The role of intracellular glutathione in the progression of Chlamydia trachomatis infection

Лазарев, В. Н.; Borisenko, Grigory G.; Shkarupeta, Marina M.; Demina, Irina; Serebryakova, Marina V.; Galyamina, M. A.; Levitskiy, Sergey A.; Govorun, Vadim M.

doi:10.1016/j.freeradbiomed.2010.09.024

Cited by 13 publications

(13 citation statements)

References 59 publications

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“…Alternatively, host-derived factors could contribute to modulation of bonding in surfaceexposed chlamydial proteins. In support of this model, there have been several studies highlighting the necessity of host oxidoreductase factors in productive chlamydial infection (2,11,12,26). Interestingly, host protein disulfide isomerase (PDI) is a multifunctional enzyme ubiquitously expressed in eukaryotic cells, where it functions as a mediator of redox reactions at the cell surface (11,12,42).…”

Section: Discussionmentioning

confidence: 97%

“…Thus far, disulfide bonding among MOMP, OmcA, and OmcB are thought to constitute a highly crosslinked supramolecular envelope complex in EBs (14,19). Conversion of EBs to RBs is accompanied by reduction of these disulfide bonds (17,32) and appears to occur as early as invasion, since evidence suggests that EB proteins must be reduced for productive infection (2,11,26,35). Later in development, during RB to EB differentiation, disulfide bonds are re-formed (4,17,20,21,32,33,36).…”

Section: Discussionmentioning

confidence: 99%

“…These observations are consistent with our data indicating that the alterations in CdsF-specific disulfide bonding can occur in attached, yet extracellular EBs. Finally, another study recently provided evidence that intracellular glutathione (GSH) is an additional key player in reduction of the C. trachomatis OM during the initial stages of infection (26). Hence, a combination of chlamydial and host factors may contribute to the reduction of disulfide bonds in EBs during differentiation to RBs and subsequent oxidation of reactive sulfhydryls during RB to EB conversion.…”

Section: Discussionmentioning

confidence: 99%

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Disulfide Bonding within Components of the Chlamydia Type III Secretion Apparatus Correlates with Development

Betts-Hampikian

Fields

2011

J Bacteriol

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Chlamydia spp. exhibit a unique biphasic developmental cycle whereby infectious elementary bodies (EBs) invade host epithelial cells and differentiate into noninfectious, metabolically active reticulate bodies (RBs). EBs posses a unique outer envelope where rigidity is achieved by disulfide bonding among cysteine-rich envelope-associated proteins. Conversely, these disulfide bonds become reduced in RBs to accommodate vegetative growth, thereby linking the redox status of cysteine-rich envelope proteins with progression of the developmental cycle. We investigated the potential role of disulfide bonding within the chlamydial type III secretion system (T3SS), since activity of this system is also closely linked to development. We focused on structural components of the T3S apparatus that contain an unusually high number of cysteine residues compared to orthologs in other secretion systems. Nonreducing SDS-PAGE revealed that EB-localized apparatus proteins such as CdsF, CdsD, and CdsC form higher-order complexes mediated by disulfide bonding. The most dramatic alterations were detected for the needle protein CdsF. Significantly, disulfide bonding patterns shifted during differentiation of developmental forms and were completely reduced in RBs. Furthermore, at later time points during infection following RB to EB conversion, we found that CdsF is reoxidized into higher-order complexes. Overall, we conclude that the redox status of specific T3SS apparatus proteins is intimately linked to the developmental cycle and constitutes a newly appreciated aspect of functionally significant alterations within proteins of the chlamydial envelope.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Disulfide Bonding within Components of the Chlamydia Type III Secretion Apparatus Correlates with Development

Betts-Hampikian

Fields

2011

J Bacteriol

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“…Early work by the Hackstadt group has already postulated that reduction of outer membrane protein complex proteins is a prerequisite for chlamydial EB to RB transition [49]. Recently, GSH has been suggested to be the natural agent responsible for the reduction of the outer membrane proteins of C. trachomatis during EB to RB transition [50]. We observed decreased chlamydial infectivity due to decrease in cellular GSH during later time points of Chlamydia infection indicating a more important role of GSH for chlamydial infectivity.…”

Section: Discussionmentioning

confidence: 99%

Imbalanced Oxidative Stress Causes Chlamydial Persistence during Non-Productive Human Herpes Virus Co-Infection

et al. 2012

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Both human herpes viruses and Chlamydia are highly prevalent in the human population and are detected together in different human disorders. Here, we demonstrate that co-infection with human herpes virus 6 (HHV6) interferes with the developmental cycle of C. trachomatis and induces persistence. Induction of chlamydial persistence by HHV6 is independent of productive virus infection, but requires the interaction and uptake of the virus by the host cell. On the other hand, viral uptake is strongly promoted under co-infection conditions. Host cell glutathione reductase activity was suppressed by HHV6 causing NADPH accumulation, decreased formation of reduced glutathione and increased oxidative stress. Prevention of oxidative stress restored infectivity of Chlamydia after HHV6-induced persistence. We show that co-infection with Herpes simplex virus 1 or human Cytomegalovirus also induces chlamydial persistence by a similar mechanism suggesting that Chlamydia -human herpes virus co-infections are evolutionary shaped interactions with a thus far unrecognized broad significance.

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“…The cellular GSH balance may affect intracellular bacteria by a variety of mechanisms. GSH has been found to act as a major cysteine source of intracellular bacteria 48 and it has been reported to indirectly affect chlamydial energy supply by increasing cell wall permeability 49 . GSH depletion is also known to induce K+ efflux 50 which, in turn, can promote the chlamydial replication via the induction of NLRP3 inflammasome in the host cells 33, 51 .…”

Section: Resultsmentioning

confidence: 99%

Assaying Chlamydia pneumoniae persistence in monocyte-derived macrophages identifies schisandrin lignans as phenotypic switchers

Taavitsainen

Kortesoja

Hanski

2019

Preprint

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23Antibiotic-tolerant persister bacteria involve frequent treatment failures, relapsing infections and the need 24 for extended antibiotic treatment. Taking persisters into account in susceptibility assays is thus an essential 25 success factor in antibacterial drug discovery. The virulence of the obligate intracellular bacterium 26Chlamydia pneumoniae is tightly linked to its propensity for persistence, but current susceptibility 27 screening on this gram-negative respiratory pathogen relies on permissive epithelial cells. To establish an 28 improved antichlamydial susceptibility assay allowing the analysis of both actively growing and persister 29 bacteria, we studied C. pneumoniae clinical isolate CV-6 infection kinetics in THP-1 macrophages by qPCR 30 and quantitative culture. Indicated by the steady increase of chlamydial genome copy numbers and 31 infectious progeny as well as the failure of azithromycin to eradicate the intracellular forms of the 32 bacterium, the macrophages were found to harbor a subpopulation of persister C. pneumoniae cells. The 33 potential of the assay for the discovery of anti-persister molecules against intracellular bacteria was 34 demonstrated by the identification of the differential effects of two dibenzocyclooctadiene lignans on C. 35 pneumoniae infection. While schisandrin reverted C. pneumoniae persistence and promoted productive 36 infection, schisandrin C was superior to azithromycin in eradicating the C. pneumoniae infection. The 37 phenotypic switch was associated with the suppression of cellular glutathione pools, implying that targeting 38 glutathione homeostasis may provide a novel means for intracellular bacteria resuscitation. In conclusion, 39 these data highlight the value of macrophages over permissive cell lines in anti-persister agent discovery on 40 intracellular bacteria and targeting host cell redox status to fight persistent infections. 41 42 43 Keywords: persistent infection, antibiotic persistence, dormancy, phenotypic switch, glutathione, 44 antibacterial agent 45 46 47 48 49 50 51 52Owing to redundant mechanisms, these phenotypical variants are able to survive under antibiotic pressure 58 and revert back to metabolically more active phenotype when stressful conditions are cleared off. 59In clinical settings, bacterial dormancy is associated with hard-to-treat infections via two mechanistically 60 overlapping phenomena, persistent infections evading host immune responses and antibiotic persistence 61 defined based on the presence of drug-tolerant subpopulations of bacteria. Both of these features are 62 typical to infections caused by Chlamydia pneumoniae, a gram-negative obligate intracellular human 63 pathogen that causes respiratory infections from dry cough to pneumonia. While a majority of C. 64 pneumoniae infections are subclinical, nearly everyone getting infected during their lifetime, the bacterium 65 is also responsible for 5-10% of community-acquired pneumonia cases worldwide 3, 4 . C. pneumoniae has a 66 unique biphasic development cycle, whe...

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The role of intracellular glutathione in the progression of Chlamydia trachomatis infection

Cited by 13 publications

References 59 publications

Disulfide Bonding within Components of the Chlamydia Type III Secretion Apparatus Correlates with Development

Disulfide Bonding within Components of the Chlamydia Type III Secretion Apparatus Correlates with Development

Imbalanced Oxidative Stress Causes Chlamydial Persistence during Non-Productive Human Herpes Virus Co-Infection

Assaying Chlamydia pneumoniae persistence in monocyte-derived macrophages identifies schisandrin lignans as phenotypic switchers

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