Human guanylate binding proteins potentiate the anti-chlamydia effects of interferon-γ

Illya Tietzel, Christelle El-Haibi, Rey A Carabeo

Research output: Contribution to journalArticle

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Abstract

Chlamydiae are obligate intracellular pathogens that are sensitive to pro-inflammatory cytokine interferon-gamma. IFN-gamma-inducible murine p47 GTPases have been demonstrated to function in resistance to chlamydia infection in vivo and in vitro. Because the human genome does not encode IFN-gamma-inducible homologues of these proteins, the significance of the p47 GTPase findings to chlamydia pathogenesis in humans is unclear. Here we report a pair of IFN-gamma-inducible proteins, the human guanylate binding proteins (hGBPs) 1 and 2 that potentiate the anti-chlamydial properties of IFN-gamma. hGBP1 and 2 localize to the inclusion membrane, and their anti-chlamydial functions required the GTPase domain. Alone, hGBP1 or 2 have mild, but statistically significant and reproducible negative effects on the growth of Chlamydia trachomatis, whilst having potent anti-chlamydial activity in conjunction with treatment with a sub-inhibitory concentration of IFN-gamma. Thus, hGBPs appear to potentiate the anti-chlamydial effects of IFN-gamma. Indeed, depletion of hGBP1 and 2 in cells treated with IFN-gamma led to an increase in inclusion size, indicative of better growth. Interestingly, chlamydia species/strains harboring the full-length version of the putative cytotoxin gene, which has been suggested to confer resistance to IFN-gamma was not affected by hGBP overexpression. These findings identify the guanylate binding proteins as potentiators of IFN-gamma inhibition of C. trachomatis growth, and may be the targets of the chlamydial cytotoxin.
Original languageEnglish
Article numbere6499
Number of pages10
JournalPloS ONE
Volume4
Issue number8
DOIs
Publication statusPublished - 4 Aug 2009

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Chlamydia
GTP Phosphohydrolases
interferons
Interferons
binding proteins
Carrier Proteins
Chlamydia trachomatis
Cytotoxins
guanosinetriphosphatase
cytotoxins
Growth
Genes
Chlamydia Infections
Pathogens
Human Genome
Interferon-gamma
Proteins
Cytokines
Membranes
interferon-gamma

Keywords

  • microscopy, fluorescence
  • polymerase chain reaction
  • gene knockdown techniques
  • base sequence
  • interferon-gamma
  • HeLa cells
  • humans
  • intracellular membranes
  • DNA primers
  • chlamydia trachomatis
  • GTP-binding proteins
  • RNA, small interfering

Cite this

Human guanylate binding proteins potentiate the anti-chlamydia effects of interferon-γ. / Tietzel, Illya; El-Haibi, Christelle; Carabeo, Rey A.

In: PloS ONE, Vol. 4, No. 8, e6499, 04.08.2009.

Research output: Contribution to journalArticle

Tietzel, Illya ; El-Haibi, Christelle ; Carabeo, Rey A. / Human guanylate binding proteins potentiate the anti-chlamydia effects of interferon-γ. In: PloS ONE. 2009 ; Vol. 4, No. 8.
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AB - Chlamydiae are obligate intracellular pathogens that are sensitive to pro-inflammatory cytokine interferon-gamma. IFN-gamma-inducible murine p47 GTPases have been demonstrated to function in resistance to chlamydia infection in vivo and in vitro. Because the human genome does not encode IFN-gamma-inducible homologues of these proteins, the significance of the p47 GTPase findings to chlamydia pathogenesis in humans is unclear. Here we report a pair of IFN-gamma-inducible proteins, the human guanylate binding proteins (hGBPs) 1 and 2 that potentiate the anti-chlamydial properties of IFN-gamma. hGBP1 and 2 localize to the inclusion membrane, and their anti-chlamydial functions required the GTPase domain. Alone, hGBP1 or 2 have mild, but statistically significant and reproducible negative effects on the growth of Chlamydia trachomatis, whilst having potent anti-chlamydial activity in conjunction with treatment with a sub-inhibitory concentration of IFN-gamma. Thus, hGBPs appear to potentiate the anti-chlamydial effects of IFN-gamma. Indeed, depletion of hGBP1 and 2 in cells treated with IFN-gamma led to an increase in inclusion size, indicative of better growth. Interestingly, chlamydia species/strains harboring the full-length version of the putative cytotoxin gene, which has been suggested to confer resistance to IFN-gamma was not affected by hGBP overexpression. These findings identify the guanylate binding proteins as potentiators of IFN-gamma inhibition of C. trachomatis growth, and may be the targets of the chlamydial cytotoxin.

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