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Altered developmental expression of polymorphic membrane proteins in penicillin-stressed Chlamydia trachomatis.

ABSTRACT: Late Chlamydia trachomatis inclusions express each member of the surface-exposed polymorphic membrane protein family (Pmp subtypes A through I) with a reproducible distribution of fully-on, fully-off and intermediate phenotypes. This observation is consistent with observed variable Pmp antibody profiles in C. trachomatis-infected patients and has led to the hypothesis that the pmp gene family forms the basis of a phase variation-like mechanism of antigenic variation. Here we investigate and compare the developmental expression of each of the nine pmp genes under conditions of optimal in vitro growth with that under conditions that promote prolonged survival of chlamydiae when exposed to penicillin-induced stress. We demonstrate that the pmp gene family includes distinct transcriptional units that are differentially expressed along development and differentially responsive to stress. In particular, our results indicate that expression of pmpA, pmpD and pmpI is uniquely unaffected by stress, suggesting that the PmpA, PmpD and PmpI proteins play a critical role in the pathogenesis of C. trachomatis.

SUBMITTER: Carrasco JA

PROVIDER: S-EPMC3116966 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Altered developmental expression of polymorphic membrane proteins in penicillin-stressed Chlamydia trachomatis.

Carrasco Jose A JA Tan Chun C Rank Roger G RG Hsia Ru-ching RC Bavoil Patrik M PM

Cellular microbiology 20110426 7

Late Chlamydia trachomatis inclusions express each member of the surface-exposed polymorphic membrane protein family (Pmp subtypes A through I) with a reproducible distribution of fully-on, fully-off and intermediate phenotypes. This observation is consistent with observed variable Pmp antibody profiles in C. trachomatis-infected patients and has led to the hypothesis that the pmp gene family forms the basis of a phase variation-like mechanism of antigenic variation. Here we investigate and comp ...[more]

PMID: 21504531

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Project description:Chlamydia trachomatis is the most important infectious cause of infertility in women with important implications in public health and for which a vaccine is urgently needed. Recent immunoproteomic vaccine studies found that four polymorphic membrane proteins (PmpE, PmpF, PmpG and PmpH) are immunodominant, recognized by various MHC class II haplotypes and protective in mouse models. In the present study, we aimed to evaluate genetic and protein features of Pmps (focusing on the N-terminal 600 amino acids where MHC class II epitopes were mapped) in order to understand antigen variation that may emerge following vaccine induced immune selection. We used several bioinformatics platforms to study: i) Pmps' phylogeny and genetic polymorphism; ii) the location and distribution of protein features (GGA(I, L)/FxxN motifs and cysteine residues) that may impact pathogen-host interactions and protein conformation; and iii) the existence of phase variation mechanisms that may impact Pmps' expression. We used a well-characterized collection of 53 fully-sequenced strains that represent the C. trachomatis serovars associated with the three disease groups: ocular (N=8), epithelial-genital (N=25) and lymphogranuloma venereum (LGV) (N=20). We observed that PmpF and PmpE are highly polymorphic between LGV and epithelial-genital strains, and also within populations of the latter. We also found heterogeneous representation among strains for GGA(I, L)/FxxN motifs and cysteine residues, suggesting possible alterations in adhesion properties, tissue specificity and immunogenicity. PmpG and, to a lesser extent, PmpH revealed low polymorphism and high conservation of protein features among the genital strains (including the LGV group). Uniquely among the four Pmps, pmpG has regulatory sequences suggestive of phase variation. In aggregate, the results suggest that PmpG may be the lead vaccine candidate because of sequence conservation but may need to be paired with another protective antigen (like PmpH) in order to prevent immune selection of phase variants.

Project description:BackgroundChlamydia trachomatis is a major human pathogen with a unique obligate intracellular developmental cycle that takes place inside a modified cytoplasmic structure known as an inclusion. Following entry into a cell, the infectious elementary body (EB) differentiates into a non-infectious replicative form known as a reticulate body (RB). RBs divide by binary fission and at the end of the cycle they redifferentiate into EBs. Treatment of C.trachomatis with penicillin prevents maturation of RBs which survive and enlarge to become aberrant RBs within the inclusion in a non-infective persistent state. Persistently infected individuals may be a reservoir for chlamydial infection. The C.trachomatis genome encodes the enzymes for peptidoglycan (PG) biosynthesis but a PG sacculus has never been detected. This coupled to the action of penicillin is known as the chlamydial anomaly. We have applied video microscopy and quantitative DNA assays to the chlamydial developmental cycle to assess the effects of penicillin treatment and establish a framework for investigating penicillin induced chlamydial persistence.Principal findingsAddition of penicillin at the time of cell infection does not prevent uptake and the establishment of an inclusion. EB to RB transition occurs but bacterial cytokinesis is arrested by the second binary fission. RBs continue to enlarge but not divide in the presence of penicillin. The normal developmental cycle can be recovered by the removal of penicillin although the large, aberrant RBs do not revert to the normal smaller size but remain present to the completion of the developmental cycle. Chromosomal and plasmid DNA replication is unaffected by the addition of penicillin but the arrest of bacterial cytokinesis under these conditions results in RBs accumulating multiple copies of the genome.ConclusionsWe have applied video time lapse microscopy to the study of the chlamydial developmental cycle. Linked with accurate measures of genome replication this provides a defined framework to analyse the developmental cycle and to investigate and provide new insights into the effects of antibiotic treatments. Removal of penicillin allows recovery of the normal developmental cycle by 10-20 hrs and the process occurs by budding from aberrant RBs.

Dataset Information

Altered developmental expression of polymorphic membrane proteins in penicillin-stressed Chlamydia trachomatis.

Publications

Altered developmental expression of polymorphic membrane proteins in penicillin-stressed Chlamydia trachomatis.

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