Chlamydial protease-like activity factor—insights into immunity and vaccine development

South Texas Center for Emerging Infectious Diseases, Department of Biology, University of Texas at San Antonio, One UTSA circle, San Antonio, TX 78249, USA.
Journal of Reproductive Immunology (Impact Factor: 2.82). 10/2009; 83(1-2):179-84. DOI: 10.1016/j.jri.2009.05.007
Source: PubMed


Chlamydia trachomatis is a Gram-negative obligate intracellular pathogen that remains the leading cause of bacterial sexually transmitted disease worldwide, despite the availability of efficacious antimicrobial therapy. Given that chlamydial infections cause severe pathological sequelae in the upper genital tract, a licensed vaccine to prevent infection and disease would be an ideal solution. Chlamydial protease-like activity factor (CPAF) is a protein secreted in considerable amounts into the cytosol of infected cells and released into the extracellular milieu upon cellular lysis, which therefore is accessible to the host immune system. This is further substantiated by the observation that CPAF is immunodominant among other antigens in Chlamydia sero-positive humans. The efficacy of vaccination with CPAF against genital chlamydial challenge has been evaluated extensively in the murine model. This review will discuss important insights into the potential of CPAF as a component of an anti-chlamydial vaccine.

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    • "In addition, CPAF released from infected cells may play a prominent role in tissue colonization or dissemination in infected animals. Indeed, experimentally infected animals and human patients develop a strong humoral response to CPAF, and immunization with recombinant CPAF is protective against infections (Murthy et al., 2009, 2011), suggesting that this protein may have extracellular roles in tissue infections. It should also be emphasized that our findings are restricted to the role of CPAF in strain LGV-L2. "
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    ABSTRACT: The secreted Chlamydia protease CPAF cleaves a defined set of mammalian and Chlamydia proteins in vitro. As a result, this protease has been proposed to modulate a range of bacterial and host cellular functions. However, it has recently come into question the extent to which many of its identified substrates constitute bona fide targets of proteolysis in infected host cell rather than artifacts of postlysis degradation. Here, we clarify the role played by CPAF in cellular models of infection by analyzing Chlamydia trachomatis mutants deficient for CPAF activity. Using reverse genetic approaches, we identified two C. trachomatis strains possessing nonsense, loss-of-function mutations in cpa (CT858) and a third strain containing a mutation in type II secretion (T2S) machinery that inhibited CPAF activity by blocking zymogen secretion and subsequent proteolytic maturation into the active hydrolase. HeLa cells infected with T2S(-) or CPAF(-) C. trachomatis mutants lacked detectable in vitro CPAF proteolytic activity and were not defective for cellular traits that have been previously attributed to CPAF activity, including resistance to staurosporine-induced apoptosis, Golgi fragmentation, altered NFκB-dependent gene expression, and resistance to reinfection. However, CPAF-deficient mutants did display impaired generation of infectious elementary bodies (EBs), indicating an important role for this protease in the full replicative potential of C. trachomatis. In addition, we provide compelling evidence in live cells that CPAF-mediated protein processing of at least two host protein targets, vimentin filaments and the nuclear envelope protein lamin-associated protein-1 (LAP1), occurs rapidly after the loss of the inclusion membrane integrity, but before loss of plasma membrane permeability and cell lysis. CPAF-dependent processing of host proteins correlates with a loss of inclusion membrane integrity, and so we propose that CPAF plays a role late in infection, possibly during the stages leading to the dismantling of the infected cell prior to the release of EBs during cell lysis.
    Foodborne Pathogens and Disease 05/2014; 71(3). DOI:10.1111/2049-632X.12179 · 1.91 Impact Factor
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    • "The protection induced by CPAF in mice was dependent on CD4þ T cells [46] and IFNg [47] and the role of anti-CPAF antibodies in protection against chlamydial infection was limited [48]. Although the CPAF-induced murine protection mechanism [49] is consistent with the knowledge on immunity of chlamydial infection in mice [50], it remains unknown whether CPAF-specific immune responses play any role in chlamydial infection and pathogenesis in humans and which immune mechanisms are involved. Thus, it has now become necessary to evaluate whether humans produce CD4þ T cell responses to CPAF during chlamydial infection and whether the CPAFspecific cellular responses are protective. "
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    ABSTRACT: CPAF is a conserved and secreted protease from obligate intracellular bacteria of the order Chlamydiae. Recently, it was demonstrated that most of its host targets are an artifact of inaccurate methods. This review aims to summarize key features of CPAF and propose new approaches for evaluating its role in chlamydial pathogenesis.
    Microbes and Infection 10/2013; 15(14-15). DOI:10.1016/j.micinf.2013.09.008 · 2.86 Impact Factor
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    • "The differences in the level of protective immunity observed between i.n. C. pne versus C. mur immunized groups correlated with the differences in levels of splenic antigen-specific IFN-γ production. The production of Chlamydia-specific IFN-γ has been shown to be crucial in mediating enhanced clearance and protective immunity against C. mur challenge [1], [3], [18]. "
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    ABSTRACT: Chlamydia trachomatis is the most common bacterial sexually transmitted disease in the world and specifically in the United States, with the highest incidence in age-groups 14-19 years. In a subset of females, the C. trachomatis genital infection leads to serious pathological sequelae including pelvic inflammatory disease, ectopic pregnancy, and infertility. Chlamydia pneumoniae, another member of the same genus, is a common cause of community acquired respiratory infection with significant number of children aged 5-14 yr displaying sero-conversion. Since these bacteriae share several antigenic determinants, we evaluated whether intranasal immunization with live C. pneumoniae (1×10(6) inclusion forming units; IFU) in 5 week old female C57BL/6 mice would induce cross-species protection against subsequent intravaginal challenge with Chlamydia muridarum (5×10(4) IFU), which causes a similar genital infection and pathology in mice as C. trachomatis in humans. Mice vaccinated intranasally with live C. pneumoniae, but not mock (PBS) immunized animals, displayed high levels of splenic cellular antigen-specific IFN-γ production and serum antibody response against C. muridarum and C. trachomatis. Mice vaccinated with C. pneumoniae displayed a significant reduction in the vaginal C. muridarum shedding as early as day 12 after secondary i.vag. challenge compared to PBS (mock) immunized mice. At day 19 after C. muridarum challenge, 100% of C. pneumoniae vaccinated mice had cleared the infection compared to none (0%) of the mock immunized mice, which cleared the infection by day 27. At day 80 after C. muridarum challenge, C. pneumoniae vaccinated mice displayed a significant reduction in the incidence (50%) and degree of hydrosalpinx compared to mock immunized animals (100%). These results suggest that respiratory C. pneumoniae infection induces accelerated chlamydial clearance and reduction of oviduct pathology following genital C. muridarum challenge, and may have important implications to the C. trachomatis-induced reproductive disease in humans.
    PLoS ONE 05/2013; 8(5):e64917. DOI:10.1371/journal.pone.0064917 · 3.23 Impact Factor
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