Extensive Characterization of IFN-Induced GTPases mGBP1 to mGBP10 Involved in Host Defense

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237

Many microbes create and maintain pathogen-containing vacuoles (PVs) as an intracellular niche permissive for microbial growth and survival. The destruction of PVs by IFNγ-inducible guanylate binding protein (GBP) and immunity-related GTPase (IRG) host proteins is central to a successful immune response directed against numerous PV-resident pathogens. However, the mechanism by which IRGs and GBPs cooperatively detect and destroy PVs is unclear. We find that host cell priming with IFNγ prompts IRG-dependent association of Toxoplasma- and Chlamydia-containing vacuoles with ubiquitin through regulated translocation of the E3 ubiquitin ligase tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6). This initial ubiquitin labeling elicits p62-mediated escort and deposition of GBPs to PVs, thereby conferring cell-autonomous immunity. Hypervirulent strains of Toxoplasma gondii evade this process via specific rhoptry protein kinases that inhibit IRG function, resulting in blockage of downstream PV ubiquitination and GBP delivery. Our results define a ubiquitin-centered mechanism by which host cells deliver GBPs to PVs and explain how hypervirulent parasites evade GBP-mediated immunity.

Section: Discussionsupporting

confidence: 89%

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

Haldar

Foltz

Finethy

et al. 2015

146

237

“…In mice, five GBPs had been initially described (16)(17)(18). Using Affymetrix and in silico analyses, we recently identified the complete mGBP gene family with the additional members mGbp6, mGbp7, mGbp8, mGbp9, mGbp10, and mGbp11 (14,19). The genes of the mGBP family were located on clusters on chromosomes 3 (mGbp1, mGbp2, mGbp3, mGbp5, and mGbp7) and 5 (mGbp4, mGbp6, mGbp8, mGbp9, mGbp10, and mGbp11) (14).…”

mentioning

confidence: 99%

Murine Guanylate Binding Protein 2 (mGBP2) controlsToxoplasma gondiireplication

Degrandi

Kravets

Konermann

et al. 2012

Self Cite

171

235

IFN-γ orchestrates the host response against intracellular pathogens. Members of the guanylate binding proteins (GBP) comprise the most abundant IFN-γ-induced transcriptional response. mGBPs are GTPases that are specifically up-regulated by IFN-γ, other proinflammatory cytokines, toll-like receptor agonists, as well as in response to Listeria monocytogenes and Toxoplasma gondii infection. mGBP2 localizes at the parasitophorous vacuole (PV) of T. gondii; however, the molecular function of mGBP2 and its domains in T. gondii infection is not known. Here, we show that mGBP2 is highly expressed in several cell types, including T and B cells after stimulation. We provide evidence that the Cterminal domain is sufficient and essential for recruitment to the T. gondii PV. Functionally, mGBP2 reduces T. gondii proliferation because mGBP2-deficient cells display defects in the replication control of T. gondii. Ultimately, mGBP2-deficient mice reveal a marked immune susceptibility to T. gondii. Taken together, mGBP2 is an essential immune effector molecule mediating antiparasitic resistance.pathogen defense | cell-autonomous immunity | host-pathogen interaction

“…This comparison revealed 196 genes that were up-regulated during infection, many with known immunological roles, including the chemokine receptor Ccr2, which was recently shown to influence murine histoplasmosis (11). Many genes included in this subset are IFN-γ-induced, including Stat1 and genes encoding six guanylate-binding proteins (12).…”

Section: Resultsmentioning

confidence: 99%

Genetic control of immune cell types in fungal disease

Mayfield

Fontana

Rine

2010

Millions of people harbor latent infections of the fungus Histoplasma capsulatum. Such persistent infections represent a stalemate between mechanisms of virulence and the immune response. The differing responses of inbred mouse strains to the same pathogen reflect variation in the genes that control the outcome of infection. Here we show that a 250-fold difference in H. capsulatum susceptibility between inbred mouse strains is attributable to the genotype at the MHC H2 locus. Gene expression analysis of strains varying only at the H2 locus identified genotype-specific and genotype-independent expression signatures, including infection-induced genes such as the fungal pattern recognition receptor Clec7a. Surprisingly, B-cell-specific gene expression was negatively correlated with fungal burden, whereas neutrophil-specific genes were correlated with superior disease outcome. Indeed, disease outcome improved when B cells were eliminated and neutrophils were more active, a previously unknown aspect of the host response. These data refine the understanding of genetic influences on histoplasmosis, reveal how shifts in the composition of immune cell populations compel different disease outcomes, and uncover how innate immunity modulation alters histoplasmosis.G enetic differences among individuals can have profound effects on infectious disease susceptibility and severity; for example, severe infections with the dimorphic fungal pathogen Coccidioides immitis are more frequent in males and people of African or Asian descent (1). This relationship inspires the hope that uncovering the pivotal genes affecting disease outcome might lead to new therapeutic strategies for controlling disease. For histoplasmosis, a fungal pneumonia affecting millions of people worldwide (2), infection outcomes vary greatly among mouse strains with only minor differences in cytokine profiles (3, 4). Although molecular ablation has connected an orderly and well-defined cytokine response to histoplasmosis outcome (5-7), previous mouse strain studies have highlighted the unexplained aspects of a successful immune response. The experiments reported herein identify a major influence of the H2 locus on experimental infections of mice with the fungal pathogen Histoplasma capsulatum, uncover gene expression signatures of neutrophils and B cells in resistant strains of mice, show that B cells impair the antifungal response, and implicate the innate immune system as an early control point. ResultsGenetic Control of Disease Outcome After H. capsulatum Infection.We previously mapped quantitative trait loci controlling the phenotype of fungal burden using recombinant inbred mice (3). These data identify two regions on chromosome 17 linked to 250-fold lower fungal burden in the spleens of resistant A/J mice compared with sensitive C57BL/6 (B6) mice. One of those regions is tightly linked to the MHC H2, a highly variable multigene complex encoding the proteins responsible for antigen presentation. To test the contribution of the H2 locus to the immune respon...