Directing Defense: ZBP1 Activation during MPXV Infection 2309240

Abstract

Abstract Introduction Monkeypox virus (MPXV) remains a global health concern due to the recent outbreak that exhibited an increase in human transmission. This highlights the need to better understand the viral host interactions to identify novel antiviral strategies. Z-DNA Binding Protein-1 (ZBP1) is an innate immune sensor that can recognize Z-ribonucleic acid (Z-RNA). Z-RNA is a novel pathogen-associated molecular pattern (PAMP), produced during early viral replication, and can be sensed by ZBP1. Activation of ZBP1 can initiate antiviral signaling pathways that can restrict viral replication and limit disease progression. However, whether ZBP1 contributes to controlling MPXV replication and spread remains a significant gap in knowledge. Methods Wild-type (WT) and ZBP1-knockout (ZBP1-KO) bone-marrow-derived-macrophages (BMDMs) were infected with MPXV to determine the viral replication and spread using single-step and multi-step growth curves. Viral titers were quantified by plaque assay, and viral gene expression was measured by RT-qPCR. In vivo, WT and ZBP1-KO mice were infected intranasally with MPXV, mimicking the respiratory route transmission. Lung tissues were collected at 1, 3, and 5 days post-infection (dpi) to quantify viral titers and viral gene expression. Results Findings reveal that ZBP1 deficiency results in increased MPXV replication and spread during single and multi-step growth curves of MPXV infection, as indicated by an elevated viral titer. Increased viral gene expression was also observed in lung tissues from ZBP1-KO at 3dpi, suggesting an antiviral role for the host ZBP1 during MPXV infection. Conclusion Together, these results demonstrate that ZBP1 plays an antiviral role during MPXV infection. However, further studies are needed to define the host defense pathways involved, such as TBK1 and NF-κB signaling. Understanding how ZBP1 restricts MPXV as Z-RNA is produced during early MPXV infection can help address a significant gap in understanding the viral host interactions. Funding Source GR00012379 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)