How did we get here? Insights into mechanisms of immunity-related GTPase targeting to intracellular pathogens

Dockterman, Jacob; Coers, Jörn

doi:10.1016/j.mib.2022.102189

Cited by 10 publications

(9 citation statements)

References 111 publications

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“…IRGs and GBPs work cooperatively in the cell-autonomous immune response to Toxoplasma in mouse cells and have been shown to promote each other’s recruitment to PVs ( 12 – 14 ). The mechanism by which IRGs and GBPs are delivered to Toxoplasma PVs is only poorly understood but likely involves the concerted action of multiple events, including the attachment of ubiquitin-like Atg8 proteins to PV membranes through a noncanonical autophagy-related process, recognition of missing-self patterns, the sensing of specific lipid species enriched in PV membranes, and the ubiquitylation of PV membranes ( 21 , 25 – 32 ). Members of the murine M clade of IRG (IRGM) proteins facilitate the delivery of effector IRGs to PV membranes and are also essential for PV ubiquitylation in mouse cells ( 28 , 30 ).…”

Section: Introductionmentioning

confidence: 99%

Interferon-Inducible E3 Ligase RNF213 Facilitates Host-Protective Linear and K63-Linked Ubiquitylation of Toxoplasma gondii Parasitophorous Vacuoles

Hernandez

Walsh

Sanchez

et al. 2022

mBio

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Section: Introductionmentioning

confidence: 99%

Interferon-Inducible E3 Ligase RNF213 Facilitates Host-Protective Linear and K63-Linked Ubiquitylation of Toxoplasma gondii Parasitophorous Vacuoles

Hernandez

Walsh

Sanchez

et al. 2022

mBio

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“…IIG biology is regulated transcriptionally and post-translationally via localization, phosphorylation and prenylation 13 , 14 , 39 – 42 . We expected host effectors regulating parasite clearance to be differentially enriched on PV under IFNγ-treated conditions compared to non-restrictive conditions.…”

Section: Resultsmentioning

confidence: 99%

“…IFNγ receptor signaling through STAT1 transcriptionally upregulates interferon-inducible GTPases (IIGs) which survey cells for damaged or non-self-membranes and target them for removal (Fig. 1a ) 13 – 15 . In mice, the p47 immunity-related GTPases (IRG) 16 , Irgb6 17 , Irga6 18 are recruited to the PVM 19 , 20 , under the regulatory control of IRGM1, −2 and −3 16 , 21 – 23 .…”

Section: Introductionmentioning

confidence: 99%

iNOS is necessary for GBP-mediated T. gondii clearance in murine macrophages via vacuole nitration and intravacuolar network collapse

Zhao,

Lempke,

Urbán Arroyo

et al. 2024

Nat Commun

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Toxoplasma gondii is an obligate intracellular parasite of rodents and humans. Interferon-inducible guanylate binding proteins (GBPs) are mediators of T. gondii clearance, however, this mechanism is incomplete. Here, using automated spatially targeted optical micro proteomics we demonstrate that inducible nitric oxide synthetase (iNOS) is highly enriched at GBP2+ parasitophorous vacuoles (PV) in murine macrophages. iNOS expression in macrophages is necessary to limit T. gondii load in vivo and in vitro. Although iNOS activity is dispensable for GBP2 recruitment and PV membrane ruffling; parasites can replicate, egress and shed GBP2 when iNOS is inhibited. T. gondii clearance by iNOS requires nitric oxide, leading to nitration of the PV and collapse of the intravacuolar network of membranes in a chromosome 3 GBP-dependent manner. We conclude that reactive nitrogen species generated by iNOS cooperate with GBPs to target distinct structures in the PV that are necessary for optimal parasite clearance in macrophages.

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“…Mice possess three paralogs of IRGM (Irgm1, Irgm2, and Irgm3), which were initially thought to primarily control cell-autonomous immunity to intracellular pathogens such as C. trachomatis ( 26 ). Murine Irgm proteins regulate the localization and activity of a subset of “effector” GKS IRG proteins, which are expressed upon stimulation with the cytokine gamma-interferon (IFNγ) and traffic to intracellular pathogens to mediate their destruction via partially understood mechanisms ( 27 – 31 ). In the absence of Irgm1 and Irgm3, IFNγ stimulation leads to mislocalization and cytoplasmic aggregation of GKS IRGs and a failure to target and restrict the growth of most intracellular pathogens in an IFNγ-dependent manner ( 30 , 32 , 33 ).…”

Section: Introductionmentioning

confidence: 99%

Irgm proteins attenuate inflammatory disease in mouse models of genital Chlamydia infection

Dockterman,

Reitano,

Everitt

et al. 2024

mBio

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Chlamydiae are obligate intracellular bacterial pathogens that may cause genital pathology via induction of destructive host immune responses. Human-adapted Chlamydia trachomatis causes inflammatory disease in human hosts but is easily cleared in mice, and mouse-adapted Chlamydia muridarum establishes a productive and pathogenic infection in murine hosts. While numerous anti-chlamydial host resistance factors have been discovered in mice and humans alike, little is known about host factors promoting host fitness independent of host resistance. Here, we show that interferon-inducible immunity-related GTPase M (Irgm) proteins function as such host factors ameliorating infection-associated sequalae in the murine female genital tract, thus characterizing Irgm proteins as mediators of disease tolerance. Specifically, we demonstrate that mice deficient for all three murine Irgm paralogs (pan- Irgm −/− ) are defective for cell-autonomous immunity to C. trachomatis , which correlates with an early and transient increase in bacterial burden and sustained hyperinflammation in vivo . In contrast, upon infection of pan- Irgm −/− mice with C. muridarum , bacterial burden is unaffected, yet genital inflammation and scarring pathology are nonetheless increased, demonstrating that Irgm proteins can promote host fitness without altering bacterial burden. Additionally, pan- Irgm −/− mice display increased granulomatous inflammation in genital Chlamydia infection, implicating Irgm proteins in the regulation of granuloma formation and maintenance. These findings demonstrate that Irgm proteins regulate pathogenic immune responses to Chlamydia infection in vivo , establishing an effective infection model to examine the immunoregulatory functions and mechanisms of Irgm proteins. IMPORTANCE In response to genital Chlamydia infection, the immune system mounts a proinflammatory response to resist the pathogen, yet inflammation must be tightly controlled to avoid collateral damage and scarring to host genital tissue. Variation in the human IRGM gene is associated with susceptibility to autoinflammatory diseases but its role in ameliorating inflammatory diseases caused by infections is poorly defined. Here, we use mice deficient for all three murine Irgm paralogs to demonstrate that Irgm proteins not only provide host resistance to Chlamydia infections but also limit associated inflammation in the female genital tract. In particular, we find that murine Irgm expression prevents granulomatous inflammation, which parallels inflammatory diseases associated with variants in human IRGM. Our findings therefore establish genital Chlamydia infection as a useful model to study the roles for Irgm proteins in both promoting protective immunity and limiting pathogenic inflammation.

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How did we get here? Insights into mechanisms of immunity-related GTPase targeting to intracellular pathogens

Cited by 10 publications

References 111 publications

Interferon-Inducible E3 Ligase RNF213 Facilitates Host-Protective Linear and K63-Linked Ubiquitylation of Toxoplasma gondii Parasitophorous Vacuoles

Interferon-Inducible E3 Ligase RNF213 Facilitates Host-Protective Linear and K63-Linked Ubiquitylation of Toxoplasma gondii Parasitophorous Vacuoles

iNOS is necessary for GBP-mediated T. gondii clearance in murine macrophages via vacuole nitration and intravacuolar network collapse

Irgm proteins attenuate inflammatory disease in mouse models of genital Chlamydia infection

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