STING induces early IFN-β in the liver and constrains myeloid cell-mediated dissemination of murine cytomegalovirus

Tegtmeyer, Pia-Katharina; Spanier, Julia; Borst, Katharina; Becker, Stephan; Riedl, André; Hirche, Christoph; Ghita, Luca; Skerra, Jennifer; Baumann, Kira; Lienenklaus, Stefan; Doering, Marius; Ruzsics, Zsolt; Kalinke, Ulrich

doi:10.1038/s41467-019-10863-0

Cited by 38 publications

(40 citation statements)

References 70 publications

(126 reference statements)

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“…MyTrMaSt null mice were generated as described [12]. From postnatal day 8, C57BL/6JOlaHsd mice (Envigo Laboratories, Israel) or MyTrMaSt null mice were injected intraperitoneally (i.p.)…”

Section: Micementioning

confidence: 99%

Mice defective in interferon signaling help distinguish between primary and secondary pathological pathways in a mouse model of neuronal forms of Gaucher disease

Vardi

Ben‐Dor

Cho

et al. 2020

J Neuroinflammation

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Background: The type 1 interferon (IFN) response is part of the innate immune response and best known for its role in viral and bacterial infection. However, this pathway is also induced in sterile inflammation such as that which occurs in a number of neurodegenerative diseases, including neuronopathic Gaucher disease (nGD), a lysosomal storage disorder (LSD) caused by mutations in GBA. Methods: Mice were injected with conduritol B-epoxide, an irreversible inhibitor of acid beta-glucosidase, the enzyme defective in nGD. MyTrMaSt null mice, where four adaptors of pathogen recognition receptors (PRRs) are deficient, were used to determine the role of the IFN pathway in nGD pathology. Activation of inflammatory and other pathways was analyzed by a variety of methods including RNAseq. Results: Elevation in the expression of PRRs associated with the IFN response was observed in CBE-injected mice. Ablation of upstream pathways leading to IFN production had no therapeutic benefit on the lifespan of nGD mice but attenuated neuroinflammation. Primary and secondary pathological pathways (i.e., those associated or not with mouse survival) were distinguished, and a set of~210 genes including those related to sphingolipid, cholesterol, and lipoprotein metabolism, along with a number of inflammatory pathways related to chemokines, TNF, TGF, complement, IL6, and damage-associated microglia were classified as primary pathological pathways, along with some lysosomal and neuronal genes. Conclusions: Although IFN signaling is the top elevated pathway in nGD, we demonstrate that this pathway is not related to mouse viability and is consequently defined as a secondary pathology pathway. By elimination, we defined a number of critical pathways that are directly related to brain pathology in nGD, which in addition to its usefulness in understanding pathophysiological mechanisms, may also pave the way for the development of novel therapeutic paradigms by targeting such pathways.

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“…MyTrMaSt null mice were generated as described [12]. From postnatal day 8, C57BL/6JOlaHsd mice (Envigo Laboratories, Israel) or MyTrMaSt null mice were injected intraperitoneally (i.p.)…”

Section: Micementioning

confidence: 99%

Mice defective in interferon signaling help distinguish between primary and secondary pathological pathways in a mouse model of neuronal forms of Gaucher disease

Vardi

Ben‐Dor

Cho

et al. 2020

J Neuroinflammation

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“…Moreover, MACs deficient in MyD88, TRIF and mitochondrial antiviral signaling (MAVS) protein maintained a IFN I response in MCMV infection (39). The identification of the stimulator of interferon genes (STING) (40,41) (45). STING-mediated IFN I was induced as early as 4 h post infection (hpi) (45).…”

Section: And Cytosolic Sensorsmentioning

confidence: 99%

Cytomegaloviruses and Macrophages—Friends and Foes From Early on?

2020

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Starting at birth, newborn infants are exposed to numerous microorganisms. Adaptation of the innate immune system to them is a delicate process, with potentially advantageous and harmful implications for health development. Cytomegaloviruses (CMVs) are highly adapted to their specific mammalian hosts, with which they share millions of years of co-evolution. Throughout the history of mankind, human CMV has infected most infants in the first months of life without overt implications for health. Thus, CMV infections are intertwined with normal immune development. Nonetheless, CMV has retained substantial pathogenicity following infection in utero or in situations of immunosuppression, leading to pathology in virtually any organ and particularly the central nervous system (CNS). CMVs enter the host through mucosal interfaces of the gastrointestinal and respiratory tract, where macrophages (MACs) are the most abundant immune cell type. Tissue MACs and their potential progenitors, monocytes, are established target cells of CMVs. Recently, several discoveries have revolutionized our understanding on the pre-and postnatal development and site-specific adaptation of tissue MACs. In this review, we explore experimental evidences and concepts on how CMV infections may impact on MAC development and activation as part of host-virus co-adaptation.

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“…In the first phase of MCMV infection, type I IFN and Natural Killer (NK) cells have the most important role in containing propagation [85,86]. Initial IFN production takes place within the first 8 h in a cGAS/STING dependent manner in liver Kupffer cells [87] and in splenic stromal cells [88]. This early IFN wave restricts viral production through NK cells activation and orchestrates posterior CMV control [89].…”

Section: Innate Immune Response To CMV Is Relevant For Its Vector Promentioning

confidence: 99%

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

2019

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Cytomegalovirus (CMV) species have been gaining attention as experimental vaccine vectors inducing cellular immune responses of unparalleled strength and protection. This review outline the strengths and the restrictions of CMV-based vectors, in light of the known aspects of CMV infection, pathogenicity and immunity. We discuss aspects to be considered when optimizing CMV based vaccines, including the innate immune response, the adaptive humoral immunity and the T-cell responses. We also discuss the antigenic epitopes presented by unconventional major histocompatibility complex (MHC) molecules in some CMV delivery systems and considerations about routes for delivery for the induction of systemic or mucosal immune responses. With the first clinical trials initiating, CMV-based vaccine vectors are entering a mature phase of development. This impetus needs to be maintained by scientific advances that feed the progress of this technological platform.Vaccines 2019, 7, 152 2 of 28 CMV-based vaccines, the large pool of functional antigen-specific T cells in the periphery and the possibility to modify CMV genomes due to improvements in viral genetics [11] draw a strong interest to CMV as a vaccine vector [12,13] (Table 1). The inflationary response appears linked to immune protection [14,15] and has been proposed as a target for immunization induction [16]. Vaccines 2019, 7, 152 3 of 28 Full-length HPV16 E6 and E7 Antigen fused to the C-terminus of ie2 Transient limitation of tumour cell growth MCMV IE2E7 [14] MHC-I restricted HPV16 E7 49-57 epitope Epitope fused to the C-terminus of ie2 No tumour cell growth upon challenge MCMV-M79-FKBP-E7 [36] MCMV Smith Strain with FKBP-mediated destabilization of the essential M79 gene Vaccines 2019, 7, 152 5 of 28Besides the exceptional induction of adaptive immune response in humans [2,37], CMV possesses assets that conveniently address weaknesses common to other vector candidates. The cloning of CMV genomes as bacterial artificial chromosomes in Escherichia coli [38] has allowed genetic engineering approaches to effectively express multiple exogenous immunogens or modify large genome portions [39,40]. Furthermore, CMV is known to superinfect hosts with a history of prior exposure to the virus [41] due to its immune evasive properties that protect the virus from recognition by primed T-cells [42] and CMV vectors induce protective immunity in experimentally vaccinated animals with documented prior exposure to 36]. Therefore, CMV vector candidates would avoid immune interference as described for AdV. CMV is a pathogenic organism in immunodeficient populations [43] or in congenitally infected children. Therefore, it is imperative for any HCMV vaccine vector to be attenuated. The generation of replication deficient CMVs that maintain their immunogenicity [36,44] and the modification of genome portions that contain evasions genes [45], as well as the insertion of activating ligands to increase immune control of CMV [46][47][48] are strategies that will be described in this review. Inter...

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STING induces early IFN-β in the liver and constrains myeloid cell-mediated dissemination of murine cytomegalovirus

Cited by 38 publications

References 70 publications

Mice defective in interferon signaling help distinguish between primary and secondary pathological pathways in a mouse model of neuronal forms of Gaucher disease

Mice defective in interferon signaling help distinguish between primary and secondary pathological pathways in a mouse model of neuronal forms of Gaucher disease

Cytomegaloviruses and Macrophages—Friends and Foes From Early on?

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

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