The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis

Erttmann, Saskia F.; Swacha, Patrycja; Aung, Kyaw Min; Brindefalk, Björn; Jiang, Hui; Härtlová, Anetta; Uhlin, Bernt Eric; Wai, Sun Nyunt; Gekara, Nelson O.

doi:10.1016/j.immuni.2022.04.006

Cited by 186 publications

(122 citation statements)

References 71 publications

(95 reference statements)

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“…Therefore, for OMVs to inhibit MNV replication, they must counteract MNV suppression of inflammatory responses or induce antiviral responses through pathways that are not controlled by MNV. Interestingly, it has been recently shown that OMVs from commensal bacteria can induce STING-mediated inflammatory pathways leading to control of systemic infection of both RNA and DNA viruses ( 68 ). Moreover, while artificial induction of STING responses can lead to control of MNV replication, MNV infection itself does not influence STING expression ( 69 ).…”

Section: Discussionmentioning

confidence: 99%

Bacterial extracellular vesicles control murine norovirus infection through modulation of antiviral immune responses

et al. 2022

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Human norovirus is the primary cause of non-bacterial gastroenteritis globally and is the second leading cause of diarrheal deaths in children in developing countries. However, effective therapeutics which prevent or clear norovirus infection are not yet available due to a lack of understanding regarding norovirus pathogenesis. Evidence shows that noroviruses can bind to the surface of commensal bacteria, and the presence of these bacteria alters both acute and persistent murine norovirus infection through the modulation of host immune responses. Interestingly, norovirus-bacterial interactions also affect the bacteria by inducing bacterial stress responses and increasing the production of bacterial extracellular vesicles. Given the established ability of these vesicles to easily cross the intestinal barriers, enter the lamina propria, and modulate host responses, we hypothesized that bacterial extracellular vesicles influence murine norovirus infection through modulation of the antiviral immune response. In this study, we show that murine norovirus can attach to purified bacterial vesicles, facilitating co-inoculation of target cells with both virus and vesicle. Furthermore, we have found that when murine noroviruses and vesicles are used to co-inoculate macrophages, viral infection is reduced compared to virus infection alone. Specifically, co-inoculation with bacterial vesicles results in higher production and release of pro-inflammatory cytokines in response to viral infection. Ultimately, given that murine norovirus infection increases bacterial vesicle production in vivo, these data indicate that bacterial vesicles may serve as a mechanism by which murine norovirus infection is ultimately controlled and limited to a short-term disease.

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Section: Discussionmentioning

confidence: 99%

Bacterial extracellular vesicles control murine norovirus infection through modulation of antiviral immune responses

et al. 2022

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“…Reduced IFN-α/β is observed in the serum of GF or antibiotic-treated mice before and after treatment with TLR agonists ( 134 , 146 , 176 ) or infection with the alphavirus chikungunya virus (CHIKV) ( 144 ). As a result, pDCs and CD11c + DCs isolated from GF mice during steady-state conditions have reduced expression of IFN-stimulated genes (ISGs) ( 134 , 146 ).…”

Section: Impact Of Microbiota-derived Metabolites On DC Activationmentioning

confidence: 99%

“…This phenotype is restored when antibiotic-treated mice are gavaged with Clostridium orbiscindens , implicating another member of the Clostridium species in the protection against viral respiratory infections. Recently, the cGas/STING pathway has been implicated in regulating tonic IFN-I ( 176 ). Mice lacking cGas or Sting have reduced basal IFN-I which is unaffected by antibiotic treatment.…”

Section: Impact Of Microbiota-derived Metabolites On DC Activationmentioning

confidence: 99%

“…Furthermore, basal IFN-I levels are unaffected in mice lacking MyD88 and Ticam1 . This suggests that reduced IFN-I levels following antibiotic treatment is due to reduced cGas/STING activation, and not TLR activation ( 176 ). Interestingly, the authors suggest that cGas/STING activation occurs due to host cells recognizing microbiota-derived DNA which is delivered systemically via membrane vesicles.…”

Section: Impact Of Microbiota-derived Metabolites On DC Activationmentioning

confidence: 99%

“…Interestingly, the authors suggest that cGas/STING activation occurs due to host cells recognizing microbiota-derived DNA which is delivered systemically via membrane vesicles. As proof of principle, mice inoculated with membrane vesicles isolated from Escherichia coli ( E. coli ) prior to infection are better protected against HSV and vesicular stomatitis virus ( 176 ). Given pDCs are thought to be essential in tonic IFN-I production ( 134 , 146 ), it is important for future studies to investigate exactly how these cells are more susceptible to microbiota-derived signals.…”

Section: Impact Of Microbiota-derived Metabolites On DC Activationmentioning

confidence: 99%

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Microbial Metabolites in the Maturation and Activation of Dendritic Cells and Their Relevance for Respiratory Immunity

et al. 2022

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The respiratory tract is a gateway for viruses and bacteria from the external environment to invade the human body. Critical to the protection against these invaders are dendritic cells (DCs) - a group of highly specialized myeloid cells that monitors the lung microenvironment and relays contextual and antigenic information to T cells. Following the recognition of danger signals and/or pathogen molecular associated patterns in the lungs, DCs undergo activation. This process arms DCs with the unique ability to induce the proliferation and differentiation of T cells responding to matching antigen in complex with MHC molecules. Depending on how DCs interact with T cells, the ensuing T cell response can be tolerogenic or immunogenic and as such, the susceptibility and severity of respiratory infections is influenced by the signals DCs receive, integrate, and then convey to T cells. It is becoming increasingly clear that these facets of DC biology are heavily influenced by the cellular components and metabolites produced by the lung and gut microbiota. In this review, we discuss the roles of different DC subsets in respiratory infections and outline how microbial metabolites impact the development, propensity for activation and subsequent activation of DCs. In particular, we highlight these concepts in the context of respiratory immunity.

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ATP‐Responsive Manganese‐Based Bacterial Materials Synergistically Activate the cGAS‐STING Pathway for Tumor Immunotherapy

Yang,

Guo

et al. 2024

Advanced Materials

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Stimulating the cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway is a crucial strategy by which bacteria activate the tumor immune system. However, the limited stimulation capability poses significant challenges in advancing bacterial immunotherapy. In this study, we successfully engineered an adenosine 5′‐triphosphate (ATP)‐responsive manganese (Mn)‐based bacterial material (E. coli@PDMC‐PEG) that exhibits an exceptional ability to synergistically activate the cGAS‐STING pathway. In the tumor microenvironment, which is characterized by elevated ATP levels, this biohybrid material degrades, resulting in the release of divalent manganese ions (Mn2+) and subsequent bacteria exposure. This combination synergistically activates the cGAS‐STING pathway, as Mn2+ enhances the sensitivity of cGAS to the extracellular DNA (eDNA) secreted by the bacteria. The results of the in vivo experiments demonstrated that the biohybrid materials E. coli@PDMC‐PEG and VNP20009@PDMC‐PEG effectively inhibited the growth of subcutaneous melanoma in mice and in situ liver cancer in rabbits. Our work provides valuable insights for the development of bacteria‐based tumor immunotherapy.This article is protected by copyright. All rights reserved

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The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis

Cited by 186 publications

References 71 publications

Bacterial extracellular vesicles control murine norovirus infection through modulation of antiviral immune responses

Bacterial extracellular vesicles control murine norovirus infection through modulation of antiviral immune responses

Microbial Metabolites in the Maturation and Activation of Dendritic Cells and Their Relevance for Respiratory Immunity

ATP‐Responsive Manganese‐Based Bacterial Materials Synergistically Activate the cGAS‐STING Pathway for Tumor Immunotherapy

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