- Heine W, Beckstette M, Heroven AK, Thiemann S, Heise U, Nuss AM, Pisano F, Strowig T, and Dersch P. (2018) Loss of CNFY toxin-induced inflammation drives Yersinia pseudotuberculosis into persistency. PLoS Pathog. 14(2): e1006858.
- Nuss AM*, Beckstette M*, Pimenova M, Schmühl C, Opitz W, Pisano F, Heroven AK, Dersch P. (2017) Tissue dual RNA-seq allows fast discovery of infection-specific functions and riboregulators shaping host-pathogen transcriptome. Proc. Natl. Acad. Sci. USA. 114(5): E791-E800 etc.
- Pezoldt J+, Pisano F +, Heine W, Pasztoi M, Rosenheinrich M, Nuss AM, Pils MC, Prinz I, Förster R, Huehn J, Dersch P*. Impact of CCR7 on T-cell response and susceptibility to Yersinia pseudotuberculosis infection. J. Infect. Dis. 2017; 216: 752-760.
- Avican K, Fahlgren A, Heroven AK, Huss M, Beckstette M, Dersch P, Fällman M. Reprogramming of Yersinia from virulent to persistent mode revealed by complex in vivo RNA-seq analysis. PLoS Pathog. 2015; 11: e1004600.
- Schweer J, Kulkarni D, Kochut A, Pezoldt J, Pisano F, Pils MC, Genth H, Huehn J, Dersch P. The cytotoxic necrotizing factor of Yersinia pseudotuberculosis (CNFY) enhances inflammation and Yop delivery during infection by activation of Rho GTPases. PLoS Pathog. 2013; 9(11): e1003746.
- Pasztoi M., Kulkarni D., Bonifacius A., Niemz J., Pezoldt J., Teich R., Prinz I., Rohde M., Pisano F., Dersch P., Huehn J. Yersinia pseudotuberculosis supports Th17 differentiation and limits de novo regulatory T cell induction by directly interfering with T cell receptor signaling (2017) Cellular and Molecular Life Sciences 74(15):2839-2850.
- Elfiky A., Bonifacius A., Pezoldt J., Pasztoi M., Chaoprasid P., Sadana P., El-Sherbeeny N., Hagras M, Scrima A., Dersch P., Huehn J. (2018) Yersinia pseudotuberculosis modulates regulatory T cell stability via injection of Yersinia outer proteins in a type III secretion system-dependent manner. European Journal of Microbiology and Immunology 8(4), 101-106.
Roles of the CNFY toxin for Yersinia pseudotuberculosis for crossing intestinal barriers, colonization of subepithelial tissue and pathology
Exotoxins such as the cytotoxic necrotizing factor CNFY of the enteric pathogen Yersinia pseudotuberculosis are key virulence factors of pathogenic bacteria that target and subvert the functions of host cells to induce breaking of cellular barriers, promote colonization of host tissues and/or defeat host immune responses. In our previous work we could demonstrate that the CNFY toxin can be delivered in a wide range of host cells, including intestinal epithelial cells and professional phagocytes (neutrophils, macrophages) either directly or via outer membrane vesicles.
On the cellular level, toxin delivery triggers activation of the Rho GTPases Rho, Rac1 and Cdc42 leading to a remodelling of the cell membrane. This induces the formation of actin-rich membrane ruffles and filopodia in epithelial cells which are also formed upon internalization of the pathogen, and first experiments have shown that CNFY triggers host cell uptake of Yersinia in vitro. We further found that CNFY enhances the delivery of antiphagocytic Yop effectors by the Yersinia type III secretion system into neutrophils and macrophages and protects the bacteria from attacks of innate immune cells after transcytosis through the intestinal barrier. The analysis of the host immune response further demonstrated that presence of CNFY leads to a strong reduction of professional phagocytes during the infection, supporting a role for the toxin in suppression of the antibacterial response. The analysis of the functional consequences of CNFY for host-pathogen interaction during the infection further revealed that the toxin contributes significantly to the induction of acute inflammatory responses and to the formation of necrotic areas in intestinal lymphoid tissues, whereas downregulation of the cnfY gene abolishes inflammation and drives the bacteria into persistency.
How all these processes are induced by CNFY triggering Rho GTPase activation and how this influences the intestinal barrier function is still unclear. In future studies, we will therefore address the capacity of CNFY (directly or within outer membrane vesicles) to (i) modulate the intestinal barrier function, (ii) to promote bacterial uptake by epithelial/endothelial cells, and (iii) to prevent phagocytosis by innate immune cells, e.g. by enhancing injection of Yop effectors via cell membrane remodelling. A particular focus will be the characterization of signalling factors/regulators important for the CNFY-triggered induction of inflammatory responses of gut-associated lymphoid tissues, induction of immune cell death and formation of necrotic lesions, and how this influences the intestinal barrier. This will allow us to link cellular factors and processes in the infected host important for toxin function during infections with pathogenic bacteria targeting Rho GTPases. It will further help us to evaluate potential host factors counteracting CNFY toxin-triggered detrimental inflammatory responses and tissue destruction.
Prof. Dr. rer. nat. Petra Dersch
Project time: 7/2020 - 6/2024