Nlrp6 regulates intestinal antiviral innate immunity

Wang, Penghua; Zhu, Shu; Yang, Long; Cui, Shuang; Pan, Wen; Jackson, Ruaidhrí; Zheng, Yunjiang; Rongvaux, Anthony; Sun, Qiangming; Yang, Guang; Gao, Shandian; Lin, Rongtuan; You, Fangtian; Flavell, Richard A.; Fikrig, Erol

doi:10.1126/science.aab3145

Cited by 213 publications

(175 citation statements)

References 37 publications

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“…This is best illustrated by the epithelial innate immune sensor NLRP6, a member of the NOD-like receptor family, which is involved in viral recognition as well as inflammasome formation (Levy et al 2015a;Wang et al 2015a). The inflammasome pathway is influenced by the microbiotamodulated metabolites taurine, histamine, and spermine, thereby regulating the level of epithelial IL-18 production, anti-microbial peptide secretion, and intestinal community composition (Levy et al 2015b).…”

Section: Metabolites As Regulators Of Symbiosismentioning

confidence: 99%

Metabolites: messengers between the microbiota and the immune system

2016

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The mammalian intestine harbors one of the largest microbial densities on Earth, necessitating the implementation of control mechanisms by which the host evaluates the state of microbial colonization and reacts to deviations from homeostasis. While microbial recognition by the innate immune system has been firmly established as an efficient means by which the host evaluates microbial presence, recent work has uncovered a central role for bacterial metabolites in the orchestration of the host immune response. In this review, we highlight examples of how microbiota-modulated metabolites control the development, differentiation, and activity of the immune system and classify them into functional categories that illustrate the spectrum of ways by which microbial metabolites influence host physiology. A comprehensive understanding of how microbiota-derived metabolites shape the human immune system is critical for the rational design of therapies for microbiota-driven diseases.The mammalian intestine harbors a dense and complex microbial community, termed the microbiota. The commensal microbiome and, in particular, the dense and diverse microbial community inhabiting the gastrointestinal tract play a pivotal role in the maintenance of organismal homeostasis and stable physiology. Research over the last decade has highlighted the concept that the eukaryotic host and its microbiota, rather than existing in isolation, compose a complex meta-organism termed the "holobiont," jointly regulating multiple aspects of mammalian physiology, including immune system development, metabolism, and nervous system function (Sommer and Backhed 2013). The interaction between the microbiota and the host is most prominent at mucosal surfaces, which provide an interface between the mostly microbe-free host, the microbiota, and the environment. At the same time, the presence of the microbial community within the eukaryotic host necessitates the development of a sophisticated immune system that controls and maintains a beneficial symbiosis of the holobiont through the continuous communication between the microbiome and the host.

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Section: Metabolites As Regulators Of Symbiosismentioning

confidence: 99%

Metabolites: messengers between the microbiota and the immune system

2016

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“…NLRP4 negatively regulates type-I interferon signaling by promoting TBK1 degradation (Cui et al, 2012). Nlrp6 binds viral RNA via RNA helicase Dhx15 and interacts with MAVS (mitochondrial anti-viral signaling) to induce type-I/III interferons (Wang et al, 2015). Although the role of NLRP3 inflammasome in HIV-infected human monocytes is known to trigger IL-1β (Chattergoon et al, 2014; Guo et al, 2014), the role of NLRs in modulating HIV-1 induced type-I interferon and HIV-1 infection remains unexplored.…”

Section: Introductionmentioning

confidence: 99%

NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses

Guo

König

Deng

et al. 2016

Cell Host & Microbe

130

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SUMMARY Understanding the negative regulators of anti-viral immune responses will be critical for advancing immune-modulated antiviral strategies. NLRX1, an NLR protein that negatively regulates innate immunity, was previously identified in an unbiased siRNA screen as required for HIV infection. We find that NLRX1 depletion results in impaired nuclear import of HIV-1 DNA in human monocytic cells. Additionally, NLRX1 was observed to reduce type-I interferon (IFN-I) and cytokines in response to HIV-1 reverse-transcribed DNA. NLRX1 sequesters the DNA sensing adaptor STING from interaction with TANK-binding kinase 1 (TBK1), which is a requisite for IFN-1 induction in response to DNA. NLRX1-deficient cells generate an amplified STING-dependent host response to cytosolic DNA, c-di-GMP, cGAMP, HIV-1 and DNA viruses. Accordingly, Nlrx1−/− mice infected with DNA viruses exhibit enhanced innate immunity and reduced viral load. Thus, NLRX1 is a negative regulator of the host innate immune response to HIV-1 and DNA viruses.

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“…Given that DHX9 binds Alu elements of transcribed regions of host genes [8], how does DHX9 distinguish viral dsRNA and host-derived RNA? Previous studies by the Flavell and Fikrig groups have shown that NLRP6 cooperated with the RNA helicase DHX15 in mediating the recognition of viral RNA, contributing to the host defense against the ssRNA virus EMCV [9]. These studies raise the question of whether there is a universal partnership between DHX and NLR family members.…”

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confidence: 68%