Innate Resistance against Toxoplasma gondii: An Evolutionary Tale of Mice, Cats, and Men

Gazzinelli, Ricardo T.; Mendonça-Neto, Rondon; Lilue, Jingtao; Howard, Jonathan C.; Sher, Alan

doi:10.1016/j.chom.2014.01.004

Cited by 122 publications

(129 citation statements)

References 25 publications

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“…High IDO activity, which could result in the depletion of Trp, is considered a key weapon against T. gondii growth in human fibroblasts treated with IFN-γ, but it does not seem to occur in mouse fibroblasts (20,28,29). Human MSCs treated with IFN-γ were found to exhibit an IDO-mediated antimicrobial effector function against various pathogens, suggesting a similar mechanism that might be used to curtail T. gondii (9).…”

Section: Discussionmentioning

confidence: 99%

Guanylate-binding protein 1 (GBP1) contributes to the immunity of human mesenchymal stromal cells against Toxoplasma gondii

Qin

Lai

Liu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mesenchymal stromal cells (MSCs) have recently been shown to play important roles in mammalian host defenses against intracellular pathogens, but the molecular mechanism still needs to be clarified. We confirmed that human MSCs (hMSCs) prestimulated with IFN-γ showed a significant and dose-dependent ability to inhibit the growth of two types of Toxoplasma gondii [type I RH strain with green fluorescent proteins (RH/GFP) or type II PLK strain with red fluorescent proteins (PLK/RED)]. However, in contrast to previous reports, the anti-T. gondii activity of hMSCs was not mediated by indoleamine 2,3-dioxygenase (IDO). Genome-wide RNA sequencing (RNA-seq) analysis revealed that IFN-γ increased the expression of the p65 family of human guanylate-binding proteins (hGBPs) in hMSCs, especially hGBP1. To analyze the functional role of hGBPs, stable knockdowns of hGBP1, -2, and -5 in hMSCs were established using a lentiviral transfection system. hGBP1 knockdown in hMSCs resulted in a significant loss of the anti-T. gondii host defense property, compared with hMSCs infected with nontargeted control sequences. hGBP2 and -5 knockdowns had no effect. Moreover, the hGBP1 accumulation on the parasitophorous vacuole (PV) membranes of IFN-γ-stimulated hMSCs might protect against T. gondii infection. Taken together, our results suggest that hGBP1 plays a pivotal role in anti-T. gondii protection of hMSCs and may shed new light on clarifying the mechanism of host defense properties of hMSCs.human stem cells | parasitic protozoan | innate immunity | in vitro cultivation

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Section: Discussionmentioning

confidence: 99%

Guanylate-binding protein 1 (GBP1) contributes to the immunity of human mesenchymal stromal cells against Toxoplasma gondii

Qin

Lai

Liu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…are increasingly linked to a number of diseases, and the lack of TLR11 in people is a possible explanation for the human susceptibility to urinary tract infections, toxoplasmosis and Salmonella typhi infections (Mathur et al, 2012;Gazzinelli et al, 2014). However, so little is currently known regarding TLR11 that these early observations should be treated with caution.…”

Section: A Toll-like Receptors and Their Nomenclaturementioning

confidence: 99%

“…2A). TLR11, a receptor most closely related to TLR5, is expressed in mice but not humans and has been suggested to detect bacterial and, along with another mouse TLR, TLR12, protozoal ligands (Andersen-Nissen et al, 2007a;Mathur et al, 2012;Gazzinelli et al, 2014). Genetic defects in TLR5…”

Section: A Toll-like Receptors and Their Nomenclaturementioning

confidence: 99%

“…TLR5 has been shown to be important in recognizing bacteria such as Salmonella enterica serovar Typhimurium in the gut epithelial cells and E. coli in the urinary tract Andersen-Nissen et al, 2007a,b). TLR11 detects uropathogenic E. coli, enteric salmonellae (both serovars Typhimurium and Typhi), and the parasite Toxoplasma gondii (Mathur et al, 2012;Gazzinelli et al, 2014).…”

Section: B Structural Biology Of the Toll-like Receptorsmentioning

confidence: 99%

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International Union of Basic and Clinical Pharmacology. XCVI. Pattern Recognition Receptors in Health and Disease

et al. 2015

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“…4). [32][33][34] Given the role of GTPases in intracellular immunity to T. gondii, 34 it is an intriguing hypothesis that protozoans may have fortuitously enhanced immunity against retroviral pathogens. That such complexity is seemingly recapitulated within an MHC-I structural gene 4 is profound, and might suggest a previously unrecognized level of evolutionary interplay between these two types of pathogens and the genesis of the human adaptive immune system.…”

Section: Gov) H (Helix) Hth (Helix-turn-helix) Hss (Helix-strand-smentioning

confidence: 99%

TE-domestication and horizontal transfer in a putative Nef-AP1mu mimic of HLA-A cytoplasmic domain re-trafficking

Murray¹,

Murray²

2016

Mobile Genetic Elements

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Genes of the major histocompatibility complex (MHC; also called HLA in human) are polymorphic elements in the genomes of sharks to humans. Class-I and class-II MHC loci appear responsible for much of the genetic linkage to myriad disease states via the capacity to bind short (~8-15 a.a.) peptides of a given pathogen's proteome, or in some cases, the altered proteomes of cancerous cells, and even (in autoimmunity) certain nominal 'self' peptides (Janeway, 2004).1 Unfortunately, little is known about how the canonical structure of the MHC-I/-II peptide-presenting gene evolved, particularly since beyond~500 Mya (sharks) no paralogs exist.2, 3 We previously reported that HLA-A isotype alleles with the a1-helix, R65 motif, are wide-spread in phylogeny, but that the a 2-helix, H151R motif, has apparently segregated out of most species. Surprisingly, an uncharacterized orf in T. syrichta (Loc-103275158) encoded R151, but within a truncated A-23 like gene containing 5 0 -and 3 0 -footprints of the transposon (TE), tigger-1; the extant tarsier A-23 allele is totally missing exon-3 and part-of exon-4; together, suggesting TE-mediated inactivation of an intact/ancestral A-23 allele (Murray, 2015a). 4 The unique Loc-103275158 orf encodes a putative 15-exon transcript with no apparent paralogs throughout phylogeny. However, an HLA-A11 like gene in M. leucophaeus with a shortened C-terminal domain, and an HLA-A like orf in C. atys with two linked a1/a2/a3 domains, both contain a second transmembrane segment, which is conserved in Loc-103275158. Thus, we could model the putative protein with its Nef-like tail domain docked to its MHC-I like a3 domain (i.e., on the same side of a membrane). This modeled tertiary structure is strikingly similar to the solved structure of the Nef:MHC-I CD:AP1mu transporter (Jia, 2012).5 Nef:AP1mu binds the CD of MHC-I in trafficking MHC-I away from the trans-golgi and into the endocytic pathway in HIV-1 infected cells. The CD loop of the Loc-103275158 provisional protein conserved the nominal MHC-I CD tyrosine phosphorylation site, and it has an N-terminal SH3 domain that we docked in one conformation to its internal Nef-like domain. Here, we suggest that phosphorylation of the protein's CD-loop signals an exchange between the internal Nef-like domain and a lentiviral-Nef for binding the N-terminal SH3 domain -freeing the Nef-like domain to bind MHC-I CD. Since the 5 0 -tigger sequence encodes part of the pseudo a1/a2 MHC-I domain, and the 3 0 -tigger part of the Nef-like domain, we speculate that transposition proceeded phylogenetically disparate horizontal transfers, involving adjacent 5 0 -and 3 0 -parasitic footprints, which we also found in the Loc-103275158 orf.

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Innate Resistance against Toxoplasma gondii: An Evolutionary Tale of Mice, Cats, and Men

Cited by 122 publications

References 25 publications

Guanylate-binding protein 1 (GBP1) contributes to the immunity of human mesenchymal stromal cells against Toxoplasma gondii

Guanylate-binding protein 1 (GBP1) contributes to the immunity of human mesenchymal stromal cells against Toxoplasma gondii

International Union of Basic and Clinical Pharmacology. XCVI. Pattern Recognition Receptors in Health and Disease

TE-domestication and horizontal transfer in a putative Nef-AP1mu mimic of HLA-A cytoplasmic domain re-trafficking

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