Characterization of CPAF Critical Residues and Secretion during Chlamydia trachomatis Infection

Yang, Zhangsheng; Tang, Lingli; Sun, Xi; Chai, Jijie; Zhong, Guangming

doi:10.1128/iai.00275-15

Cited by 20 publications

(14 citation statements)

References 46 publications

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“…survival in the mouse lower genital tract whereas a similar transformation performed with a mCherry-expressing control plasmid failed to do so. The significant but partial rescue of the chlamydial infectivity by the CPAF complementation may have been a consequence of either the interference from the excessive amount of the incompletely processed CPAF fragments in the complemented strain (38,(40)(41)(42)44) or a CPAF-independent defect inherited in the parental L2-17 strain (34). Nevertheless, the complementation experiments have demonstrated that the failure of L2-17 to survive in the mouse lower genital tract was at least partially due to the lack of CPAF.…”

Section: Discussionmentioning

confidence: 92%

“…CPAF is a unique serine protease (38)(39)(40)(41)(42) that is secreted into the host cell cytosol via a sec-dependent type II secretion pathway (34,43). We have recently validated the secretion of CPAF into the host cell cytosol (44). To further investigate the role of CPAF in chlamydial pathogenesis, we took advantage of chemically derived C. trachomatis L2 mutants (34,45,46) and compared a CPAF-deficient C. trachomatis strain to a control strain derived by lateral gene transfer (34) for survival in the mouse genital tract.…”

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confidence: 99%

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The Chlamydia-Secreted Protease CPAF Promotes Chlamydial Survival in the Mouse Lower Genital Tract

et al. 2016

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dDespite the extensive in vitro characterization of CPAF (chlamydial protease/proteasome-like activity factor), its role in chlamydial infection and pathogenesis remains unclear. We now report that a Chlamydia trachomatis strain deficient in expression of CPAF (L2-17) is no longer able to establish a successful infection in the mouse lower genital tract following an intravaginal inoculation. The L2-17 organisms were cleared from the mouse lower genital tract within a few days, while a CPAF-sufficient C. trachomatis strain (L2-5) survived in the lower genital tract for more than 3 weeks. However, both the L2-17 and L2-5 organisms maintained robust infection courses that lasted up to 4 weeks when they were directly delivered into the mouse upper genital tract. The CPAF-dependent chlamydial survival in the lower genital tract was confirmed in multiple strains of mice. Thus, we have demonstrated a critical role of CPAF in promoting C. trachomatis survival in the mouse lower genital tracts. It will be interesting to further investigate the mechanisms of the CPAF-dependent chlamydial pathogenicity.

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Section: Discussionmentioning

confidence: 92%

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confidence: 99%

The Chlamydia-Secreted Protease CPAF Promotes Chlamydial Survival in the Mouse Lower Genital Tract

et al. 2016

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“…The intrainclusion C. trachomatis organisms are known to secrete various proteins, including CPAF and Pgp3, into host cell cytosol (2,20,33,(44)(45)(46). Both CPAF and Pgp3 are accumulated in large quantities in the cytosol of the infected cells prior to the lysis of the infected cells (18,20). Thus, we hypothesize that the prestored CPAF and Pgp3 in the host cell cytosol can be rapidly released to target extracellular antimicrobial peptides upon cell lysis.…”

Section: Discussionmentioning

confidence: 99%

“…The strong antibacterial activity of AMPs has selected many bacterial species to evolve countermeasures for evading the same defense mechanism (15)(16)(17). We have recently shown that the chlamydial chromosome-encoded serine protease CPAF, which is secreted out of the chlamydial inclusion (18), can degrade LL-37 and neutralize its antichlamydial activity (19).…”

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Chlamydial Plasmid-Encoded Virulence Factor Pgp3 Neutralizes the Antichlamydial Activity of Human Cathelicidin LL-37

et al. 2015

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dChlamydia trachomatis infection in the lower genital tract can ascend to and cause pathologies in the upper genital tract, potentially leading to severe complications, such as tubal infertility. However, chlamydial organisms depleted of plasmid or deficient in the plasmid-encoded Pgp3 are attenuated in ascending infection and no longer are able to induce the upper genital tract pathologies, indicating a significant role of Pgp3 in chlamydial pathogenesis. We now report that C. trachomatis Pgp3 can neutralize the antichlamydial activity of human cathelicidin LL-37, a host antimicrobial peptide secreted by both genital tract epithelial cells and infiltrating neutrophils. Pgp3 bound to and formed stable complexes with LL-37. We further showed that the middle region of Pgp3 (Pgp3m) was responsible for both the binding to and neutralization of LL-37, suggesting that Pgp3m can be targeted for attenuating chlamydial pathogenicity or developed for blocking LL-37-involved non-genital-tract pathologies, such as rosacea and psoriasis. Thus, the current study has provided significant information for both understanding the mechanisms of chlamydial pathogenesis and developing novel therapeutic agents. Chlamydia trachomatis infection in women's lower genital tract can ascend to and cause inflammatory pathologies in the upper genital tract, resulting in complications such as ectopic pregnancy and tubal infertility (1, 2). However, the mechanisms of how the C. trachomatis organisms ascend to the upper genital tract remain unknown. It is thought that the organisms' ability to complete intracellular replication and to spread from cell to cell significantly contributes to chlamydial pathogenicity (3-6). Chlamydial intracellular infection starts with the entry of an infectious elementary body (EB) into an epithelial cell via pathogen-induced endocytosis (7,8). The endocytosed EB differentiates to a noninfectious but metabolically active reticulate body (RB). After replication, the progeny RBs differentiate back to EBs that exit the infected cells to invade adjacent cells (6). The spreading from cell to cell inevitably exposes the progeny EBs to the extracellular mucosal environment, in which numerous host defense molecules, such as antimicrobial peptides (AMPs), are available for attacking the extracellular EBs. It is unclear how the C. trachomatis EB organisms manage to overcome these host defense mechanisms to ascend to the upper genital tract.Cationic peptides that possess antimicrobial activities are defined as AMPs, which include human alpha-defensins (HADs) or human neutrophil peptides (HNPs), human beta-defensins (HBDs), and cathelicidin LL-37 (9-12). LL-37 is a C-terminal 37-amino-acid peptide starting with double leucines (LL) processed from human cationic antimicrobial protein 18 (hCAP; 18 kDa) that contains a highly conserved amino-terminal cathelinlike domain and a variable carboxy-terminal domain (9, 11). The mouse orthologue is called cathelin-related antimicrobial peptide (CRAMP) (13). HNPs are produced mainly by neu...

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“…It is known that C. trachomatis organisms can secrete numerous proteins into host cell cytoplasm [18,19]. Among them, Chlamydial Protease-Like Activity Factor (CPAF), a chlamydial type II secretion protein, may serve as a promising candidate of virulence factor as proposed [16,[20][21][22].…”

Section: Introductionmentioning

confidence: 99%

CPAF selectively degrades chlamydial T cell antigens for inhibiting antigen presentation

Zhang

Zhong

Cai

et al. 2017

J Infect Dev Ctries

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Introduction: Chlamydia trachomatis is the leading cause of sexually transmitted bacterial disease, which may cause significant threats, such as pelvic inflammatory disease and tubal factor infertility, to women if untreated. The pathological mechanisms of chlamydia-induced disease remain largely unknown, but it has been proposed that CPAF, a chlamydia-secreted serine protease, may play major roles in aiding chlamydial infection and contribute to chlamydia pathogenesis during in vivo infection. According to previous results, CPAF targets host immunity by degrading antimicrobial peptides and neutralizing complement activity; however, whether CPAF is involved in chlamydial antigen presentation has never been reported. Methodology: Antigen presentation assay was used to monitor the effects of CPAF on OT1-, OT2-, and chlamydia T cell antigen-mediated antigen presentation. In vitro cell-free degradation assay was used to detect CPAF processing of chlamydia T cell antigens. Results: We found that CPAF preferably inhibits OT2-but not OT1-mediated antigen presentation. CPAF inhibits OT2 antigen presentation by direct proteolytic cleavage in the wild type CPAF, but not enzymatic mutants. Importantly, several previously identified chlamydial T cell antigens were selectively degraded by CPAF when co-incubated in vitro. In addition, specific inhibition T cell antigen presentation by CPAF was correlated with T cell antigen cleavage by CPAF in vitro assay. Conclusions: Our experiments demonstrated that CPAF selectively and specifically degrades chlamydial T cell antigens, which chlamydia may utilize as a novel mechanism for evading host immune responses to promote chlamydia survival.

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Characterization of CPAF Critical Residues and Secretion during Chlamydia trachomatis Infection

Cited by 20 publications

References 46 publications

The Chlamydia-Secreted Protease CPAF Promotes Chlamydial Survival in the Mouse Lower Genital Tract

The Chlamydia-Secreted Protease CPAF Promotes Chlamydial Survival in the Mouse Lower Genital Tract

Chlamydial Plasmid-Encoded Virulence Factor Pgp3 Neutralizes the Antichlamydial Activity of Human Cathelicidin LL-37

CPAF selectively degrades chlamydial T cell antigens for inhibiting antigen presentation

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