Perforin-2 Restricts Growth of Chlamydia trachomatis in Macrophages

Fields, Kenneth A.; McCormack, Ryan; Armas, Lesley R. de; Podack, Eckhard R.

doi:10.1128/iai.00497-13

Cited by 43 publications

(56 citation statements)

References 49 publications

(46 reference statements)

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“…Shield-1-sensitive fusion proteins offered unparalleled posttranslational control over a particular substrate; however, they are model proteins, and it is unknown whether Chlamydia infections happen to target elements of these fusion proteins or DRiPs in general. While in vitro experiments have demonstrated that cells of hematopoietic origin, such as dendritic cells and macrophages (42,43), can be infected with different Chlamydia species, epithelial cells are the primary target of infections in vivo and antigenic peptides derived from DRiPs are present in different amounts depending on the cell type (44). However, the phenomenon is not limited to JY cells, since an epithelial cell line transiently transfected with SCRAP-SVG also increased DRiP presentation, while stable protein accumulation was diminished (Fig.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection

et al. 2016

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The direct major histocompatibility complex (MHC) class I antigen presentation pathway ensures intracellular peptides are displayed at the cellular surface for recognition of infected or transformed cells by CD8 ؉ cytotoxic T lymphocytes. Chlamydia spp. are obligate intracellular bacteria and, as such, should be targeted by CD8 ؉ T cells. It is likely that Chlamydia spp. have evolved mechanisms to avoid the CD8 ؉ killer T cell responses by interfering with MHC class I antigen presentation. Using a model system of self-peptide presentation which allows for posttranslational control of the model protein's stability, we tested the ability of various Chlamydia species to alter direct MHC class I antigen presentation. Infection of the JY lymphoblastoid cell line limited the accumulation of a model host protein and increased presentation of the model-protein-derived peptides. Enhanced selfpeptide presentation was detected only when presentation was restricted to defective ribosomal products, or DRiPs, and total MHC class I levels remained unaltered. Skewed antigen presentation was dependent on a bacterial synthesized component, as evidenced by reversal of the observed phenotype upon preventing bacterial transcription, translation, and the inhibition of bacterial lipooligosaccharide synthesis. These data suggest that Chlamydia spp. have evolved to alter the host antigen presentation machinery to favor presentation of defective and rapidly degraded forms of self-antigen, possibly as a mechanism to diminish the presentation of peptides derived from bacterial proteins.

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Section: Discussionmentioning

confidence: 99%

Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection

et al. 2016

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“…In cell-based infection studies, the proliferation of a number of intracellular bacterial pathogens is greatly enhanced when cellular Perforin-2 levels are reduced, suggesting that Perforin-2 targets vacuole-and plasma membrane-bound bacteria (15). Additionally, at least one intracellular pathogen, Chlamydia trachomatis, has evolved to actively block inductive Perforin-2 expression in epithelial cells (16). Thus, it appears that while Perforin-2 targets intracellular bacteria, it also can be targeted itself by pathogens in order to enhance their intracellular replication.…”

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confidence: 99%

“…We have recently shown that the mammalian MPEG1 homolog is constitutively expressed in macrophages, whereas in fibroblast-and endothelium-derived cells its expression is induced by interferons as well as infection with intracellular bacterial pathogens (15,16). In mice and humans the MPEG1 gene product, which is designated Perforin-2, is a 72-kDa protein possessing an MACPF domain in addition to a putative transmembrane and cytosolic domains.…”

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confidence: 99%

Perforin-2 Protects Host Cells and Mice by Restricting the Vacuole to Cytosol Transitioning of a Bacterial Pathogen

et al. 2016

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The host-encoded Perforin-2 (encoded by the macrophage-expressed gene 1, Mpeg1), which possesses a pore-forming MACPF domain, reduces the viability of bacterial pathogens that reside within membrane-bound compartments. Here, it is shown that Perforin-2 also restricts the proliferation of the intracytosolic pathogen Listeria monocytogenes. Within a few hours of systemic infection, the massive proliferation of L. monocytogenes in Perforin-2 ؊/؊ mice leads to a rapid appearance of acute disease symptoms. We go on to show in cultured Perforin-2 ؊/؊ cells that the vacuole-to-cytosol transitioning of L. monocytogenes is greatly accelerated. Unexpectedly, we found that in Perforin-2 ؊/؊ macrophages, Listeria-containing vacuoles quickly (<15 min) acidify, and that this was coincident with greater virulence gene expression, likely accounting for the more rapid translocation of L. monocytogenes to its replicative niche in the cytosol. This hypothesis was supported by our finding that a L. monocytogenes strain expressing virulence factors at a constitutively high level replicated equally well in Perforin-2 ؉/؉ and Perforin-2 ؊/؊ macrophages. Our findings suggest that the protective role of Perforin-2 against listeriosis is based on it limiting the intracellular replication of the pathogen. This cellular activity of Perforin-2 may derive from it regulating the acidification of Listeria-containing vacuoles, thereby depriving the pathogen of favorable intracellular conditions that promote its virulence gene activity. Both extracellular bacteria and virus-infected cells are targeted by innate defense responses that employ pore-forming proteins (1). Extracellular bacteria that become bound with the complement factor C3b and the C5b-8 complex trigger the polymerization of C9, resulting in a doughnut-shaped pore with a diameter of 100 Å that constitutes the membrane attack complex (MAC) (2-4). Similarly, virus-infected cells are recognized and eliminated by natural killer (NK) and cytotoxic T lymphocytes (CTL) that, as part of their respective killing programs, secrete Perforin-1, which forms a cluster of lethal pores in the membrane of the infected cell (5, 6). The complement proteins C6 to C9 and Perforin-1 all possess a membrane-attack-complex-perforin (MACPF) domain, which mediates the homopolymerization process that drives pore formation.A gene predicted to encode a third MACPF-containing protein, macrophage expressed gene-1 (Mpeg1), recently has been described in a number of invertebrates and zebrafish and plays a role in innate immune responses in these species to bacterial pathogens (7-11). Phylogenic analyses indicate that the MACPF domain of Mpeg1 is the ancestor of the MACPF domains in the complement and Perforin-1 proteins (12). Interestingly, although homologous Mpeg1 genes are found in most metazoan genomes spanning from sponges to humans, Mpeg1, or MACPF-encoding genes more generally, so far have not been identified in nonmetazoan clades of eukaryotes. However, the MACPF domain itself bears a striking structural si...

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“…Intracellular bacterial killing assays were performed as previously described (2,9). Briefly, cells were infected with M. avium or S. aureus for 1 hour or S. typhimurium for 30 minutes.…”

Section: Methodsmentioning

confidence: 99%

“…Importantly, all cells have the ability to express MPEG1, including barrier cells, such as keratinocytes and mucosal epithelium, and parenchymal cells (2,6). Perforin-2 has been shown to play a role in antibacterial defense in both invertebrate organisms, such as the disk abalone, and in vertebrates such as zebrafish, mouse, and human cells (2,(7)(8)(9). Murine macrophages and embryonic fibroblasts restrict intracellular bacterial growth through the agency of perforin-2 (2, 6, 9), whereas Mpeg1…”

Section: Introductionmentioning

confidence: 99%

MPEG1/perforin-2 mutations in human pulmonary nontuberculous mycobacterial infections

McCormack¹,

Szymanski²,

Hsu³

et al. 2017

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Perforin-2 Restricts Growth of Chlamydia trachomatis in Macrophages

Cited by 43 publications

References 49 publications

Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection

Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection

Perforin-2 Protects Host Cells and Mice by Restricting the Vacuole to Cytosol Transitioning of a Bacterial Pathogen

MPEG1/perforin-2 mutations in human pulmonary nontuberculous mycobacterial infections

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