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2015 ; 83
(12
): 4740-9
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Guanylate binding proteins enable rapid activation of canonical and noncanonical
inflammasomes in Chlamydia-infected macrophages
#MMPMID26416908
Finethy R
; Jorgensen I
; Haldar AK
; de Zoete MR
; Strowig T
; Flavell RA
; Yamamoto M
; Nagarajan UM
; Miao EA
; Coers J
Infect Immun
2015[Dec]; 83
(12
): 4740-9
PMID26416908
show ga
Interferon (IFN)-inducible guanylate binding proteins (GBPs) mediate
cell-autonomous host resistance to bacterial pathogens and promote inflammasome
activation. The prevailing model postulates that these two GBP-controlled
activities are directly linked through GBP-dependent vacuolar lysis. It was
proposed that the rupture of pathogen-containing vacuoles (PVs) by GBPs destroyed
the microbial refuge and simultaneously contaminated the host cell cytosol with
microbial activators of inflammasomes. Here, we demonstrate that GBP-mediated
host resistance and GBP-mediated inflammatory responses can be uncoupled. We show
that PVs formed by the rodent pathogen Chlamydia muridarum, so-called inclusions,
remain free of GBPs and that C. muridarum is impervious to GBP-mediated
restrictions on bacterial growth. Although GBPs neither bind to C. muridarum
inclusions nor restrict C. muridarum growth, we find that GBPs promote
inflammasome activation in C. muridarum-infected macrophages. We demonstrate that
C. muridarum infections induce GBP-dependent pyroptosis through both
caspase-11-dependent noncanonical and caspase-1-dependent canonical
inflammasomes. Among canonical inflammasomes, we find that C. muridarum and the
human pathogen Chlamydia trachomatis activate not only NLRP3 but also AIM2. Our
data show that GBPs support fast-kinetics processing and secretion of
interleukin-1? (IL-1?) and IL-18 by the NLRP3 inflammasome but are dispensable
for the secretion of the same cytokines at later times postinfection. Because
IFN-? fails to induce IL-1? transcription, GBP-dependent fast-kinetics
inflammasome activation can drive the preferential processing of constitutively
expressed IL-18 in IFN-?-primed macrophages in the absence of prior Toll-like
receptor stimulation. Together, our results reveal that GBPs control the kinetics
of inflammasome activation and thereby shape macrophage responses to Chlamydia
infections.
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