Secreted Effectors Modulating Immune Responses to Toxoplasma gondii
Abstract
:1. Introduction
2. Defending Home Base: Effectors on the Parasitophorous Vacuole Membrane
2.1. ROP18 Virulence Complex: An Inhibitor of IFNγ-Induced IRG Loading (ROP18/ROP17/ROP5/GRA7)
2.2. GRA60, GRA12, ROP54: IRG/GBP Modulators
2.3. GRA15: An Activator of NF-κB Signaling
2.4. GRA15: A Mediator of IFNγ-Induced Cell-Autonomous Immune Reaction
2.5. ROP38: An Inhibitor of NF-κB Signaling
2.6. GRA6: An Activator of NFAT4 Signaling and CCL2 Secretion
2.7. GRA25: An Additional CCL2 Inducer
3. Taking It on the Road: Effectors in the Endoplasmic Reticulum
ROP18 and the ER
4. Taking It on the Road: Effectors in the Cytoplasm
4.1. GRA18: ß-Catenin Induced M2 Cytokines Secretion
4.2. MAG1: An Effector, Matrix, and Cyst Wall Protein
5. Attacking Enemy Headquarters: Effectors Found in the Host Nucleus
5.1. ROP16: An Inducer of M2 Polarization
5.2. GRA28: An Inducer of CCL22 Chemokine Secretion
5.3. GRA24: A Modulator of p38 α Mitogen-Activated Protein
5.4. GRA16: A Modulator of HAUSP and PP2A
5.5. HCE1/TEEGR: A Modulation of E2F Activation
5.6. TgIST: A Suppressor of Interferon Signaling
5.7. TgNSM: A Suppressor of IFNγ-Induced Necroptosis
6. Translocation of GRA Effectors
7. Effector Translocation in T. gondii Tissue Cysts
8. Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
EZH2 | enhancer of zeste homolog 2 |
GBP | p65 guanylate binding protein |
IRG | immunity-related GTPase |
IVN | intravacuolar network |
NF-κB | nuclear factor kappa B |
NLS | nuclear localization signal |
PVM | parasitophorous vacuolar membrane |
QTL | quantitative trait locus |
STAT | signal transducer and activator of transcription |
TRAF | TNF receptor-associated factor |
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Name | Location | Functions | Interacting Partner | Mouse Virulence of KO Parasites | Gene Name | Ortholog in Cystoisospora | Ortholog in Sarcocystis | Ortholog in Eimeria | Essentiality Score [26] | NonSyn/Snyn SNP | References |
---|---|---|---|---|---|---|---|---|---|---|---|
ROP5I/III | PVM | Pseudokinase inhibits IRG coating by preparing Irga6 for phosphorylation by ROP18. | Irga6 | Highly avirulent [27,28] | TGME49_308090 | Y | Y | Y | n/a | 3 | [27,28] |
ROP18I/II | PVM/ER | Serine-threonine kinase inhibits IRG coating by phosphorylating monomeric Irga6. Suppresses unfolded protein response and antigen presentation. Induces apoptosis in neurons by RTN1-C. | IRGs (preferentially Irga6), ATF6ß, RTN1-C | Slightly reduced, ∆rop18/17 double mutant is highly avirulent [29] | TGME49_205250 | Y | Y | Y | 0.89 | 4.5 | [30] |
GRA7 | PVM | Alter the turnover kinetics of Irga6. Activate inflammasome. | Irga6, TRAF6, ASC | Slightly reduced, ∆rop18/gra7 double mutant is highly avirulent [31] | TGME49_203310 | N | N | N | 1.9 | 4 | [31] |
ROP17 | PVM | Serine-threonine kinase disassembles polymerized Irgb6. | IRGs (preferentially Irgb6) | Slightly reduced, ∆rop18/17 double mutant is highly avirulent [29] | TGME49_258580 | Y | Y | Y | 1.29 | 3.8 | [29] |
GRA60 | PVM | Prevents Irga6 and Irgb10 coating on PVM. | n/a | Slightly reduced [32] | TGME49_204270 | N | N | N | -0.59 | 2.41 | [32] |
ROP54 | PVM | Reduces GBP2 loading on PVM. | n/a | Reduced [33] | TGME49_210370 | N | N | N | 1.07 | 1.58 | [33] |
GRA12 | IVN/PVM | Prevents IFNγ-induced parasite destruction. | n/a | Highly avirulent [34] | TGME49_288650 | Y | Y | Y | 1.75 | 0.64 | [34] |
GRA15II | PVM | Activates NF-κB, induce secretion of IL-12 and IL-1ß. Mediates IFNγ-induced PV-lysosome fusion and IRG loading. | TRAF2/TRAF6 | No difference [35], more virulent [36] | TGME49_275470 | N | N | N | 2.33 | 3.75 | [35,37,38] |
ROP38 | IVN/PVM | Inhibits NF-κB pathway and IL-12 production. | n/a | Reduced [39], no difference [40] | TGME49_242110 | Y | Y | Y | n/a | 4.5 | [41,42] |
GRA6 | IVN/PVM | Induces CXCL2/CCL2 by activation NFAT4, recruits monocytes/neutrophils, and disseminates parasites. | CAMLG | Reduced [43] | TGME49_275440 | N | N | N | 1.84 | 8.25 | [43] |
GRA25 | PV | Induces CCL2 secretion. | n/a | Reduced [44] | TGME49_290700 | N | N | N | 1.31 | 3.08 | [44] |
GRA18 | Cytoplasm | Activates ß-catenin and release anti-inflammatory chemokines CCL22 and CCL17. | GSK3/PP2A-B56 | Reduced [45] | TGME49_288840 | N | N | N | 1.66 | 1.93 | [45] |
MAG1 | PVM/Cytoplasm | Suppresses IL-1ß secretion in macrophages. | n/a | Reduced [46] | TGME49_270240 | Y | N | N | 1.25 | 1 | [46] |
ROP16I/III | Nucleus | Suppresses Th1/M1 response, induces Th2/M2 response. Protects mice from lethal ileitis. | STAT3/5/6 | More virulent [47,48] | TGME49_262730 | N | N | N | 1.11 | 2.37 | [47,48] |
GRA28 | Nucleus | Induces CCL22 secretion. | n/a | No difference [49] | TGME49_231960 | N | N | N | 1.48 | 5.25 | [49] |
GRA24 | Nucleus | Activates p38α MAPK and induces Th1/M1 cytokines and chemokines secretion (e.g., IL-12, IL-6, CCL2, CCL5). | p38α MAPK | No difference [50] | TGME49_230180 | N | N | N | 2.86 | 2.69 | [50] |
GRA16 | Nucleus | Interferes p53-dependent apoptosis and inhibits NF-κB pathway (in parasite-free tumor model). | HAUSP, PP2A-B55 | Reduced in type II strain but not in type I [51] | TGME49_208830 | N | N | N | 2.28 | 3.13 | [51] |
HCE1/TEEGR | Nucleus | Represses NF-κB-induced gene expression (e.g., IL-6, IL-8, IL-1ß). | E2F | Reduced [52] | TGME49_239010 | N | N | N | 1.46 | 5.46 | [52,53] |
TgIST | Nucleus | Represses IFN-induced gene expression (e.g., IRGs loading). | STAT1/2, NuRD | Highly avirulent [54,55] | TGME49_240060 | N | N | N | 1.44 | 5.67 | [54,55] |
TgNSM | Nucleus | Represses IFN-induced gene expression and necroptosis. | NCoR/SMRT | n/a | TGME49_235140 | N | N | N | 1.41 | 6.73 | [56] |
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Tomita, T.; Guevara, R.B.; Shah, L.M.; Afrifa, A.Y.; Weiss, L.M. Secreted Effectors Modulating Immune Responses to Toxoplasma gondii. Life 2021, 11, 988. https://doi.org/10.3390/life11090988
Tomita T, Guevara RB, Shah LM, Afrifa AY, Weiss LM. Secreted Effectors Modulating Immune Responses to Toxoplasma gondii. Life. 2021; 11(9):988. https://doi.org/10.3390/life11090988
Chicago/Turabian StyleTomita, Tadakimi, Rebekah B. Guevara, Lamisha M. Shah, Andrews Y. Afrifa, and Louis M. Weiss. 2021. "Secreted Effectors Modulating Immune Responses to Toxoplasma gondii" Life 11, no. 9: 988. https://doi.org/10.3390/life11090988