Microbial pathogens have been selected for the capacity to evade or manipulate host responses in order to survive after infection. Chlamydia, an obligate intracellular pathogen and the causative agent for many human diseases, can escape T lymphocyte immune recognition by degrading host transcription factors required for major histocompatibility complex (MHC) antigen expression. We have now identified a chlamydial protease– or proteasome–like activity factor (CPAF) that is secreted into the host cell cytosol and that is both necessary and sufficient for the degradation of host transcription factors RFX5 and upstream stimulation factor 1 (USF-1). The CPAF gene is highly conserved among chlamydial strains, but has no significant overall homology with other known genes. Thus, CPAF represents a unique secreted protein produced by an obligate intracellular bacterial pathogen to interfere with effective host adaptive immunity.

We have previously shown that the obligate intracellular pathogen chlamydia can suppress interferon (IFN)-γ–inducible major histocompatibility complex (MHC) class II expression in infected cells by degrading upstream stimulation factor (USF)-1. We now report that chlamydia can also inhibit both constitutive and IFN-γ–inducible MHC class I expression in the infected cells. The inhibition of MHC class I molecule expression correlates well with degradation of RFX5, an essential downstream transcription factor required for both the constitutive and IFN-γ–inducible MHC class I expression. We further demonstrate that a lactacystin-sensitive proteasome-like activity identified in chlamydia-infected cell cytosolic fraction can degrade both USF-1 and RFX5. This proteasome-like activity is dependent on chlamydial but not host protein synthesis. Host preexisting proteasomes may not be required for the unique proteasome-like activity. These observations suggest that chlamydia-secreted factors may directly participate in the proteasome-like activity. Efforts to identify the chlamydial factors are underway. These findings provide novel information on the molecular mechanisms of chlamydial evasion of host immune recognition.

Chlamydia pneumoniae is a causative agent for many respiratory infections and has been associated with cardiovascular diseases in humans. The pathogenicity of C. pneumoniae is thought to depend on its ability to cause persistent infection and to evade host defense. Genome sequence analysis indicates that C. pneumoniae encodes a homologue of a chlamydial protease-like activity factor from C. trachomatis (CPAFct). We designated the C. pneumoniae homologue as CPAFcp. Recombinant CPAFcp was produced and found to degrade RFX5, a host transcription factor required for major histocompatibility complex (MHC) antigen expression. The degradation was inhibitable by lactacystin, an irreversible proteasome inhibitor. Furthermore, CPAFcp was secreted into host cytosol by C. pneumoniae organisms. Depletion of the C. pneumoniae-secreted CPAFcp with specific antibodies completely ablated the RFX5 degradation activity in the infected cells, suggesting that CPAFcp is necessary for the degradation of host transcription factors required for MHC antigen expression during C. pneumoniae infection. These observations have revealed a unique molecular mechanism for C. pneumoniae to evade host adaptive immunity that may aid in its persistence.Chlamydia is an obligate intracellular pathogen that has to replicate within a cytoplasmic vacuole of eukaryotic cells (13). There are two major chlamydial species that cause human diseases (12, 17). The Chlamydia trachomatis species is a leading cause of trachoma and sexually transmitted diseases (12), while the C. pneumoniae species causes various respiratory infections (11). Although the C. pneumoniae-induced respiratory infections are often asymptomatic, its association with atherosclerosis has attracted the attention of many investigators (10). C. pneumoniae organisms have been detected in a large proportion of atherotic plaques but not in nonatherotic cardiovascular tissues (20,25). In cell culture, C. pneumoniae infection was able to transform macrophages into foam cells (15), a hallmark of atherosclerosis. Several groups including ourselves have demonstrated that respiratory infection with C. pneumoniae organisms can greatly enhance atherosclerotic lesion development in animal models (3,6,14,18). More importantly, antibiotic treatment of the infected animals can prevent the C. pneumoniae exacerbation of atherosclerosis (5,19). Despite the important role of C. pneumoniae infection in atherosclerosis, the mechanism of the C. pneumoniae atherogenicity is still not clear.It is thought that the continuous release of inflammatory cytokines by persistently infected cells may play a major role in chlamydial pathogenesis (2, 22). One of the hallmarks of C. pneumoniae infection is persistence (1, 7, 9). The question is how C. pneumoniae is able to successfully maintain the persistence in its hosts. We have previously demonstrated that C. trachomatis organisms can escape from host immune detection by secreting a proteolytically active molecule (designated CPAFct for chlamydial protease-like activity fact...

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