Autophagy restrictsChlamydia trachomatisgrowth in human macrophages via IFNG-inducible guanylate binding proteins

Abstract

Interferon γ (IFNG) is a key host response regulator of intracellular pathogen replication, including that of Chlamydia spp The antichlamydial functions of IFNG manifest in a strictly host, cell-type and chlamydial strain dependent manner. It has been recently shown that the IFNG-inducible family of immunity-related GTPases (IRG) proteins plays a key role in the defense against nonhost adapted chlamydia strains in murine epithelial cells. In humans, IFN-inducible guanylate binding proteins (hGBPs) have been shown to potentiate the antichlamydial effect of IFNG; however, how hGBPs regulate this property of IFNG is unknown. In this study, we identified hGBP1/2 as important resistance factors against C. trachomatis infection in IFNG-stimulated human macrophages. Exogenous IFNG reduced chlamydial infectivity by 50 percent in wild-type cells, whereas shRNA hGBP1/2 knockdown macrophages fully supported chlamydial growth in the presence of exogenous IFNG. hGBP1/2 were recruited to bacterial inclusions in human macrophages upon stimulation with IFNG, which triggered rerouting of the typically nonfusogenic bacterial inclusions for lysosomal degradation. Inhibition of lysosomal activity and autophagy impaired the IFNG-mediated elimination of inclusions. Thus, hGBP1/2 are critical effectors of antichlamydial IFNG responses in human macrophages. Through their capacity to remodel classically nonfusogenic chlamydial inclusions and stimulate fusion with autophagosomes, hGBP1/2 disable a major chlamydial virulence mechanism and contribute to IFNG-mediated pathogen clearance.

Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins

“…IFNγ priming induces GBP-mediated cell-autonomous immunity that results in the degradation of C. trachomatis inside autophagolysosomes (24,27). Because antimicrobial autophagy (also called xenophagy) often depends on host-mediated ubiquitination of invading microbes (28), we asked whether IFNγ priming would lead to the accumulation of ubiquitin on C. trachomatis PVs (referred to henceforth as "inclusions" in agreement with accepted nomenclature).…”

“…Because GBPs mediate IFNγ-induced cell-autonomous resistance to C. trachomatis infections (24,27,40), we next asked whether the diminished targeting of GBPs to PVs in p62 −/− and TRAF6 −/− cells would debilitate the cell-autonomous defense system of the host cell. We found that IFNγ-primed cells lacking either p62 or enzymatically active TRAF6 elicited a less effective cell-autonomous immune response to C. trachomatis (Fig.…”

Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1

“…Nevertheless, the observation of tethering underlines the functional similarity of GBPs with atlastins and also other dynamin family members as recently shown for mitofusin (53). Recent studies on the antibacterial effect of GBPs indicate that hGBP1 and 2 are recruited to bacterial inclusions of Chlamydia trachomatis and trigger their rerouting for lysosomal degradation (54). It is tempting to speculate that the tethering effect of hGBP1 and its localization along the phagolysosomal pathway, which we report here, could be the basis for the physiological function of the protein.…”

Genital Chlamydia trachomatis: Understanding the Roles of Innate and Adaptive Immunity in Vaccine Research

“…However, unlike epithelial cells, M are not a hospitable niche for chlamydial intracellular replication, as illustrated by the fact that compared to the case in epithelial cells, only a small fraction of chlamydial RBs are detected in M (49). C. trachomatis destruction inside M has been associated with host cell autophagy, a process by which cells degrade cytoplasmic proteins and organelles (49)(50)(51). Also, studies have demonstrated that M autophagy can enhance antigen presentation to T cells (52).…”