gspd-1-RNAi knockdown Caenorhabditis elegans was used as an immune-compromised model to investigate the role of G6PD in host-pathogen interactions. A shorted lifespan, increased bacterial burden and bacterial translocation were observed in
gspd-1-knockdown C. elegans infected with Klebsiella pneumoniae (KP). RNAseq revealed that the innate immune pathway, including
clc-1 and
tsp-1, was affected by
gspd-1 knockdown. qPCR confirmed that tight junction (
zoo-1,
clc-1) and immune-associated genes (
tsp-1) were down-regulated in
gspd-1-knockdown C. elegans and following infection with KP. The down-regulation of antimicrobial effector lysozymes, including
lys-1,
lys-2,
lys-7,
lys-8,
ilys-2 and
ilys-3, was found in
gspd-1-knockdown C. elegans infected with KP. Deletion of
clc-1,
tsp-1,
lys-7, and
daf-2 in
gspd-1-knockdown C. elegans infected with KP abolished the shorten lifespan seen in the Mock control. GSPD-1 deficiency in C. elegans resulted in bacterial accumulation and lethality, possibly due to a defective immune response. These findings indicate that GSPD-1 has a protective role in microbial defense in C. elegans by preventing bacterial colonization through bacterial clearance.