The Gamak virus (GAKV) is a recently identified shrew-associated paramyxovirus in the genus Parahenipavirus, which also contains the zoonotic Langya virus (LayV). Using integrated in vitro and in vivo approaches, the authors examined host pathways that detect GAKV and coordinate antiviral responses. In human A549 epithelial cells, GAKV infection triggered robust innate immune signaling, evidenced by activation of IRF3 and phosphorylation of STAT1, induction of type I interferon, and upregulation of interferon-stimulated genes (ISGs). These responses indicate engagement of canonical RNA-sensing and interferon pathways during GAKV infection.
Transcriptomic analysis of infected cells revealed coordinated enrichment of gene sets associated with antiviral defense and with intrinsic apoptosis pathways. The concurrent induction of antiviral effectors and apoptotic signaling suggested a mechanistic link: innate immune activation during GAKV infection appears to be coupled with initiation of programmed cell death pathways. The authors interpreted these transcriptomic signatures as evidence that host antiviral signaling and apoptosis are coordinated responses to limit viral replication.
To define upstream sensors and adaptors, genetic analyses were performed. The study identified retinoic acid-inducible gene I (RIG-I) and mitochondrial antiviral signaling protein (MAVS) as essential mediators of both antiviral signaling and apoptosis during GAKV infection. Loss of RIG-I or MAVS impaired the antiviral transcriptional program and attenuated apoptosis, supporting a model in which RIG-I-mediated recognition of viral RNA signals via MAVS to activate downstream interferon and cell death pathways.
The investigators assessed the contribution of interferon signaling to apoptotic outcomes. Disruption of type I IFN–STAT1 signaling reduced apoptosis during GAKV infection, indicating that interferon pathway activation contributes to the execution or amplification of programmed cell death in infected cells. This finding places type I interferon signaling downstream of RIG-I–MAVS recognition in the pathway that links innate sensing to apoptosis.
A key downstream effector implicated by the study is NOXA. Knockdown of NOXA decreased apoptosis and led to increased viral replication in infected cells, identifying NOXA as a mediator that links innate immune activation to apoptotic control of GAKV. These results support a role for NOXA in enforcing a cell-intrinsic antiviral barrier that limits viral propagation by promoting apoptosis following RIG-I–MAVS–IFN pathway activation.
Complementing in vitro data, the authors performed intranasal infection of six-week-old female wild-type BALB/c mice with GAKV. In this model, viral RNA was detected in the lung and antiviral responses were induced, but animals did not display overt disease. The in vivo findings are consistent with a lung-restricted infection that elicits innate antiviral signaling without causing severe pathology under the conditions tested.
Together, the in vitro and in vivo results support a signaling axis in which viral recognition by RIG-I engages MAVS, drives type I interferon and STAT1 activation, and induces the pro-apoptotic effector NOXA to couple antiviral defense and apoptosis during GAKV infection. The authors present this RIG-I–MAVS–IFN–NOXA axis as a mechanistic framework for host defense against parahenipaviruses.
Notes and scope limitations
This report is a preprint and has not been peer reviewed. The abstract and article text describe the major findings summarized above; detailed experimental methods, quantitative results, and additional data are provided in the full preprint and supplementary materials. Where the source did not report specific experimental parameters or numerical results in the abstract, those details are not included here.