Sen Guo
Dong SunIn contrast to functional redundancy of the Legionella pneumophila type IV secretion system (T4SS) effectors (Song et al., 2021; Fu et al., 2022a; Song et al., 2022), deletion of a single T4SS effector coding gene results in substantially less virulence of Coxiella burnetii (Weber et al., 2013; Fu et al., 2022b), the causative agent of Q fever. Elucidating the biological functions of T4SS effectors of C. burnetii lays a prerequisite for the development of anti-infection drugs, which is of great significance for treating and preventing Q fever. However, little is known about the biochemical activities of C. burnetii effector proteins.
NF-κB regulates several signaling pathways critical to immunity, cell proliferation and apoptosis, making them common targets for pathogens that manipulate host cell function (Rahman and McFadden, 2011). NF-κB has been demonstrated to be inhibited in the late stage of C. burnetii infection (Mahapatra et al., 2016). This inhibition has been attributed to virulence proteins transported by the bacterial Dot/Icm system (Mahapatra et al., 2016) but the specific mechanism remains unclear. In order to address this issue, Zhang et al. (2022) screened the regulatory activities of C. burnetii effectors library in NF-κB signalling pathway using the NF-κB reporter system, and discovered that the effector protein CinF (Cbu_0513) inhibits NF-κB activation effectively. Surprisingly, by the bioinformatic analysis, CinF showed high similarities to ST0318, a fructose-1,6-bisphosphate (FBP) aldolase/phosphatase found in numerous bacteria, especially the certain Archaea species (Fushinobu et al., 2011). However, CinF lacks phosphatase activity against FBP despite being highly similar to ST0318 and is unable to dephosphorylate when p-nitrophenyl phosphate is used as the substrate. The biological functions of CinF and ST0318 are therefore different, even though their structures are similar. Further experiments have demonstrated that CinF is a protein phosphatase that exhibits high specificity towards IκBα.
In conclusion, the results of this study confirmed that CinF is a novel protein phosphatase, and the target of CinF in host cells is the key regulatory protein IκBα in the NF-κB immune pathway. Dephosphorylation of IκBα prevents itself from being degraded by proteases, thus inhibiting NF-κB activation during infection, which is critical to the survival and proliferation of the pathogen. This study not only identified a C. burnetii effector protein that inhibits NF-κB, filling a gap in previous studies, but also systematically discussed the biological significance of this protein in bacterial infection and intracellular growth. The study provides a solid foundation for studying the infection mechanism of intracellular pathogens.
Although CinF is structurally similar to ST0318, their biochemical activities are quite different. Protein is the substrate of this new phosphatase rather than carbohydrates or lipids. This study also suggests that metabolic enzymes such as those involved in glycolysis of distantly related microorganisms have been acquired by C. burnetii through horizontal gene transfer, and evolved into proteins that are capable of interfering with the immune response, expanding the current knowledge of mechanisms utilized by pathogens to evade host immunity.
Author Contributions
SG, Conceptualization, Writing – original draft; DS, Conceptualization, Writing – review and editing. All authors contributed to the article and approved the submitted version
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: Coxiella burnetii, type IV secretion system, NF-κB, phosphatase, sugar metabolism
Citation: Guo S and Sun D (2022) Rolling With Host Immunity: Virulence Beyond The Glycolysis. Front. Cell. Infect. Microbiol. 12:939828. doi: 10.3389/fcimb.2022.939828
Received: 09 May 2022; Accepted: 23 May 2022;
Published: 15 June 2022.
Edited by:
Xiaolu Xiong, Beijing Institute of Microbiology and Epidemiology, ChinaReviewed by:
Jun Jiao, Beijing Institute of Microbiology and Epidemiology, ChinaYan Ge, Tongji University, China
Copyright © 2022 Guo and Sun. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Dong Sun, sundong@qiluhospital.com