Abstract
Chlamydiae are obligate intracellular pathogens that are sensitive to pro-inflammatory cytokine interferon-γ. IFN-γ-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-γ-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-γ-inducible proteins, the human guanylate binding proteins (hGBPs) 1 and 2 that potentiate the anti-chlamydial properties of IFN-γ. 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-γ. Thus, hGBPs appear to potentiate the anti-chlamydial effects of IFN-γ. Indeed, depletion of hGBP1 and 2 in cells treated with IFN-γ 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-γ was not affected by hGBP overexpression. These findings identify the guanylate binding proteins as potentiators of IFN-γ inhibition of C. trachomatis growth, and may be the targets of the chlamydial cytotoxin.
Highlights
Infections of the obligate intracellular pathogens chlamydiae elicit an inflammatory Th1 response from the host resulting in their eventual clearance, with interferon-c (IFN-c) playing a prominent role in this process [1,2,3,4]
Results human guanylate binding proteins (hGBPs) induction by IFN-c correlated well with growth inhibition of chlamydia hGBPs are induced by treatment with IFN-c in other cell types, and a similar IFN-c responsiveness was investigated in HeLa cells
Expression levels of hGBP1 and 2 after treatment with different doses of IFN-c were examined by qRT-PCR at 24 h post-treatment
Summary
Infections of the obligate intracellular pathogens chlamydiae elicit an inflammatory Th1 response from the host resulting in their eventual clearance, with interferon-c (IFN-c) playing a prominent role in this process [1,2,3,4]. Seminal studies from Byrne and colleagues have identified the IFN-c-induced gene encoding for the catabolic enzyme indole 2,3-dideoxygenase (IDO) as the primary anti-chlamydial effector of IFN-c [5]. IFN-c stimulation of cells in vivo and in vitro induces the transcription of numerous genes that cooperate to eliminate intracellular bacteria, and their roles in resolving bacterial infections are just beginning to be understood at the molecular level. There are other IFN-c-induced genes that have not been characterized for bactericidal activity, and in addition to IDO may be required for the full manifestation of the anti-chlamydial function of this cytokine. A prominent subset of these IFN-c-induced genes includes a family of GTP-binding proteins, collectively termed large GTPases to which the 65 kD guanylate binding proteins (p65 GBPs) belong [11,12,13,14,15]. A prominent subset of these IFN-c-induced genes includes a family of GTP-binding proteins, collectively termed large GTPases to which the 65 kD guanylate binding proteins (p65 GBPs) belong [11,12,13,14,15]. p65 GBPs represent well-conserved GTPases in vertebrates, and are highly induced by IFN-c and less so by IFN-
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
