Polymorphisms in the Chlamydia trachomatis Cytotoxin Locus Associated with Ocular and Genital Isolates

Abstract

Chlamydia trachomatis is a strict human pathogen producing infections that cause medically important chronic inflammatory diseases, such as blinding trachoma and tubal factor infertility. Isolates exist as serotypes that fall into distinct biologic and pathological groups corresponding to differences in infection tissue tropism and invasion properties. Paradoxically, genome sequencing of several diverse strains has revealed a remarkable level of genomic synteny, suggesting that minor genetic differences determine the pathogen hostand tissue-specific infection characteristics. To better understand the genetic basis of chlamydial pathobiologic diversity, we performed comparative DNA-DNA microarray genomic hybridizations with all 15 C. trachomatis serovariants. We found there are few major genetic differences among the 15 serovars. An exception was the cytotoxin locus located in the plasticity zone, a region that exhibited significant polymorphisms among serovars. We therefore sequenced this region from all 15 serovars. The cytotoxin gene was interrupted by extensive mutations and deletions among the different serovars; however, three basic open reading frame motifs were discovered that correlated with noninvasive oculotropic, urogenitotropic, and invasive serovars. Of interest, only noninvasive genitotropic serovars possessed an intact N-terminal portion of the putative toxin gene. This region contains the UDP-glucose binding domain and the glycosyltransferase domain required for enzymatic activity of the clostridial toxin homologs, suggesting a role in urogenital infection or pathogenesis.Chlamydia trachomatis is an obligate intracellular prokaryote characterized by a complex intracellular development cycle. Isolates can be differentiated into biovars or serovars based on their in vitro infection properties and type of disease (26) or on antigenic variation of the major outer membrane protein (OmpA), respectively (36). Isolates are serologically classified into 15 OmpA serovariants. Serovars A to C are the etiologic agents of trachoma (15, 26); serovars D to K and L1 to L3 are sexually transmitted pathogens causing cervicitis and urethritis or lymphogranuloma venereum (LGV), respectively. Serovars A to K produce infections restricted to the mucosae, whereas the LGV serovars infect monocytes and disseminate to local draining lymph nodes (26). The serovars associated with mucosal infections produce a wide spectrum of infection outcomes that range from asymptomatic to chronic inflammatory disease (26). Severe inflammatory disease can result in trachoma, the leading cause of blindness, or in pelvic inflammatory disease, a leading cause of tubal factor infertility.The genomes of several chlamydial strains have been sequenced. Comparative genomics has shown that the small genomes (1.04 to 1.3 Mb) share a striking degree of synteny in that gene order and content are highly conserved (23,24,31). One exception is a polymorphic region of the genome termed the plasticity zone (PZ). Read et al. (23) initially hypothesized, ...

The AlternativeTranslational Profile That Underlies the Immune-Evasive State of Persistence in Chlamydiaceae Exploits Differential Tryptophan Contents of the Protein Repertoire

“…Cytotoxin genes are located within a unique chlamydial region of variability called the plasticity zone (see reference 82 and references therein). The cytotoxin gene of C. trachomatis D/UW-3 has undergone extensive degradation and is mostly nonfunctional, although one fragment (CT166) retains some function (23). Even at the serovar level, cytotoxin variability is evident.…”

Chlamydia trachomatis: Genome sequence analysis of lymphogranuloma venereum isolates

“…The variation in size of the C. trachomatis PZ is largely due to differential deletion of the cytotoxin gene(s), which have been almost entirely deleted from strain L2, leaving two gene remnants CTL0420 and CTL0421 (Belland et al 2001;Carlson et al 2004) (Fig. 3).…”

“…synteny and genome-sequence conservation, although some gene differences were identified that may account for the differing disease outcomes associated with the different biovars (Caldwell et al 2003;Carlson et al 2004). Thus, comparison of an LGV isolate with these related strains is likely to provide further insights into the mechanisms that may influence disease outcome and the underlying genetic differences that differentiate these biovariants.…”

Development of a vaccine for Chlamydia trachomatis: challenges and current progress

“…Although the ocular and genital strains of C. trachomatis are strictly differentiated, with ocular strains lacking tryptophan synthase function, 22 the genomes of C. trachomatis serovars are more than 99% identical, 23,24 and the host-pathogen interactions in chlamydial infections are known to be serovarspecific. A recent report from a Dutch STI clinic showed that in comparison with the other urogenital isolates, serovars D and E, two of the most prevalent urogenital serovars worldwide, 25,26 induced the highest serological immunoglobulin G responses in women with urogenital C. trachomatis infections.…”