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Monitoring the Assembly of a Secreted Bacterial Virulence Factor Using Site-specific Crosslinking
Published on: December 17, 2013
Chlamydial plasmid-encoded virulence factor Pgp3 interacts with human cathelicidin peptide LL-37 to modulate immune
Shuping Hou1, Xin Sun2, Xiaohua Dong3
1The 3rd Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Dermatovenereology, Tianjin Medical University General Hospital, 154 Anshan Rd, Tianjin, 300052, China; Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX, 78229, USA.
Abstract:
We have previously reported that Chlamydia trachomatis plasmid-encoded Pgp3 is able to neutralize anti-chlamydial activity of human cathelicidin peptide LL-37 by binding to and forming stable complex with LL-37. Besides its microbicidal activity, LL-37 also modulates immune response, including inducing cytokine/chemokine production in fibroblast/epithelial cells and recruitment of inflammatory cells. We now report that LL-37 was significantly induced in the genital tracts of women diagnosed positive for C. trachomatis. Both the LL-37-stimulated IL-6/8 production in human endometrial epithelial cells and the LL-37-induced neutrophil chemotaxis were blocked by Pgp3. Interestingly, although Pgp3 itself alone could not induce cytokines in epithelial cell cells, it did so in neutrophils. Importantly, the Pgp3 proinflammatory activity in neutrophils was significantly enhanced by forming complex with LL-37 although LL-37 alone failed to induce cytokine production in neutrophils. Thus, we have demonstrated that Pgp3 can modulate the proinflammatory activities of LL-37 on epithelial cells by forming stable complex with LL-37 but the Pgp3's own proinflammatory activity on myeloid cells is enhanced by forming the same complex. We hypothesize that Chlamydia may use Pgp3 to both block detrimental inflammation for improving its own fitness in the genital tract epithelial tissue and activate myeloid cell-mediated inflammation for potentially promoting spreading between the hosts, the latter of which may inevitably contribute to the development of inflammatory sequelae such as tubal fibrosis.
Insights
Chlamydia trachomatis Pgp3 protein neutralizes the immune peptide LL-37 in epithelial cells but enhances its own inflammation in neutrophils. This suggests a dual role in host-pathogen interaction and disease development.
Area of Science:
- Microbiology
- Immunology
- Molecular Biology
Background:
- Chlamydia trachomatis utilizes plasmid-encoded Pgp3 to evade host defenses.
- Human cathelicidin LL-37 exhibits antimicrobial and immune-modulating functions.
- LL-37 is induced in the female genital tract during C. trachomatis infection.
Purpose of the Study:
- To investigate the immunomodulatory effects of Pgp3 in the context of LL-37 activity.
- To elucidate the mechanisms by which Pgp3 influences inflammation during Chlamydia infection.
- To explore the potential role of Pgp3-LL-37 interactions in Chlamydia pathogenesis and sequelae.
Main Methods:
- In vitro studies using human endometrial epithelial cells and neutrophils.
- Assays to measure cytokine/chemokine production (e.g., IL-6/8).
- Neutrophil chemotaxis assays.
- Analysis of Pgp3-LL-37 complex formation and its functional consequences.
Main Results:
- Pgp3 neutralized LL-37's ability to induce IL-6/8 production in epithelial cells and block neutrophil chemotaxis.
- Pgp3 alone did not induce cytokines in epithelial cells but did in neutrophils.
- Complex formation between Pgp3 and LL-37 enhanced Pgp3's proinflammatory activity in neutrophils.
- LL-37 alone failed to induce cytokine production in neutrophils.
Conclusions:
- Pgp3 modulates LL-37's anti-inflammatory effects on epithelial cells via complex formation.
- Pgp3 exhibits its own proinflammatory activity in neutrophils, which is enhanced by LL-37 complexation.
- Chlamydia may use Pgp3 to balance detrimental inflammation for survival and promote myeloid cell inflammation for transmission.
- These interactions could contribute to inflammatory sequelae like tubal fibrosis.
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