Plasmid-mediated virulence in Chlamydia

Abstract

Chlamydia trachomatis infection of ocular conjunctiva can lead to blindness, while infection of the female genital tract can lead to chronic pelvic pain, ectopic pregnancy, and/or infertility. Conjunctival and fallopian tube inflammation and the resulting disease sequelae are attributed to immune responses induced by chlamydial infection at these mucosal sites. The conserved chlamydial plasmid has been implicated in enhancing infection, via improved host cell entry and exit, and accelerating innate inflammatory responses that lead to tissue damage. The chlamydial plasmid encodes eight open reading frames, three of which have been associated with virulence: a secreted protein, Pgp3, and putative transcriptional regulators, Pgp4 and Pgp5. Although Pgp3 is an important plasmid-encoded virulence factor, recent studies suggest that chlamydial plasmid-mediated virulence extends beyond the expression of Pgp3. In this review, we discuss studies of genital, ocular, and gastrointestinal infection with C. trachomatis or C. muridarum that shed light on the role of the plasmid in disease development, and the potential for tissue and species-specific differences in plasmid-mediated pathogenesis. We also review evidence that plasmid-associated inflammation can be independent of bacterial burden. The functions of each of the plasmid-encoded proteins and potential molecular mechanisms for their role(s) in chlamydial virulence are discussed. Although the understanding of plasmid-associated virulence has expanded within the last decade, many questions related to how and to what extent the plasmid influences chlamydial infectivity and inflammation remain unknown, particularly with respect to human infections. Elucidating the answers to these questions could improve our understanding of how chlamydia augment infection and inflammation to cause disease.

Molecular pathogenesis of Chlamydia trachomatis

“…The plasmid encodes 8 glycoproteins (pGP1-8) that have a variety of functions including promoting infection ascension, inducing pro-inflammatory responses, and promoting extrusion processes. pGP4, is a putative transcriptional regulator of both plasmid and chromosomal genes ( Turman et al., 2023 ). Virulence plasmid-deficient or pGP3-deficient strains resulted in attenuated infections ( Carlson et al., 2008 ).…”

Requirement of GrgA for Chlamydia infectious progeny production, optimal growth, and efficient plasmid maintenance

“…Importantly, we show that GrgA is necessary for RB-to-EB differentiation and is also required for optimal RB growth. We further demonstrate that GrgA regulates the maintenance of the normal copy number of the plasmid, which encodes Pgp3 (a secreted virulence factor), Pgp4 (a transcriptional regulator of specific chromosomal genes as well as Pgp3), and proteins involved in plasmid replication ( 31 – 33 ). These findings provide further evidence that GrgA is a major regulator of σ66, σ28, and σ54 target genes, and plays important regulatory roles in governing the chlamydial developmental cycle.…”

“…In addition to the replication origin, we kept all eight genes encoded by the wild-type C. trachomatis plasmid in the shuttle vector. This is because Pgp1, 2, 6, and 8 are essential for plasmid maintenance, while Pgp3 and 4 are a virulence determinant and regulator of certain chromosomal genes, respectively ( 31 – 33 ). Compared to the native chromosomal grgA allele containing a Targetron-insertion site between nucleotides 67 and 68 ( Fig.…”

Infection of human organoids supports an intestinal niche forChlamydia trachomatis

“…The importance of the plasmid for the successful colonization of the GI tract by Chlamydia has been demonstrated in the mouse model of infection [26]. The importance of the plasmid is further evidenced by the fact that naturally occurring plasmid-free clinical isolates are very rare [36, 37].…”