scholarly journals Inhibition of Apoptosis by Gamma Interferon in Cells and Mice Infected with Chlamydia muridarum (the Mouse Pneumonitis Strain of Chlamydia trachomatis)

2002 ◽  
Vol 70 (5) ◽  
pp. 2559-2565 ◽  
Author(s):  
Jean-Luc Perfettini ◽  
Toni Darville ◽  
Alice Dautry-Varsat ◽  
Roger G. Rank ◽  
David M. Ojcius
Keyword(s):  
Chlamydia Trachomatis ◽  
Inhibitory Effect ◽  
Gamma Interferon ◽  
Apoptotic Cells ◽  
Chlamydia Muridarum ◽  
Infected Cells ◽  
Heterogenous Population ◽  
Ifn Γ ◽  
In Cells

ABSTRACT The effect of gamma interferon (IFN-γ) on apoptosis due to infection by Chlamydia muridarum (the mouse pneumonitis strain of Chlamydia trachomatis) was studied in epithelial cells in culture and in the genital tracts of mice. IFN-γ concentrations that induce the formation of aberrant, persistent chlamydiae inhibit apoptosis due to C. muridarum infection. In cells treated with an IFN-γ concentration that leads to the development of a heterogenous population of normal and aberrant Chlamydia vacuoles, apoptosis was inhibited preferentially in cells that contained the aberrant vacuoles. The inhibitory effect of IFN-γ appears to be due in part to expression of host cell indoleamine 2,3-dioxygenase activity, since inhibition of apoptosis could be partially reversed through coincubation with exogenous tryptophan. Apoptotic cells were observed in the genital tracts of wild-type mice infected with C. muridarum, and a significantly larger number of apoptotic cells was detected in infected IFN-γ-deficient mice. These results suggest that IFN-γ may contribute to pathogenesis of persistent Chlamydia infections in vivo by preventing apoptosis of infected cells.

scholarly journals Inhibition of SUMO-independent PML oligomerization by the human cytomegalovirus IE1 protein

2006 ◽  
Vol 87 (8) ◽  
pp. 2181-2190 ◽  
Author(s):  
Heejung Kang ◽  
Eui Tae Kim ◽  
Hye-Ra Lee ◽  
Jung-Jin Park ◽  
Yoon Young Go ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Insect Cells ◽  
Inhibitory Effect ◽  
Sumo Protease ◽  
Sumo Proteases ◽  
Specific Protease ◽  
Infected Cells ◽  
In Cells

In human cytomegalovirus-infected cells, the immediate-early IE1 protein disrupts the subnuclear structures known as the PML oncogenic domains or PODs, via the induction of PML desumoylation. This activity correlates with the functions of IE1 in transcriptional regulation and in the stimulation of lytic infection. Here, the effects of IE1 in induction of desumoylation of PML were characterized. IE1 did not interfere with the formation of sumoylated forms of PML in vitro. In in vitro assays using the sumoylated proteins, a SUMO-specific protease SENP1 desumoylated both PML and IE1. However, the IE1 proteins generated from bacteria or insect cells were unable to desumoylate PML in the same conditions. Although both IE1 and SUMO proteases such as SENP1, Axam and SuPr-1 efficiently desumoylated PML in co-transfection assays, they exerted different effects on the localization of PML. In cells transfected with either SENP1 or SuPr-1, the number of PML foci was reduced significantly and these remnant PML foci were devoid of SUMO-1 signals. However, in cells co-transfected with both SUMO proteases and IE1, these SUMO-independent PML foci were also completely disrupted. Furthermore, IE1, but not SENP1, was shown to disrupt the PML foci generated via transfection of a sumoylation-deficient mutant of PML. These data suggest that IE1 exhibits neither an inhibitory effect on sumoylation of PML nor intrinsic SUMO protease activity against PML in vitro. The finding that IE1 is capable of disrupting SUMO-independent PML aggregates suggests that inhibition of PML oligomerization by IE1 may play an important role in inducing PML desumoylation in vivo.

scholarly journals Differential Effects of Gamma Interferon on Chlamydia trachomatis Growth in Polarized and Nonpolarized Human Epithelial Cells in Culture

1998 ◽  
Vol 66 (5) ◽  
pp. 2349-2351 ◽  
Author(s):  
Colleen D. Kane ◽  
Gerald I. Byrne
Keyword(s):  
Chlamydia Trachomatis ◽  
Epithelial Cells ◽  
Gamma Interferon ◽  
Growth Modulation ◽  
Differential Effects ◽  
Cells In Culture ◽  
Human Epithelial Cells ◽  
Polarized Cells ◽  
Ifn Γ

ABSTRACT The effects of gamma interferon (IFN-γ) on Chlamydia trachomatis growth in polarized epithelial cells were examined. The range of IFN-γ concentrations causing aberrant chlamydial growth was wider in polarized than in nonpolarized cultures. Results indicate that chlamydial growth modulation in polarized cells readily leads to persistence and better reflects in vivo conditions.

scholarly journals Intracellular Tryptophan Pool Sizes May Account for Differences in Gamma Interferon-Mediated Inhibition and Persistence of Chlamydial Growth in Polarized and Nonpolarized Cells

1999 ◽  
Vol 67 (4) ◽  
pp. 1666-1671 ◽  
Author(s):  
Colleen D. Kane ◽  
Renee M. Vena ◽  
Scot P. Ouellette ◽  
Gerald I. Byrne
Keyword(s):  
Amino Acid ◽  
Host Cell ◽  
Cultured Cells ◽  
Polarization State ◽  
Cell Polarization ◽  
Gamma Interferon ◽  
Infected Cells ◽  
Ifn Γ ◽  
Pool Sizes

ABSTRACT Gamma interferon (IFN-γ) is an important factor in the modulating inhibition of intracellular chlamydial growth and persistence. In human epithelial cells and macrophages, this inhibition is the result of depletion of the essential amino acid tryptophan via the IFN-γ-induced enzyme indoleamine 2,3-dioxygenase. Under these conditions, chlamydiae must successfully compete with the host cell for limited resources in order to maintain viability. We provide evidence to support the hypothesis that the host cell polarization state influences the host-pathogen interplay and outcome of IFN-γ-mediated inhibition. In polarized cells, intracellular soluble tryptophan pools were larger than those in nonpolarized cells despite only small differences in the initial uptake rate of this amino acid compared to that in nonpolarized cells. Furthermore, in Chlamydia trachomatis-infected cells, the amounts of tryptophan consumed by the organisms were similar for cells grown in either state. We propose that intracellular tryptophan pool sizes can account for differences in IFN-γ-mediated chlamydial persistence and growth inhibition in polarized and nonpolarized cells. Collectively, these results argue that polarized cell models, which more accurately reflect the conditions in vivo, may be more relevant than conventionally cultured cells in the study of intimate intracellular host-parasite interactions.

scholarly journals Expression of Gamma Interferon-Dependent Genes Is Blocked Independently by Virion Host Shutoff RNase and by US3 Protein Kinase

2008 ◽  
Vol 82 (10) ◽  
pp. 4688-4696 ◽  
Author(s):  
Li Liang ◽  
Bernard Roizman
Keyword(s):  
Protein Kinase ◽  
Gamma Interferon ◽  
Mutant Virus ◽  
Wild Type Virus ◽  
Virion Host Shutoff ◽  
Gene Transcripts ◽  
Infected Cells ◽  
Ifn Γ ◽  
Host Shutoff ◽  
In Cells

ABSTRACT Gamma interferon receptor α (IFN-γRα) is stable but posttranslationally modified in herpes simplex virus 1(F) [HSV-1(F)]-infected cells. Studies with antibody directed to the phosphorylation site indicate that IFN-γRα is phosphorylated by the US3 kinase. The modification is abolished in cells infected with ΔUS3, ΔUL13, or Δ(US3/UL13) mutant virus. Transcripts of the IFN-γ-dependent genes do not accumulate in cells transduced with the US3 protein kinase and treated with IFN-γ. In contrast, the accumulation of IFN-γ-dependent gene transcripts is suppressed in cells infected with the wild-type virus, in cells infected with the ΔUS3 mutant virus, and to a lesser extent in the ΔUL41 virus-infected cells. The accumulation of IFN-γ-dependent gene transcripts in ΔUL41-infected cells could be due at least in part to a significant delay and reduction in the accumulation of the US3 protein. The results suggest that the expression of IFN-γ-dependent genes is blocked independently by the degradation of IFN-γ-dependent gene transcripts—a function of the virion host shutoff RNase—and by posttranslational modification of the IFN-γRα protein.

scholarly journals Gamma Interferon Blocks Gammaherpesvirus Reactivation from Latency

2006 ◽  
Vol 80 (1) ◽  
pp. 192-200 ◽  
Author(s):  
Ashley L. Steed ◽  
Erik S. Barton ◽  
Scott A. Tibbetts ◽  
Daniel L. Popkin ◽  
Mary L. Lutzke ◽  
...  
Keyword(s):  
Immune Surveillance ◽  
Viral Gene Expression ◽  
Gamma Interferon ◽  
Viral Gene ◽  
Herpesvirus Infection ◽  
Murine Gammaherpesvirus ◽  
Ifn Γ ◽  
Gammaherpesvirus 68 ◽  
Novel Strategy

ABSTRACT Establishment of latent infection and reactivation from latency are critical aspects of herpesvirus infection and pathogenesis. Interfering with either of these steps in the herpesvirus life cycle may offer a novel strategy for controlling herpesvirus infection and associated disease pathogenesis. Prior studies show that mice deficient in gamma interferon (IFN-γ) or the IFN-γ receptor have elevated numbers of cells reactivating from murine gammaherpesvirus 68 (γHV68) latency, produce infectious virus after the establishment of latency, and develop large-vessel vasculitis. Here, we demonstrate that IFN-γ is a powerful inhibitor of reactivation of γHV68 from latency in tissue culture. In vivo, IFN-γ controls viral gene expression during latency. Importantly, depletion of IFN-γ in latently infected mice results in an increased frequency of cells reactivating virus. This demonstrates that IFN-γ is important for immune surveillance that limits reactivation of γHV68 from latency.

scholarly journals Resistance to Acute Babesiosis Is Associated with Interleukin-12- and Gamma Interferon-Mediated Responses and Requires Macrophages and Natural Killer Cells

2003 ◽  
Vol 71 (4) ◽  
pp. 2002-2008 ◽  
Author(s):  
Irma Aguilar-Delfin ◽  
Peter J. Wettstein ◽  
David H. Persing
Keyword(s):  
Nk Cells ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
No Production ◽  
Cytokine Responses ◽  
Early Production ◽  
Ifn Γ ◽  
Crucial Part

ABSTRACT We examined the role of the cytokines gamma interferon (IFN-γ) and interleukin-12 (IL-12) in the model of acute babesiosis with the WA1 Babesia. Mice genetically deficient in IFN-γ-mediated responses (IFNGR2KO mice) and IL-12-mediated responses (Stat4KO mice) were infected with the WA1 Babesia, and observations were made on the course of infection and cytokine responses. Levels of IFN-γ and IL-12 in serum increased 24 h after parasite inoculation. The augmented susceptibility observed in IFNGR2KO and Stat-4KO mice suggests that the early IL-12- and IFN-γ-mediated responses are involved in protection against acute babesiosis. Resistance appears to correlate with an increase in nitric oxide (NO) production. In order to assess the contribution of different cell subsets to resistance against the parasite, we also studied mice lacking B cells, CD4+ T cells, NK cells, and macrophages. Mice genetically deficient in B lymphocytes or CD4+ T lymphocytes were able to mount protective responses comparable to those of immunosufficient mice. In contrast, in vivo depletion of macrophages or NK cells resulted in elevated susceptibility to the infection. Our observations suggest that a crucial part of the response that protects from the pathogenic Babesia WA1 is mediated by macrophages and NK cells, probably through early production of IL-12 and IFN-γ, and induction of macrophage-derived effector molecules like NO.

scholarly journals Recombinant murine gamma interferon inhibits Chlamydia trachomatis serovar L1 in vivo.

1988 ◽  
Vol 56 (1) ◽  
pp. 283-286 ◽  
Author(s):  
G M Zhong ◽  
E M Peterson ◽  
C W Czarniecki ◽  
L M de la Maza
Keyword(s):  
Chlamydia Trachomatis ◽  
Gamma Interferon

scholarly journals Development of a Human Gamma Interferon Enzyme Immunoassay and Comparison with Tuberculin Skin Testing for Detection ofMycobacterium tuberculosis Infection

1998 ◽  
Vol 5 (4) ◽  
pp. 531-536 ◽  
Author(s):  
Nuket Desem ◽  
Stephen L. Jones
Keyword(s):  
Enzyme Immunoassay ◽  
Skin Test ◽  
Skin Testing ◽  
Gamma Interferon ◽  
Tuberculin Skin Testing ◽  
In Vitro Test ◽  
Detection Range ◽  
Ifn Γ

ABSTRACT A sensitive two-step simultaneous enzyme immunoassay (EIA) for human gamma interferon (IFN-γ) has been developed and used as an in vitro test for human tuberculosis (TB) in comparison with tuberculin skin testing. The EIA was shown to be highly sensitive, detecting less than 0.5 IU of recombinant human IFN-γ per ml within a linear detection range of 0.5 to 150 IU/ml. The assay was highly reproducible and specific for native IFN-γ. In addition, the assay detected chimpanzee, orangutan, gibbon, and squirrel monkey IFN-γs. Cross-reactions with other human cytokines or with IFN-γs derived from mice, cattle, or Old World monkeys were not evident. The assay was used to detect TB infection by incubating whole blood overnight with human, avian, and bovine tuberculin purified protein derivatives (PPDs), as well as positive (mitogen)- and negative-control preparations. The levels of IFN-γ in plasma supernatants were then determined. Blood from 10 tuberculin skin test-positive individuals responded predominantly to the human tuberculin PPD antigen and to a lesser extent to bovine and avian PPD antigens. By contrast, blood from 10 skin test-negative individuals showed minimal responses or no response to any of the tuberculin PPDs. Detectable levels of IFN-γ were present in all blood samples stimulated with mitogen. In vivo tuberculin reactivity was correlated with IFN-γ responsiveness in vitro. These results support the further study of the blood culture–IFN-γ EIA system as an alternative to skin testing for the detection of human TB infection.

scholarly journals Persistent Chlamydia trachomatis Infection of HeLa Cells Mediates Apoptosis Resistance through a Chlamydia Protease-Like Activity Factor-Independent Mechanism and Induces High Mobility Group Box 1 Release

2011 ◽  
Vol 80 (1) ◽  
pp. 195-205 ◽  
Author(s):  
Jürgen Rödel ◽  
Christina Große ◽  
Hangxing Yu ◽  
Katharina Wolf ◽  
Gordon P. Otto ◽  
...  
Keyword(s):  
Chlamydia Trachomatis ◽  
Host Cell ◽  
Hela Cells ◽  
Persistent Infection ◽  
High Mobility ◽  
Apoptosis Resistance ◽  
Content Type ◽  
Activity Factor ◽  
Infected Cells ◽  
Ifn Γ

ABSTRACTIntracellular persistence ofChlamydia trachomatishas been implicated in the development of chronic infection that can result in pelvic inflammatory disease and tubal sterility. By inhibition of host cell apoptosis, chlamydiae have evolved a strategy to maintain the intracellular environment for replication and persistence. Both antiapoptotic host cell-derived factors and the chlamydial protease-like activity factor (CPAF) are involved inChlamydia-mediated apoptosis resistance. Here, we show that in HeLa cells infected with gamma interferon (IFN-γ)-induced persistentC. trachomatisserovar D, the expression of CPAF is downregulated, and proapoptotic protease substrates are not cleaved. Persistent infection protected HeLa cells from apoptosis when they were exposed to staurosporine. Small-interfering RNA-mediated inhibition of myeloid cell leukemia 1 (Mcl-1) protein upregulation sensitized persistently infected cells for apoptosis. The inhibitor of apoptosis protein 2 (IAP-2) seems not to be relevant in this context because IAP-2 protein was not induced in response to IFN-γ treatment. Although apoptosis was inhibited, persistent infection caused cell membrane disintegration, as measured by the increased release of cytokeratin 18 from HeLa cells. Moreover, persistently infected cells released significantly increased amounts of high mobility group box 1 (HMGB1) protein which represents a proinflammatory damage-associated pattern molecule. The data of this study suggest that cells infected with persistentC. trachomatisare protected from apoptosis independently of CPAF but may promote chronic inflammation through HMGB1 release.

scholarly journals Gamma Interferon Is Required for Chlamydia Clearance but Is Dispensable for T Cell Homing to the Genital Tract

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Jennifer D. Helble ◽  
Rodrigo J. Gonzalez ◽  
Ulrich H. von Andrian ◽  
Michael N. Starnbach
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Chlamydia Trachomatis ◽  
Genital Tract ◽  
Gamma Interferon ◽  
Cell Homing ◽  
Content Type ◽  
T Cell Homing ◽  
Ifn Γ

ABSTRACT While there is no effective vaccine against Chlamydia trachomatis infection, previous work has demonstrated the importance of C. trachomatis-specific CD4+ T cells (NR1 T cells) in pathogen clearance. Specifically, NR1 T cells have been shown to be protective in mice, and this protection depends on the host’s ability to sense the cytokine gamma interferon (IFN-γ). However, it is unclear what role NR1 production or sensing of IFN-γ plays in T cell homing to the genital tract or T cell-mediated protection against C. trachomatis. Using two-photon microscopy and flow cytometry, we found that naive wild-type (WT), IFN-γ−/−, and IFN-γR−/− NR1 T cells specifically home to sections in the genital tract that contain C. trachomatis. We also determined that protection against infection requires production of IFN-γ from either NR1 T cells or endogenous cells, further highlighting the importance of IFN-γ in clearing C. trachomatis infection. IMPORTANCE Chlamydia trachomatis is an important mucosal pathogen that is the leading cause of sexually transmitted bacterial infections in the United States. Despite this, there is no vaccine currently available. In order to develop such a vaccine, it is necessary to understand the components of the immune response that can lead to protection against this pathogen. It is well known that antigen-specific CD4+ T cells are critical for Chlamydia clearance, but the contexts in which they are protective or not protective are unknown. Here, we aimed to characterize the importance of gamma interferon production and sensing by T cells and the effects on the immune response to C. trachomatis. Our work here helps to define the contexts in which antigen-specific T cells can be protective, which is critical to our ability to design an effective and protective vaccine against C. trachomatis.

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