Salmonella effector SopF regulates PANoptosis of intestinal epithelial cells to aggravate systemic infection

ABSTRACT

SopF, a newly discovered effector secreted by Salmonella pathogenicity island-1 type III secretion system (T3SS1), was reported to target phosphoinositide on host cell membrane and aggravate systemic infection, while its functional relevance and underlying mechanisms have yet to be elucidated. PANoptosis (pyroptosis, apoptosis, and necroptosis) of intestinal epithelial cells (IECs) has been characterized as a pivotal host defense to limit the dissemination of foodborne pathogens, whereas the effect of SopF on IECs PANoptosis induced by Salmonella is rather limited. Here, we show that SopF can attenuate intestinal inflammation and suppress IECs expulsion to promote bacterial dissemination in mice infected with Salmonella enterica serovar Typhimurium (S. Typhimurium). We revealed that SopF could activate phosphoinositide-dependent protein kinase-1 (PDK1) to phosphorylate p90 ribosomal S6 kinase (RSK) which down-regulated Caspase-8 activation. Caspase-8 inactivated by SopF resulted in inhibition of pyroptosis and apoptosis, but promotion of necroptosis. The administration of both AR-12 (PDK1 inhibitor) and BI-D1870 (RSK inhibitor) potentially overcame Caspase-8 blockade and subverted PANoptosis challenged by SopF. Collectively, these findings demonstrate that this virulence strategy elicited by SopF aggregates systemic infection via modulating IEC PANoptosis through PDK1-RSK signaling, which throws light on novel functions of bacterial effectors, as well as a mechanism employed by pathogens to counteract host immune defense.

KEYWORDS:

• Salmonella effector SopF
• intestinal epithelial cells
• PANoptosis
• Caspase-8
• PDK1-RSK

Acknowledgments

We thank Prof. Feng Shao and Dr. Yue Xu (National Institute of Biological Sciences, Beijing) for their generosity in providing the S. Typhimurium strains and technical support.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data supporting the findings are openly available at https://doi.org/10.6084/m9.figshare.21813894.v1.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2180315

Author contributions

Haibo Yuan, Liting Zhou, and Shuyan Wu designed the research and wrote the manuscript. Haibo Yuan, Liting Zhou, Yilin Chen, Jiayi You, and Hongye Hu conducted the research. Shuyan Wu, Rui Huang, and Yuanyuan Li supervised the project and edited the manuscript. All authors contributed to this article and approved the submitted version.

Additional information

Funding

This work was financially supported by grants from the National Natural Science Foundation of China (No. 32270187, No. 31970132, No. 81971899), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).