Local Necrotic Cells Trigger Systemic Immune Activation via Gut Microbiome Dysbiosis in Drosophila

Kosakamoto, Hina; Yamauchi, Teruaki; Akuzawa-Tokita, Yoriko; Nishimura, Kinya; Soga, Tomoyoshi; Murakami, Takumi; Mori, Hiroshi; Yamamoto, Kyosuke; Miyazaki, Ryo; Koto, Atsuo; Miura, Masayuki; Obata, Fumiaki

doi:10.1016/j.celrep.2020.107938

Cited by 23 publications

(33 citation statements)

References 45 publications

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“…Started OD600 was 0.01-0.1. Bacterial strains were: L. plantarum Lsi (Kosakamoto et al, 2020), A. persici Ai (Kosakamoto et al, 2020), L. brevis (NBRC3345), L. acidophilus (NBRC13951), L. murinus (NBRC14221), A.…”

Section: Bacterial Culture and Strainsmentioning

confidence: 99%

Gut Bacterial Species Distinctively Impact Host Purine Metabolites during Aging in Drosophila

Yamauchi

Kosakamoto

et al. 2020

iScience

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Summary Gut microbiota impacts the host metabolome and affects its health span. How bacterial species in the gut influence age-dependent metabolic alteration has not been elucidated. Here we show in Drosophila melanogaster that allantoin, an end product of purine metabolism, is increased during aging in a microbiota-dependent manner. Allantoin levels are low in young flies but are commonly elevated upon lifespan-shortening dietary manipulations such as high-purine, high-sugar, or high-yeast feeding. Removing Acetobacter persici in the Drosophila microbiome attenuated age-dependent allantoin increase. Mono-association with A. persici , but not with Lactobacillus plantarum , increased allantoin in aged flies. A. persici increased allantoin via activation of innate immune signaling IMD pathway in the renal tubules. On the other hand, analysis of bacteria-conditioned diets revealed that L. plantarum can decrease allantoin by reducing purines in the diet. These data together demonstrate species-specific regulations of host purine levels by the gut microbiome.

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Section: Bacterial Culture and Strainsmentioning

confidence: 99%

Gut Bacterial Species Distinctively Impact Host Purine Metabolites during Aging in Drosophila

Yamauchi

Kosakamoto

et al. 2020

iScience

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“…Neuroinflammation is often seen in COVID-19 patients, possibly via damage-associated molecular patterns (DAMPs) induced TLR4-MyD88 signaling activation (Meinhardt et al, 2020;Ren et al, 2020;. In Drosophila, non-infectious sterile inflammation can be initiated when necrotic cells release DAMPs that in turn activate immunoinflammatory pathways, including the Toll and IMD pathways (Kosakamoto et al, 2020;Obata et al, 2014). We hypothesized that ORF3a elicits a sterile inflammatory response, and found that expressing ORF3a in the CNS induced Toll pathway reporter expression (fold change vs control, Drs=10.2; Fig.…”

mentioning

confidence: 99%

“…However, IMD pathway reporters did not respond to CQ treatment (dipt=0.75, attA=0.89). One mechanism that might explain CQ specificity is that the Toll pathway is a more direct target of necrotic derived DAMPs, while the IMD pathway is not (Kosakamoto et al, 2020). A second mechanism of action for CQ could involve ORF3a-induced lysosome dysfunction.…”

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confidence: 99%

Infection and chronic disease activate a brain-muscle signaling axis that regulates muscle performance

Yang¹,

Tian

An³

2020

Preprint

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SummaryThe Coronavirus Disease 2019 (COVID-19) pandemic has caused millions of deaths and will continue to exact incalculable tolls worldwide. While great strides have been made toward understanding and combating the mechanisms of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection, relatively little is known about the individual SARS-CoV-2 proteins that contribute to pathogenicity during infection and that cause neurological sequela after viral clearance. We used Drosophila to develop an in vivo model that characterizes mechanisms of SARS-CoV-2 pathogenicity, and found ORF3a adversely affects longevity and motor function by inducing apoptosis and inflammation in the nervous system. Chloroquine alleviated ORF3a induced phenotypes in the CNS, arguing our Drosophila model is amenable to high throughput drug screening. Our work provides novel insights into the pathogenic nature of SARS-CoV-2 in the nervous system that can be used to develop new treatment strategies for post-viral syndrome.HighlightsSARS-CoV-2 ORF3a is pathogenic in the nervous system.ORF3a induces cell death, inflammation, and lysosome dysfunction.Chloroquine protects against ORF3a induced CNS distress and lysosome dysfunction.

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“…A major question at this point pertains to the activation of Relish in virus-infected flies. In the absence of bacterial infection, the IMD pathway may be activated by a response to necrotic cells possibly driven by dysbiosis (Kosakamoto et al, 2020) or by deregulation of the expression of the receptors PGRP-LC or -LF (Nandy et al, 2018;Tavignot et al, 2017). The involvement of dSTING in the regulation of Relish activity in the context of viral infections now raises the question of the mechanisms by which it gets activated.…”

Section: Relish-dependent Antiviral Immunitymentioning

confidence: 99%

Sensing and signalling viral infection in drosophila

Schneider¹,

Imler²

2021

Developmental & Comparative Immunology

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The fruitfly Drosophila melanogaster is a valuable model to unravel mechanisms of innate immunity, in particular in the context of viral infections. RNA interference, and more specifically the small interfering RNA pathway, is a major component of antiviral immunity in drosophila. In addition, the contribution of inducible transcriptional responses to the control of viruses in drosophila and other invertebrates is increasingly recognized. In particular, the recent discovery of a STING-IKK -Relish signalling cassette in drosophila has confirmed that NF-B transcription factors play an important role in the control of viral infections, in addition to bacterial and fungal infections. Here, we review recent developments in the field, which begin to shed light on the mechanisms involved in sensing of viral infections and in signalling leading to production of antiviral effectors.

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Local Necrotic Cells Trigger Systemic Immune Activation via Gut Microbiome Dysbiosis in Drosophila

Cited by 23 publications

References 45 publications

Gut Bacterial Species Distinctively Impact Host Purine Metabolites during Aging in Drosophila

Gut Bacterial Species Distinctively Impact Host Purine Metabolites during Aging in Drosophila

Infection and chronic disease activate a brain-muscle signaling axis that regulates muscle performance

Sensing and signalling viral infection in drosophila

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