Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses

Holm, Christian K.; Rahbek, Stine H.; Gad, Hans Henrik; Bak, Rasmus O.; Jakobsen, Martin R.; Jiang, Zhaozaho; Hansen, Anne Louise; Jensen, Simon Kok; Sun, Chaoyang; Thomsen, Martin K.; Laustsen, Anders; Nielsen, Camilla G.; Severinsen, Kasper; Xiong, Yingluo; Burdette, Dara; Hornung, Veit; Lebbink, Robert Jan; Duch, Mogens; Fitzgerald, Katherine A.; Bahrami, Shervin; Mikkelsen, Jacob Giehm; Hartmann, Rune; Paludan, Søren R.

doi:10.1038/ncomms10680

Cited by 185 publications

(196 citation statements)

References 34 publications

(73 reference statements)

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“…It was shown that the process of membrane fusion is sensed when enveloped viruses enter cells [19,70]. This occurs through a noncanonical STING-dependent pathway, which is independent of cGAS and cGAMP and stimulates low expression of IFNb and IFN/4 [70].…”

Section: Gradual Build-up Of Type I Ifn Productionmentioning

confidence: 99%

Innate Antiviral Defenses Independent of Inducible IFNα/β Production

Paludan

2016

Trends in Immunology

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Section: Gradual Build-up Of Type I Ifn Productionmentioning

confidence: 99%

Innate Antiviral Defenses Independent of Inducible IFNα/β Production

Paludan

2016

Trends in Immunology

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“…Whether membrane perturbations induced by HIV-1 entry are of the same nature as the ones induced by liposome fusion, for instance, remains an open question beyond the scope of our study. More recently, entry of enveloped RNA viruses such as influenza A virus was shown to induce an early type I IFN response in exposed cells, which were also STING dependent and cGAS independent (45). STING activation following liposome fusion or viral entry was genetically dissociated from the response to cGAMP using STING mutants, suggesting that both mechanisms of viral detection are independent.…”

Section: Figmentioning

confidence: 99%

Sensing of HIV-1 Entry Triggers a Type I Interferon Response in Human Primary Macrophages

Decalf

Desdouits

Rodrigues

et al. 2017

J Virol

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Along with CD4 ϩ T lymphocytes, macrophages are a major cellular source of HIV-1 replication and a potential viral reservoir. Following entry and reverse transcription in macrophages, cloaking of the viral cDNA by the HIV-1 capsid limits its cytosolic detection, enabling efficient replication. However, whether incoming HIV-1 particles are sensed by macrophages prior to reverse transcription remains unclear. Here, we show that HIV-1 triggers a broad expression of interferon (IFN)-stimulated genes (ISG) in monocyte-derived macrophages within a few hours after infection. This response does not require viral reverse transcription or the presence of HIV-1 RNA within particles, but viral fusion is essential. This response is elicited by viruses carrying different envelope proteins and thus different receptors to proceed for viral entry. Expression of ISG in response to viral entry requires TBK1 activity and type I IFNs signaling. Remarkably, the ISG response is transient but affects subsequent viral spread. Together, our results shed light on an early step of HIV-1 sensing by macrophages at the level of entry, which confers an early protection through type I IFN signaling and has potential implications in controlling the infection.IMPORTANCE HIV infection is restricted to T lymphocytes and macrophages. HIV-1-infected macrophages are found in many tissues of infected patients, even under antiretroviral therapy, and are considered a viral reservoir. How HIV-1 is detected and what type of responses are elicited upon sensing remain in great part elusive. The kinetics and localization of the production of cytokines such as interferons in response to HIV is of critical importance to understanding how the infection and the immune response are established. Our study provides evidence that macrophages can detect HIV-1 as soon as it enters the cell. Interestingly, this sensing is independent of the presence of viral nucleic acids within the particles but requires their fusion with the macrophages. This triggers a low interferon response, which activates an antiviral program protecting cells against further viral challenge and thus potentially limiting the spread of the infection. KEYWORDS human immunodeficiency virus, innate immunity, interferons, macrophages, virus entry M acrophages are present in most tissues and endowed with many functions, including sensing and clearing of pathogens. However, pathogens frequently exploit macrophages as a privileged niche for their replication (1). This is the case for HIV-1, which mainly targets two cell types for replication: macrophages and CD4 ϩ T cells (2). Infected macrophages are considered to play an important role from the onset of infection to the development of the pathogenesis (3). The HIV-1 cycle in macrophages possesses specific features compared to T cells: macrophages are resistant to

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“…STING is known as a downstream signaling adapter of the DNA PRR cyclic GMP-AMP synthase (cGAS) (37). Holm et al reported that a STING-dependent, but cGAS-independent, pathway is activated upon FLUAV entry (35). Fusion of the viral envelope with the host endosome membrane can stimulate STING and hence IFN induction; however, FLUAV counteracts this via the fusion peptide of HA subunit 2 (HA2-FP), which associates with STING and prevents its activation (35).…”

Section: Rig-i-independent Cytoplasmic Responses and Fluav Countermeamentioning

confidence: 99%

“…Holm et al reported that a STING-dependent, but cGAS-independent, pathway is activated upon FLUAV entry (35). Fusion of the viral envelope with the host endosome membrane can stimulate STING and hence IFN induction; however, FLUAV counteracts this via the fusion peptide of HA subunit 2 (HA2-FP), which associates with STING and prevents its activation (35). Interestingly, subunit 1 of HA (HA1) was recently shown to drive the degradation of the IFN receptor chain IFNAR1, thereby suppressing IFN-triggered JAK/STAT signaling (38).…”

Section: Rig-i-independent Cytoplasmic Responses and Fluav Countermeamentioning

confidence: 99%

“…Recently, the stimulator of IFN genes (STING) and the RIG-I-like PRR, melanoma differentiation-associated protein-5 (MDA5), signaling factors were identified as contributors to the antiviral response against FLUAV (34)(35)(36). STING is known as a downstream signaling adapter of the DNA PRR cyclic GMP-AMP synthase (cGAS) (37).…”

Section: Rig-i-independent Cytoplasmic Responses and Fluav Countermeamentioning

confidence: 99%

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To Conquer the Host, Influenza Virus Is Packing It In: Interferon-Antagonistic Strategies beyond NS1

Weber-Gerlach

Weber

2016

J Virol

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bThe nonstructural protein NS1 is well established as a virulence factor of influenza A virus counteracting induction of the antiviral type I interferon system. Recent studies now show that viral structural proteins, their derivatives, and even the genome itself also contribute to keeping the host defense under control. Here, we summarize the current knowledge on these NS1-independent interferon escape strategies.

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Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses

Cited by 185 publications

References 34 publications

Innate Antiviral Defenses Independent of Inducible IFNα/β Production

Innate Antiviral Defenses Independent of Inducible IFNα/β Production

Sensing of HIV-1 Entry Triggers a Type I Interferon Response in Human Primary Macrophages

To Conquer the Host, Influenza Virus Is Packing It In: Interferon-Antagonistic Strategies beyond NS1

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