CT043, a Protective Antigen That Induces a CD4⁺Th1 Response duringChlamydia trachomatisInfection in Mice and Humans

Abstract

Despite several decades of intensive studies, no vaccines against Chlamydia trachomatis, an intracellular pathogen causing serious ocular and urogenital diseases, are available yet. Infection-induced immunity in both animal models and humans strongly supports the notion that for a vaccine to be effective a strong CD4 ؉ Th1 immune response should be induced. In the course of our vaccine screening program based on the selection of chlamydial proteins eliciting cell-mediated immunity, we have found that CT043, a protein annotated as hypothetical, induces CD4 ؉ Th1 cells both in chlamydia-infected mice and in human patients with diagnosed C. trachomatis genital infection. DNA priming/protein boost immunization with CT043 results in a 2.6-log inclusion-forming unit reduction in the murine lung infection model. Sequence analysis of CT043 from C. trachomatis human isolates belonging to the most representative genital serovars revealed a high degree of conservation, suggesting that this antigen could provide cross-serotype protection. Therefore, CT043 is a promising vaccine candidate against C. trachomatis infection.Chlamydia trachomatis is an obligate intracellular human pathogen which exists in two highly specialized morphological forms: the infectious elementary body (EB) and the replicative reticulate body (RB). The pathogen has been classified into 19 different serotypes (serovars), on the basis of which variant of the major outer membrane protein (MOMP) is expressed on its surface. Worldwide, C. trachomatis is responsible for more than 92 million sexually transmitted infections and 85 million ocular infections per year (45). These infections cause several types of diseases (35, 44), including trachoma-induced blindness (serovars A to C), pelvic inflammatory disease, ectopic pregnancy and infertility (serovars D to K), and lymphogranuloma venereum (serovars L1 to L3). Furthermore, recent studies indicate that chlamydia infections facilitate the transmission of both human immunodeficiency virus (28) and hu-

Approach to discover T- and B-cell antigens of intracellular pathogens applied to the design of Chlamydia trachomatis vaccines

“…Genome/proteome-based highthroughput technologies have been exploited recently to study Chlamydia immunogenic antigens (17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Although the data are not always easily comparable because of the use of different strains, assays, and infected hosts (mice and humans), a Chlamydia immunome atlas can be compiled (Table S3) if one takes as reference the genome annotation of C. trachomatis and combines both mouse and human immunogenic antigens.…”

“…S1. These approaches including selection and preparation of recombinant proteins, preparation of a protein array and immunoscreening with human and mice sera, screening of CD4-Th1 cell target antigens, protection in a mouse model of lung infection, and confocal microscopy analysis of protein expression (51,22). Specifications and further details are provided in SI Materials and Methods.…”

“…Three antigens (TC0106, TC0313, and TC0551) belong to the group of the CD4 + T-cell inducers; TC0741 elicits high antibody titers in infected humans, and TC0210 induces both types of response. Recently TC0741 has been shown to confer protective immunity against upper genital tract pathologies in mice (26), and we recently reported that TC0313 induces significant protection in DNA immunization experiments (22).…”

“…2A, 21 antigens induced significantly higher IFN-γ production in CD4 + T cells from infected mice (>30 positive T cells per 10 5 cells) than in T cells from negative controls. Five of the 21 antigens have been described previously as targets of CD4 + T cells: MOMP (CT681), the hypothetical protein CT043 (20,22), DnaK (CT396) (19,20,27), OmcB (CT443) (20,27), and Enolase (CT587) (18). To the best of our knowledge, the remaining 16 have not been reported to induce IFN-γ-producing CD4 + T cells during C. trachomatis infection (Tables S2 and S3).…”

“…A large body of evidence derived from our understanding of Chlamydia immunity in animal models (13)(14)(15)(16) and in humans (14,17) indicates that both IFN-γ-producing, Chlamydia-specific CD4 + type 1 T helper (Th1) cells and antiChlamydia antibodies are required to mount a protective immune response. A number of chlamydial proteins eliciting CD4 + T cells and/or antibodies have been described (17)(18)(19)(20)(21)(22)(23)(24)(25)(26). However, with few exceptions, they provide only partial protection in animal models, and, in any case, their protective activity is not comparable with the protective immunity induced by infection.…”