STING-associated lung disease in mice relies on T cells but not type I interferon

Luksch, Hella; Stinson, William A.; Platt, Derek J.; Qian, Wei; Kalugotla, Gowri; Miner, Cathrine A.; Bennion, Brock G.; Gerbaulet, Alexander; Rösen‐Wolff, Angela; Miner, Jonathan J.

doi:10.1016/j.jaci.2019.01.044

Cited by 101 publications

(134 citation statements)

References 34 publications

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“…Recently it has been shown that during WNV infection causes delayed GI transit, dependent on infiltrating antiviral CD8+ T cells [80]. Furthermore, both in this model and in a lung model where STING exhibits a gain-of-function mutation, T cell-dependent chronic tissue damage occurs, supporting our findings that STING may play a broad and significant role in communicating between the innate and adaptive immune responses [80, 81]. Together, these data demonstrate an essential neuroprotective role for STING during WNV infection, potentially through a cellular mediated mechanism instead of the canonical interferon antiviral function typically attributed to STING.…”

Section: Discussionsupporting

confidence: 85%

STING is required for host defense against neuropathological West Nile virus infection

et al. 2019

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West Nile Virus (WNV), an emerging and re-emerging RNA virus, is the leading source of arboviral encephalitic morbidity and mortality in the United States. WNV infections are acutely controlled by innate immunity in peripheral tissues outside of the central nervous system (CNS) but WNV can evade the actions of interferon (IFN) to facilitate CNS invasion, causing encephalitis, encephalomyelitis, and death. Recent studies indicate that ST imulator of IN terferon G ene (STING), canonically known for initiating a type I IFN production and innate immune response to cytosolic DNA, is required for host defense against neurotropic RNA viruses. We evaluated the role of STING in host defense to control WNV infection and pathology in a murine model of infection. When challenged with WNV, STING knock out (-/-) mice displayed increased morbidity and mortality compared to wild type (WT) mice. Virologic analysis and assessment of STING activation revealed that STING signaling was not required for control of WNV in the spleen nor was WNV sufficient to mediate canonical STING activation in vitro . However, STING-/- mice exhibited a clear trend of increased viral load and virus dissemination in the CNS. We found that STING-/- mice exhibited increased and prolonged neurological signs compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the CNS of STING-/- mice, with sustained pathology after viral clearance. We found that STING was required in bone marrow derived macrophages for early control of WNV replication and innate immune activation. In vivo , STING-/- mice developed an aberrant T cell response in both the spleen and brain during WNV infection that linked with increased and sustained CNS pathology compared to WT mice. Our findings demonstrate that STING plays a critical role in immune programming for the control of neurotropic WNV infection and CNS disease.

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Section: Discussionsupporting

confidence: 85%

STING is required for host defense against neuropathological West Nile virus infection

et al. 2019

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“…When the STING signal is stimulated, apoptosis occurs more frequently in normal or cancerous T cells (119). Also, bone-marrow chimeras and gene-knockout studies have shown that T cells defect in SAVI are not associated with type-I IFN signaling or cGAS (213,214). Localization of STING at the Golgi can cause delay of T-cell mitosis and reduced proliferation independently of IRF3 and TBK1 (215).…”

Section: Cgas-sting Pathway In Autoimmune or Inflammatory Diseasesmentioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

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Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immunesurveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

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“…Excess of IFN-I ( 31 ) does not contribute to this lymphopenia. Signs of inflammation in lungs and kidneys were also IFN-independent ( 77 ), and probably driven by over-reactivity of the TCR ( 32 , 78 ). This is in line with the observation that in mice STING-associated vasculopathy, STING regulates T cell proliferation in cell culture, independently of IRF3 ( 32 ).…”

Section: Introductionmentioning

confidence: 99%

“…STING mutants also induce chronic activation of ER stress and unfolded protein response (UPR) within T lymphocytes. STING-N154S disrupts calcium homeostasis in T cells, and primes them to become hyper-responsive to T cell receptor signaling induced ER stress, leading to cell death, both in CD4+ and CD8+ T cells ( 32 , 78 ). The mouse CD4+ and CD8+ T cell death through ER stress can be restored (as well as lung disease) by changing TCR specificity ( 36 ).…”

Section: Introductionmentioning

confidence: 99%

Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

et al. 2020

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Upon recognition of microbial DNA or self-DNA, the cyclic-GMP-AMP synthase (cGAS) of the host catalyzes the production of the cyclic dinucleotide cGAMP. cGAMP is the main activator of STING, stimulator of interferon genes, leading to interferon synthesis through the STING-TBK1-IRF3 pathway. STING is also a hub for activation of NF-κB and autophagy. The present review details the striking similarities between T and B cell responses in severe coronavirus disease 2019 (COVID-19) and both animal or human models of STING gain of function (SAVI syndromes: STING-associated vasculopathy with onset in infancy). Those similarities may be further clues for a delayed activation of STING in severe COVID-19 patients, due to DNA damages following severe acute respiratory syndrome coronaviruses (SARS-CoV-2) infection and unusual role of STING in SARS-CoV-2 control. In early stages, Th2 differentiation are noticed in both severe COVID-19 and SAVI syndromes; then, CD4+ and CD8+ T cells functional exhaustion/senescent patterns due to TCR hyper-responsiveness are observed. T cell delayed over-responses can contribute to pneumonitis and delayed cytokine secretion with over-production of IL-6. Last, STING over-activation induces progressive CD4+ and CD8+ T lymphopenia in SAVI syndromes, which parallels what is observed in severe COVID-19. ACE2, the main receptor of SARS-CoV-2, is rarely expressed in immune cells, and it has not been yet proven that some human lymphocytes could be infected by SARS-CoV-2 through CD147 or CD26. However, STING, expressed in humans T cells, might be triggered following excessive transfer of cGAMP from infected antigen presenting cells into activated CD4+ and CD8+ T cells lymphocytes. Indeed, those lymphocytes highly express the cGAMP importer SLC19A1. Whereas STING is not expressed in human B cells, B cells counts are much less affected, either in COVID-19 or SAVI syndromes. The recognition of delayed STING over-activation in severe COVID-19 patients could prompt to target STING with specific small molecules inhibitors already designed and/or aspirin, which inhibits cGAS.

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STING-associated lung disease in mice relies on T cells but not type I interferon

Cited by 101 publications

References 34 publications

STING is required for host defense against neuropathological West Nile virus infection

STING is required for host defense against neuropathological West Nile virus infection

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

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