Programmed cell death as a defence against infection

Jørgensen, Ine; Rayamajhi, Manira; Miao, Edward A.

doi:10.1038/nri.2016.147

Cited by 788 publications

(695 citation statements)

References 180 publications

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“…Macrophages have a well-characterized family of pattern recognition receptors (PRRs) that activate the inflammasome and exhibit antibacterial activities (45). A possible explanation is CPAF, or CPAF proteolytically modified type 3 secretion system (T3SS) effector(s) (46), might function as pathogen-associated molecular pattern (PAMP) ligands that engage cytosolic PRR pathways in macrophages, which may be absent or expressed at a lower level in nonphagocytic cells.…”

Section: Discussionmentioning

confidence: 99%

Plasmid Negative Regulation of CPAF Expression Is Pgp4 Independent and Restricted to InvasiveChlamydia trachomatisBiovars

Patton

Chen

Yang

et al. 2018

mBio

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Chlamydia trachomatis is an obligate intracellular bacterial pathogen that causes blinding trachoma and sexually transmitted disease. C. trachomatis isolates are classified into 2 biovars-lymphogranuloma venereum (LGV) and trachomawhich are distinguished biologically by their natural host cell infection tropism.LGV biovars infect macrophages and are invasive, whereas trachoma biovars infect oculourogenital epithelial cells and are noninvasive. The C. trachomatis 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 C. trachomatis serovars A and D (trachoma biovar), a L2 serovar (LGV biovar), and the L2 serovar transformed with a plasmid containing a nonsense mutation in pgp4 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 C. trachomatis 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 plasmiddependent 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. IMPORTANCEThe Chlamydia trachomatis 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's 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 C. trachomatis 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 C. trachomatis macrophage-tropic strain. These findings are important because they define a previously unknown role for the plasmid in the pathophysiology of invasive chlamydial infection.

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Section: Discussionmentioning

confidence: 99%

Plasmid Negative Regulation of CPAF Expression Is Pgp4 Independent and Restricted to InvasiveChlamydia trachomatisBiovars

Patton

Chen

Yang

et al. 2018

mBio

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“…Pyroptosis was recently found to be a form of programmed cell death, which is initiated by inflammasomes and executed by GSDMD, resulting in pore formation and cell rupture. Unfortunately, pyroptosis kills infected host cells but does not damage the intracellular pathogens [37]; thus, it is more effective in defense against environmental stimulus. GSDMD has binding affinity for lipids that usually reside in the cytosolic leaflet of the plasma membrane and protects adjacent cells from pyroptosis [38].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Genipin Reverses HFD-Induced Liver Damage and Inhibits UCP2-Mediated Pyroptosis in Mice

Zhong

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Liver damage is a typical manifestation of nonalcoholic fatty liver disease (NAFLD). It originates from excessive fat accumulation, leading to hepatocyte death, inflammation, and fibrosis. Nonalcoholic steatohepatitis (NASH) is a type of NAFLD with a prevalence of 49% in morbidly obese patients. Pyroptosis plays an important role in the development of NASH; thus, it is important to elucidate the effect of lipid accumulation on pyroptosis. Genipin (GNP), a natural water-soluble cross-linking agent, has hepatoprotective effects and decreases lipid accumulation in the liver; however, the mechanisms underlying these effects are unknown. Methods: In this study, qPCR and Western blot were used to examine pyroptotic gene expression in high-fat diet (HFD) induced obese mice and free fatty acids (FFAs) treated hepatocytes. At the same time, relative lactate dehydrogenase (LDH) release and Hoechst & propidium iodide (PI) staining were done to verify cell death. To explore the molecular mechanism, cell transfection were constructed with siRNA or plasmid to obtain knockdown or overexpression hepatocytes. Results: We found that HFD-fed mice and FFAs-treated hepatocytes had obvious pyroptosis, and addition of GNP reversed liver damage and inhibited pyroptosis both in vitro and in vivo. Besides, UCP2 knockdown cells showed suppressed FFAs-mediated pyroptosis, as determined by decreased pyroptotic gene expression, reduced lactate dehydrogenase (LDH) release, and reduced cell death. Consistent with this, cells transfected with UCP2 had upregulated pyroptotic gene expression, increased LDH release, and increased cell death. Conclusion: GNP reverses HFD-induced liver damage and inhibits UCP2-mediated pyroptosis. Thus, GNP may serve as a potential therapeutic candidate for NAFLD.

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“…Apoptosis is a form of programmed cell death which is noninflammatory and nonlytic, whereas pyroptosis is associated with the assembly of inflammasomes, the activation of inflammatory caspases (e.g., caspase-1), the release of the proinflammatory cytokines interleukin-1␤ (IL-1␤) and IL-18, and cell lysis (45,46). Francisella novicida has been reported to activate inflammasomes in both mouse and human cells (18)(19)(20)47).…”

Section: Figmentioning

confidence: 99%

Complement C3 as a Prompt for Human Macrophage Death during Infection with Francisella tularensis Strain SCHU S4

Brock

Parmely

2017

Infect Immun

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Tularemia is caused by the Gram-negative bacterial pathogen Francisella tularensis. Infection of macrophages and their subsequent death are believed to play important roles in the progression of disease. Because complement is a particularly effective opsonin for Francisella, we asked whether complement-dependent uptake of F. tularensis strain SCHU S4 affects the survival of primary human macrophages during infection. Complement component C3 was found to be an essential opsonin in human serum not only for greatly increased uptake of SCHU S4 but also for the induction of macrophage death. Single-cell analysis also revealed that macrophage death did not require a high intracellular bacterial burden. In the presence of C3, macrophage death was observed at 24 h postinfection in a quarter of the macrophages that contained only 1 to 5 bacterial cells. Macrophages infected in the absence of C3 rarely underwent cell death, even when they contained large numbers of bacteria. The need for C3, but not extensive replication of the pathogen, was confirmed by infections with SCHU S4 ΔpurMCD, a mutant capable of phagosome escape but of only limited cytosolic replication. C3-dependent Francisella uptake alone was insufficient to induce macrophage death, as evidenced by the failure of the phagosome escape-deficient mutant SCHU S4 ΔfevR to induce cell death despite opsonization with C3. Together, these findings indicate that recognition of C3-opsonized F. tularensis, but not extensive cytosolic replication, plays an important role in regulating macrophage viability during intracellular infections with type A F. tularensis. KEYWORDS C3, Francisella tularensis, cell death, complement, macrophage F rancisella tularensis is the causative agent of the zoonotic life-threatening disease tularemia. Among the subspecies responsible for disease in human beings, F. tularensis subsp. tularensis (type A) is the most virulent and causes high morbidity and mortality when delivered via the respiratory route (1-4). Very low minimum infectious doses have been reported with pulmonary challenge in humans (2, 5). In mice, alveolar macrophages are among the earliest cells infected following respiratory challenge (6-8). F. tularensis rapidly disrupts the phagosome and enters the cytosol of cultured macrophages, where it replicates to high intracellular numbers (9-11). Likewise, phagocytic cell death and bacteremia follow infection of mice with F. tularensis and lead to secondary colonization and pathology in the spleen, liver, and draining lymph nodes (12-15). Indeed, one of the hallmark histopathological features of disseminated tularemia caused by the F. tularensis subsp. tularensis is the appearance of infected clusters of macrophages and myeloid cells (microgranulomas), which rapidly transform into necrotic foci (13)(14)(15)(16). Infection of macrophages with the laboratory strain F. tularensis subsp. tularensis SCHU S4 does not appear to activate caspase-1-mediated pyroptosis (17, 18), as has been reported for Francisella novicida strain U...

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Programmed cell death as a defence against infection

Cited by 788 publications

References 180 publications

Plasmid Negative Regulation of CPAF Expression Is Pgp4 Independent and Restricted to InvasiveChlamydia trachomatisBiovars

Plasmid Negative Regulation of CPAF Expression Is Pgp4 Independent and Restricted to InvasiveChlamydia trachomatisBiovars

Genipin Reverses HFD-Induced Liver Damage and Inhibits UCP2-Mediated Pyroptosis in Mice

Complement C3 as a Prompt for Human Macrophage Death during Infection with Francisella tularensis Strain SCHU S4

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