Chlamydia trachomatis, an obligate intracellular human pathogen, is a major cause of sexually transmitted diseases. Infections often occur without symptoms, a feature that has been attributed to the ability of the pathogen to evade the host immune response. We show here that C. trachomatis paralyses the host immune system by preventing the activation of polymorphic nuclear leukocytes (PMNs). PMNs infected with Chlamydia fail to produce neutrophil extracellular traps and the bacteria are able to survive in PMNs for extended periods of time. We have identified the secreted chlamydial protease-like activating factor (CPAF) as an effector mediating the evasion of the innate immune response since CPAF-deficient Chlamydia activate PMNs and are subsequently efficiently killed. CPAF suppresses the oxidative burst and interferes with chemical-mediated activation of neutrophils. We identified formyl peptide receptor 2 (FPR2) as a target of CPAF. FPR2 is cleaved by CPAF and released from the surface of PMNs. In contrast to previously described subversion mechanisms that mainly act on already activated PMNs, we describe here details of how Chlamydia actively paralyses PMNs, including the formation of neutrophil extracellular traps, to evade the host’s innate immune response.
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We thank D. Kretschmer and A. Peschel (Univeristy of Tübingen) for providing the HL60 cell lines and HL60 expressing FPR1 and FPR2. We thank R. Valdivia and E. Snavely (Duke University) for the CPAF-deficient and complemented strain of Chlamydia, G. Zhong (University of Texas) for the CPAF antibody and P. Lüningschrör (University of Würzburg) for the mouse synectin plasmid. We are grateful to O. Söhnlein (LMU Munich) for providing the FPR2-KO mice. C. Gehrig and D. Bunsen supported the scanning and transmission electron microscopy analyses. We acknowledge J. Sühlfleisch, N. Vollmuth and H. Czotscher for technical assistance. We thank S. Gorski, R. Sivadasan and A. Demuth for critically reading the manuscript. K.R. was supported by funds of the Frauenbüro, University of Würzburg. S.D. was funded by the Career Development Fellowship from the Graduate School of Life Sciences, University of Würzburg. This work was supported by Deutsche Forschungsgemeinschaft - GRK 2157 to T.R.
The authors declare no competing interests.
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Rajeeve, K., Das, S., Prusty, B.K. et al. Chlamydia trachomatis paralyses neutrophils to evade the host innate immune response. Nat Microbiol 3, 824–835 (2018). https://doi.org/10.1038/s41564-018-0182-y
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