Introduction
Phospholipid phosphatase 6 (PLPP6) is a membrane-associated enzyme that regulates polyisoprenoid diphosphate signaling in cell activation. In response to inflammatory stimuli, PLPP6 converts presqualene diphosphate to presqualene monophosphate. Because polyisoprenoids serve fundamental roles in cell immunology we aimed to investigate the role of PLPP6 in the context of influenza A virus (IAV) infection.

Methods
Here, we compared the immune responses between wild type (WT) and Plpp6 knockout (Plpp6-/-) mice to viral infection using a non-lethal inoculum of IAV (A/WSN/33 H1N1, 80 PFU). Methods included flow cytometry, histology and spatial transcriptomics (10x Xenium). For translation to human responses, PLPP6-siRNA was used in a human airway epithelial cell line (A549).

Results
Plpp6-/- mice had increased weight loss, higher viral burden, increased neutrophil and inflammatory macrophage recruitment to the lungs, and increased expression of inflammatory genes such as Isg15 and Il6 compared to wild-type controls following IAV. Spatial transcriptomic analysis revealed time dependent Plpp6 expression after IAV, in particular in lung epithelial cells during the resolution phase of IAV infection in WT mice. IAV infection of A549 cells led to significantly increased viral replication (viral titters) and burden (expression of M1 gene) after PLPP6-siRNA compared to control.

Conclusion
In work in progress, these findings suggest that airway epithelial PLPP6 serves in a protective role against viral infection and as a regulator of pathogen-elicited inflammation. The polyisoprenyl phosphate metabolites of PLPP6 activity that underlie this immune protection are the focus of ongoing research.