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LGV biovars infect macrophages and are invasive, whereas trachoma biovars infect oculo-urogenital epithelial cells and are noninvasive. The<jats:italic>C.\u00a0trachomatis<\/jats:italic>plasmid is an important virulence factor in the pathogenesis of these infections. Central to its pathogenic role is the transcriptional regulatory function of the plasmid protein Pgp4, which regulates the expression of plasmid and chromosomal virulence genes. As many gene regulatory functions are post-transcriptional, we employed a comparative proteomic study of cells infected with plasmid-cured<jats:italic>C.\u00a0trachomatis<\/jats:italic>serovars A and D (trachoma biovar), a L2 serovar (LGV biovar), and the L2 serovar transformed with a plasmid containing a nonsense mutation in<jats:italic>pgp4<\/jats:italic>to more completely elucidate the effects of the plasmid on chlamydial infection biology. Our results show that the Pgp4-dependent elevations in the levels of Pgp3 and a conserved core set of chromosomally encoded proteins are remarkably similar for serovars within both<jats:italic>C.\u00a0trachomatis<\/jats:italic>biovars. Conversely, we found a plasmid-dependent, Pgp4-independent, negative regulation in the expression of the chlamydial protease-like activity factor (CPAF) for the L2 serovar but not the A and D serovars. The molecular mechanism of plasmid-dependent negative regulation of CPAF expression in the LGV serovar is not understood but is likely important to understanding its macrophage infection tropism and invasive infection nature.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>The<jats:italic>Chlamydia trachomatis<\/jats:italic>plasmid is an important virulence factor in the pathogenesis of chlamydial infection. It is known that plasmid protein 4 (Pgp4) functions in the transcriptional regulation of the plasmid virulence protein 3 (Pgp3) and multiple chromosomal loci of unknown function. Since many gene regulatory functions can be post-transcriptional, we undertook a comparative proteomic analysis to better understand the plasmid\u2019s role in chlamydial and host protein expression. We report that Pgp4 is a potent and specific master positive regulator of a common core of plasmid and chromosomal virulence genes shared by multiple<jats:italic>C.\u00a0trachomatis<\/jats:italic>serovars. Notably, we show that the plasmid is a negative regulator of the expression of the chlamydial virulence factor CPAF. The plasmid regulation of CPAF is independent of Pgp4 and restricted to a<jats:italic>C.\u00a0trachomatis<\/jats:italic>macrophage-tropic strain. These findings are important because they define a previously unknown role for the plasmid in the pathophysiology of invasive chlamydial infection.<\/jats:p>","DOI":"10.1128\/mbio.02164-17","type":"journal-article","created":{"date-parts":[[2018,3,12]],"date-time":"2018-03-12T12:37:37Z","timestamp":1520858257000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":14,"title":["Plasmid Negative Regulation of CPAF Expression Is Pgp4 Independent and Restricted to Invasive<i>Chlamydia trachomatis<\/i>Biovars"],"prefix":"10.1128","volume":"9","author":[{"given":"Michael John","family":"Patton","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 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