Pyroptosis executioner gasdermin D contributes to host defense and promotes Th 1 immune response during Neospora caninum infection

Abstract

Neospora caninum (N. caninum) is an intracellular parasite and is the causative agent of neosporosis, which leads to reproductive failure in cattle. Pyroptosis is a recently discovered form of programmed cell death executed by gasdermin D (GSDMD). This cell death mechanism is an important host defense against intracellular pathogens. However, pyroptosis induced by N. caninum is poorly understood. The aim of this study was to explore the roles of GSDMD-mediated pyroptosis during N. caninum infection in vivo. N. caninum-infected wild type mice and GSDMD-deficient mice were used to evaluate host resistance and its ability to affect immune response against this parasite. The results showed that GSDMD deficiency significantly reduced survival and impaired the host’s abilities to clear parasite loads in tissues, monocytes/macrophages and neutrophils. Additionally, GSDMD was essential for circulating IL-18 and IFN-γ production induced by N. caninum infection, indicating that GSDMD can mediate the Th 1 immune response against N. caninum infection. Additional data revealed that treatment with exogenous recombinant IL-18 in N. caninum-infected Gsdmd−/− mice rescues the reduction of circulating IFN-γ production to help eliminate the parasite. Taken together, our data indicate that GSDMD-mediated pyroptosis plays a vital role in maintaining host resistance to N. caninum and is essential for clearing the parasite. This form of programmed cell death promotes the Th 1 immune response by controlling IL-18 release and is considered a host defense against N. caninum. This study expands our understanding of interactions between host immune response/defense and N. caninum infection.