PGP-5 Influences ZIP-2-Dependent Innate Immune Response During Streptococcus gordonii Exposure in Caenorhabditis...

Innate immune responses in Caenorhabditis elegans are regulated by multiple effectors that are activated upon bacterial exposure. In this study, we investigated the role of pgp-5, a transmembrane efflux transporter implicated in cellular stress responses and detoxification in host defense against Streptococcus gordonii. S. gordonii produces hydrogen peroxide (H₂O₂) as a major virulence factor and induces oxidative stress in host cells. Exposure to wild-type S. gordonii induced robust pgp-5p::GFP expression, whereas the H₂O₂-deficient spxB mutant elicited significantly lower reporter activity, suggesting that pgp-5 activation is associated with spxB-dependent H₂O₂ production. Previous studies have established that the bZIP transcription factor ZIP-2 is required for pgp-5 expression in C. elegans under xenobiotic stress conditions. However, whether pathogen-induced pgp-5 expression similarly depends on ZIP-2 remains unknown. In addition, the potential role of pgp-5 in regulating ZIP-2-dependent immune responses has not been explored. To address these questions, we examined pgp-5p::GFP expression and activation of the ZIP-2-dependent innate immune reporter irg-1p::GFP following RNAi-mediated knockdown of pgp-5 and zip-2 during exposure to wild-type and spxB mutant S. gordonii. Knockdown of zip-2 abolished S. gordonii-induced pgp-5p::GFP expression compared with empty vector control-treated worms, demonstrating that pathogen-induced pgp-5 expression is dependent on ZIP-2. In contrast, knockdown of pgp-5 resulted in significantly increased expression of irg-1p::GFP following S. gordonii exposure. These findings suggest that loss of PGP-5 enhances expression of the ZIP-2-responsive gene irg-1 under S. gordonii-induced stress, indicating that PGP-5 may influence the magnitude of the associated immune response in C. elegans.