapeutic interferon-α suppresses the infection. Molnupiravir, a clinically approved antiviral drug targeting viral RNA-dependent RNA polymerase, markedly inhibits OROV replication and mitigates virus-induced cytopathology. Combining molnupiravir with interferon-α results in synergistic antiviral activity, indicating the complementarity of virus-targeted and host-directed strategies. These findings strengthen preparedness and response to OROV emergence.

•Elevated liver enzymes are detected in a subset of Oropouche patients•OROV infects human liver organoids, triggering interferon response and cellular injury•Molnupiravir strongly inhibits OROV infection and restores cellular homeostasis•The combination of molnupiravir with interferon-alpha exhibits robust synergy

Elevated liver enzymes are detected in a subset of Oropouche patients

OROV infects human liver organoids, triggering interferon response and cellular injury

Molnupiravir strongly inhibits OROV infection and restores cellular homeostasis

The combination of molnupiravir with interferon-alpha exhibits robust synergy

Li et al. integrate liver function data from Oropouche virus (OROV)-infected patients with human liver-derived organoids to demonstrate hepatic infection and resulting cellular injury. Using organoids, they further show that molnupiravir exerts strong antiviral activity against OROV and synergizes with interferon-alpha.