Regulation of host tissue responses by pathogen-derived nitric oxide (NO)
Final Report Abstract
Within this project, we have unraveled an intriguing molecular cross-talk between specialized human pathogens (the gonorrhoea-causing bacterium Neisseria gonorrhoeae) and the mucosal epithelium. We find that the gaseous messenger molecule nitric oxide (NO), produced as a by-product of microbial anaerobic metabolism, triggers a conserved signaling pathway in the infected eukaryotic cells. This NO-dependent communication only occurs upon intimate association of the bacteria, which is provided by Opa adhesin-CEACAM receptor interaction. The NO-initiated signaling cascade triggers the production of additional proteins in the infected epithelial cells, which promote the firm attachment of the epithelial cells to the extracellular matrix. As a consequence, the infected superficial epithelial cells do not detach from the tissue and the pathogens have created a stable platform for their colonization of the mucosa. Accordingly, these pathogens exploit an existing molecular mechanism in the eukaryotic cell, thereby increasing their chances to establish a foothold on the host tissue surface. Our unexpected results create a new paradigm, how bacteria can manipulate host tissues. At the same time, these data provide a novel answer to the question, which processes are induced upon intimate association of pathogenic bacteria with the host surface. In the classical scenario, the engagement of a human membrane receptor by a specific bacterial binding protein called adhesin stimulates a response in the host cell. In contrast, we find that in the case of N. gonorrhoeae the metabolic activity of the bacteria is the critical parameter, which triggers a signaling cascade in the target cell. Thereby, receptor-binding appears merely as a means to minimize the distance between the bacteria and the host to allow sufficient amounts of the reactive radical NO to reach the NO-responsive enzymes in the cytoplasm of the eukaryotic cell. This scenario implies that microbes other than gonococci, which tightly associate with host cells and which produce NO as a metabolic by-product, might also engage in such a microscale communication via NO. While bacterially derived metabolites, such as short chain fatty acids (SCFAs), are known to influence host cells, the direct signaling activities of a microbe-derived gas have not been reported before. In contrast to stable molecules such as SCFAs, which can be degraded by co-occurring commensal bacteria or which can act on distant tissues, the short-range action of the NO radical assures that only the cell-attached NO-producing gonococci will directly profit from the exchange with the epithelium. As we have focussed our attention to the striated and squamous epithelia of the urogenital tract, the question remains, if similar tissue responses can be expected on other mucosal surfaces (e.g. the nasopharynx or the simple columnar epithelium of the intestine). As a first indication, that our findings might have relevance beyond N. gonorrhoeae, we have reported the NO-dependent upregulation of CD105 by CEACAM-binding E.coli, indicating that NO-dependent communication between microorganisms and their mammalian host might be widespread. Moreover, we have summarized our findings about the bacteria-CEACAM interaction and this microscale communication in general terms in two reviews. Given the fact that NO-induced processes are amenable to pharmacological intervention, the knowledge about NO-driven, pathogen-initiated processes during bacterial colonization of the mucosa could open up completely novel avenues to prevent or block infectious diseases.
Publications
- 2019. Adaptation to Host- Specific Bacterial Pathogens Drives Rapid Evolution of a Human Innate Immune Receptor. Curr Biol 29(4):616-630.e5
Adrian J, Bonsignore P, Hammer S, Frickey T, Hauck CR
(See online at https://doi.org/10.1016/j.cub.2019.01.058) - 2020. CEACAM3-A Prim(at)e Invention for Opsonin-Independent Phagocytosis of Bacteria. Front Immunol. 10: 3160
Bonsignore P, Kuiper JWP, Adrian J, Goob G, Hauck CR
(See online at https://doi.org/10.3389/fimmu.2019.03160) - 2020. Neisseria gonorrhoeae Blocks Epithelial Exfoliation by Nitric-Oxide-Mediated Metabolic Cross Talk to Promote Colonization in Mice. Cell Host Microbe. 27(5): 793-808.e5
Muenzner P, Hauck CR
(See online at https://doi.org/10.1016/j.chom.2020.03.010) - 2021. Microscale communication between bacterial pathogens and the host epithelium. Genes Immun. 22(5-6): 247-254
Mix AK, Goob G, Sontowski E, Hauck CR
(See online at https://doi.org/10.1038/s41435-021-00149-1) - 2022. CEACAM3-mediated phagocytosis is limited by the receptor-type protein tyrosine phosphatase PTPRJ. J Biol Chem
Goob G, Adrian J, Cossu C, Hauck CR
(See online at https://doi.org/10.1016/j.jbc.2022.102269)
