<i>Chlamydia trachomatis</i>polymorphic membrane protein D is a species-common pan-neutralizing antigen

Crane, Deborah D.; Carlson, John H.; Fischer, Elizabeth R.; Bavoil, Patrik M.; Hsia, Ru-ching; Tan, Chun Hong; Kuo, Cho‐Chou; Caldwell, Harlan D.

doi:10.1073/pnas.0508983103

Cited by 142 publications

(150 citation statements)

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“…However, recent advancements in chlamydial genetics now provide new approaches to study gene function (6)(7)(8). C. trachomatis PmpD has been implicated as an important chlamydial virulence factor, as it is a conserved surface antigen and target of neutralizing antibodies (12). However, direct evidence supporting this hypothesis is lacking.…”

Section: Discussionmentioning

confidence: 88%

“…PmpD exhibits classical AT processing resulting in a membrane translocator domain that facilitates the presentation of a passenger domain on the chlamydial surface (11). PmpD is highly conserved among all C. trachomatis strains and is the target of broadly neutralizing antibodies (12). Despite its conserved nature, surface localization, and immunological importance, little is known about the function of PmpD in the pathogenesis of C. trachomatis infection.…”

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confidence: 99%

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Chlamydia trachomatis Polymorphic Membrane Protein D Is a Virulence Factor Involved in Early Host-Cell Interactions

et al. 2014

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Chlamydia trachomatis is an obligate intracellular mucosotropic pathogen of significant medical importance. It is the etiological agent of blinding trachoma and bacterial sexually transmitted diseases, infections that afflict hundreds of millions of people globally. The C. trachomatis polymorphic membrane protein D (PmpD) is a highly conserved autotransporter and the target of broadly cross-reactive neutralizing antibodies; however, its role in host-pathogen interactions is unknown. Here we employed a targeted reverse genetics approach to generate a pmpD null mutant that was used to define the role of PmpD in the pathogenesis of chlamydial infection. We show that pmpD is not an essential chlamydial gene and the pmpD null mutant has no detectable deficiency in cultured murine cells or in a murine mucosal infection model. Notably, however, the pmpD null mutant was significantly attenuated for macaque eyes and cultured human cells. A reduction in pmpD null infection of human endocervical cells was associated with a deficiency in chlamydial attachment to cells. Collectively, our results show that PmpD is a chlamydial virulence factor that functions in early host-cell interactions. This study is the first of its kind using reverse genetics to evaluate the contribution of a C. trachomatis gene to disease pathogenesis. Chlamydia trachomatis is an obligate intracellular mucosotropic bacterium that is the most common cause of preventable blindness (1, 2) and bacterial sexually transmitted infections worldwide (3-5). The study of these medically important pathogens has been severely limited in the past by the lack of genetic tools. However, newly developed genetic approaches enable us to ask definitive questions about the contribution of specific chlamydial genes to pathogenesis (6-8). Polymorphic membrane protein D (PmpD) is one of nine putative autotransporters (ATs) encoded in the C. trachomatis genome (9). ATs are members of the Gram-negative bacterial type V secretion system and are important virulence factors that function in host-cell interactions and immune evasion (10). PmpD exhibits classical AT processing resulting in a membrane translocator domain that facilitates the presentation of a passenger domain on the chlamydial surface (11). PmpD is highly conserved among all C. trachomatis strains and is the target of broadly neutralizing antibodies (12). Despite its conserved nature, surface localization, and immunological importance, little is known about the function of PmpD in the pathogenesis of C. trachomatis infection.Here, we made a C. trachomatis pmpD null mutant using a targeted reverse genetic approach (6). pmpD was not essential for C. trachomatis growth, and the pmpD null mutant showed no deficiency in cultured murine cell lines in vitro or in a mouse urogenital infection model. However, the pmpD null mutant was attenuated in cultured human endocervical and conjunctival cells and in a nonhuman primate model of C. trachomatis ocular infection. Our findings show that C. trachomatis PmpD is a virulence fact...

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Section: Discussionmentioning

confidence: 88%

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Chlamydia trachomatis Polymorphic Membrane Protein D Is a Virulence Factor Involved in Early Host-Cell Interactions

et al. 2014

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“…The type V autotransporter Pmp13G (24) is a member of the Pmp family, representing proteins that play an important role in the pathogenesis of chlamydial infections. Several Pmps of C. trachomatis, C. pneumoniae, C. psittaci, and C. abortus have been shown to elicit a humoral immune response (13,25), with PmpD of C. trachomatis being described as a pan-neutralizing antigen (26). Pmps are differentially expressed during the chlamydial developmental cycle (27,28) and are therefore suspected to play a role in antigenic diversity and evasion of the host immune response.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Humoral Immune Responses to Surface and Virulence-Associated Chlamydiaabortus Proteins in Ovine and Human Abortions by Use of a Newly Developed Line Immunoassay

et al. 2016

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fThe obligate intracellular bacterium Chlamydia abortus is the causative agent of enzootic abortion of ewes and poses a significant zoonotic risk for pregnant women. Using proteomic analysis and gene expression library screening in a previous project, we identified potential virulence factors and candidates for serodiagnosis, of which nine were scrutinized here with a strip immunoassay. We have shown that aborting sheep exhibited a strong antibody response to surface (MOMP, MIP, Pmp13G) and virulence-associated (CPAF, TARP, SINC) antigens. While the latter disappeared within 18 weeks following abortion in a majority of the animals, antibodies to surface proteins persisted beyond the duration of the study. In contrast, nonaborting experimentally infected sheep developed mainly antibodies to surface antigens (MOMP, MIP, Pmp13G), all of which did not persist. We were also able to detect antibodies to these surface antigens in C. abortus-infected women who had undergone septic abortion, whereas a group of shepherds and veterinarians with occupational exposure to C. abortus-infected sheep revealed only sporadic immune responses to the antigens selected. The most specific antigen for the serodiagnosis of human C. abortus infections was Pmp13G, which showed no cross-reactivity with other chlamydiae infecting humans. We suggest that Pmp13G-based serodiagnosis accomplished by the detection of antibodies to virulence-associated antigens such as CPAF, TARP, and SINC may improve the laboratory diagnosis of human and animal C. abortus infections. Chlamydia abortus is an obligate intracellularly replicating zoonotic bacterium that shares a characteristic biphasic developmental cycle with all other members of the family Chlamydiaceae (1). Among chlamydiae affecting humans, Chlamydia trachomatis is the most clinically and epidemiologically relevant as a cause of oculogenital infections, including nongonococcal urethritis and cervicitis, lymphogranuloma venereum, and trachoma. Chlamydia pneumoniae is known to be involved in community-acquired pneumonia, pharyngitis, bronchitis, and sinusitis. In addition, the avian pathogen Chlamydia psittaci has well-documented zoonotic potential, causing human psittacosis (ornithosis), which may present as a generalized and life-threatening pneumonia (2).C. abortus typically occurs in ruminants such as sheep and goats and is the leading cause of enzootic abortion of ewes (EAE) worldwide (3). Even in the absence of elevated abortion rates, the agent was shown to be widespread in German sheep flocks, with 50% of flocks testing PCR positive and 94% harboring seropositive animals (4). Afterbirths and fetuses of abortion cases can contain heavy loads of the pathogen and represent the major source of transmission to susceptible humans and naive ewes, as well as environmental contamination (3). Inhalation of infective aerosols by pregnant women poses the risk of severe infection, including spontaneous abortion, stillbirth, and septicemia (3, 5, 6). However, very little is known about the clinical rel...

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“…Cumulative evidences indicate that Pmps may function as fine-tune determinants of C. trachomatis pathobiology, either by antigenic variation (15,21,63,78) or by hostcell adhesion (22,36,38), hypothetically through a shutoff mechanism at the inclusion level (77). It is posited that the accelerated evolution between paralogues is common and constitutes a mechanism for the generation of new genes and new biochemical functions (46).…”

Section: Discussionmentioning

confidence: 99%

Directional Evolution of Chlamydia trachomatis towards Niche-Specific Adaptation

et al. 2012

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On behalf of the host-pathogen "arms race," a cutting-edge approach for elucidating genotype-phenotype relationships relies on the identification of positively selected loci involved in pathoadaptation. We studied the obligate intracellular bacterium Chlamydia trachomatis, for which same-species strains display a nearly identical core and pan genome, while presenting a wide range of tissue tropism and ecological success. We sought to evaluate the evolutionary patterns underlying species separation (divergence) and C. trachomatis serovar radiation (polymorphism) and to establish genotype-phenotype associations. By analyzing 60 Chlamydia strains, we detected traces of Muller's ratchet as a result of speciation and identified positively selected genes and codons hypothetically involved in the infection of different human cell types (e.g., columnar epithelial cells of ocular or genital mucosae and mononuclear phagocytes) and also events likely driving pathogenic and ecological success dissimilarities. In general, these genes code for proteins involved in immune response elicitation, proteolysis, and the subversion of host-cell functions, and also for proteins with unknown function(s). Several genes are potentially involved in more than one adaptive process, suggesting multiple functions or a distinct modus operandi for a specific function, and thus should be considered as crucial research targets. In addition, six of the nine genes encoding the putative antigen/adhesin polymorphic membrane proteins seem to be under positive selection along specific serovars, which sustains an essential biological role of this extra-large paralogue family in chlamydial pathobiology. This study provides insight into how evolutionary inferences illuminate ecological processes such as adaptation to different niches, pathogenicity, or ecological success driven by arms races. G enomic changes of microbial pathogens are directly linked to the evolutionary "arms race" that takes place between microbe and host during the infectious process, as a result of the antagonistic interaction, and they are a consequence of polymorphisms accumulated after selective pressure from the host's inflammatory or immune response (32). However, the majority of coding genes present a higher number of synonymous rather than nonsynonymous substitutions, which indicates that purifying selection is operating to preserve the current function and structure of the protein, and only a small fraction of the genes are expected to be positively selected where diversification is favored through increased fitness (11). In order to understand the evolutionary forces that act on gene variation, major challenges are to identify loci that might have been under selection and to determine the type of natural selection that has influenced their evolutionary history (59). In the field of infectious diseases, site-specific inferences regarding positive selection on loci involved in drug resistance (19) or in the interaction with the host immune system have been proposed as complemen...

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Chlamydia trachomatispolymorphic membrane protein D is a species-common pan-neutralizing antigen

Cited by 142 publications

References 39 publications

Chlamydia trachomatis Polymorphic Membrane Protein D Is a Virulence Factor Involved in Early Host-Cell Interactions

Chlamydia trachomatis Polymorphic Membrane Protein D Is a Virulence Factor Involved in Early Host-Cell Interactions

Analysis of Humoral Immune Responses to Surface and Virulence-Associated Chlamydiaabortus Proteins in Ovine and Human Abortions by Use of a Newly Developed Line Immunoassay

Directional Evolution of Chlamydia trachomatis towards Niche-Specific Adaptation

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