ISG15 governs mitochondrial function in macrophages following vaccinia virus infection

Baldanta, Sara; Fernández‐Escobar, Mercedes; Acı́n-Pérez, Rebeca; Albert, Manuel; Camafeita, Emilio; Jorge, Inmaculada; Vázquez, Jesús; Enríquez, José Antonio; Guerra, Susana

doi:10.1371/journal.ppat.1006651

Cited by 76 publications

(93 citation statements)

References 88 publications

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“…This is because in the absence of infection, ISG15 plays a role in the maintenance of mitochondrial homeostasis (125). Specifically, ISGylation of mitochondrial components can control mitochondrial function: reducing the rate of oxidative phosphorylation (OXPHOS) and causing a corresponding decrease in mitochondrial reactive oxygen species (ROS) (126). A reduction in levels of mitochondrial ROS alters macrophage polarization, shifting these cells toward a mixed M1/M2 phenotype (126).…”

Section: Isg15mentioning

confidence: 99%

Interferon-Independent Innate Responses to Cytomegalovirus

et al. 2019

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The critical role of interferons (IFNs) in mediating the innate immune response to cytomegalovirus (CMV) infection is well established. However, in recent years the functional importance of the IFN-independent antiviral response has become clearer. IFN-independent, IFN regulatory factor 3 (IRF3)-dependent interferon-stimulated gene (ISG) regulation in the context of CMV infection was first documented 20 years ago. Since then several IFN-independent, IRF3-dependent ISGs have been characterized and found to be among the most influential in the innate response to CMV. These include virus inhibitory protein, endoplasmic reticulum-associated IFN-inducible (viperin), ISG15, members of the interferon inducible protein with tetratricopeptide repeats (IFIT) family, interferon-inducible transmembrane (IFITM) proteins and myxovirus resistance proteins A and B (MxA, MxB). IRF3-independent, IFN-independent activation of canonically IFN-dependent signaling pathways has also been documented, such as IFN-independent biphasic activation of signal transducer and activator of transcription 1 (STAT1) during infection of monocytes, differential roles of mitochondrial and peroxisomal mitochondrial antiviral-signaling protein (MAVS), and the ability of human CMV (HCMV) immediate early protein 1 (IE1) protein to reroute IL-6 signaling and activation of STAT1 and its associated ISGs. This review examines the role of identified IFN-independent ISGs in the antiviral response to CMV and describes pathways of IFN-independent innate immune response induction by CMV.

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Section: Isg15mentioning

confidence: 99%

Interferon-Independent Innate Responses to Cytomegalovirus

et al. 2019

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“…In vivo, inhibition of FAO resulted in a diminished capacity to control lymphoc yt ic choriomeningitis virus 48 . Several IFN-stimulated genes, such as ISG15, have also been linked to the regulation of mitochondrial function during viral infection suggesting a secondary wave of mitochondrial reprogramming may occur following the TLR engagement and the induction of type I IFN responses 49 . Collectively, these studies suggest that some level of OXPHOS activity may be required to mount functional antiviral immune responses but that these responses may vary by ligand and cell type.…”

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confidence: 99%

Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages

Ahmed

Roy

Jaworski

et al. 2019

Preprint

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Increasing evidence suggests that mitochondria play a critical role in driving innate immune responses against bacteria and viruses. However, it is unclear if differential reprogramming of mitochondrial function contributes to the fine tuning of pathogen specific immune responses. Here, we found that TLR3 and TLR4 engagement on murine bone marrow derived macrophages was associated with differential remodeling of electron transport chain complex expression. This remodeling was associated with differential accumulation of mitochondrial and cytosolic ROS, which were required to support ligand specific inflammatory and antiviral cytokine production.We also found that the magnitude of TLR3, but not TLR4, responses were modulated by glucose availability. Under conditions of low glucose conditions, TLR3 engagement was associated with increased ETC complex III expression, increased mitochondrial and cytosolic ROS and increased inflammatory and antiviral cytokine production. This amplification was selectively reversed by targeting superoxide production from the outer Q-binding site of the ETC complex III. These results suggest that ligand specific modulation of the ETC may act as a rheostat that fine-tunes innate immune responses via mitochondrial ROS production. Modulation of these processes may represent a novel mechanism to modulate the nature as well as the magnitude of antiviral versus inflammatory immune responses.3 Introduction:

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“…Many of the ISGs induced by T1-IFN signaling are important mediators in restricting the ability of viruses to infect and replicate within cells, although many have not been studied in the context of a VACV infection. However, during infection with VACV ISG15, which is strongly induced in a T1-IFN-independent manner in infected skin, controls mitochondrial function and limits virus replication within infected cells [68,69]. The only logical explanation from these opposing observations is that ISG expression is induced by redundant signaling pathways via the expression of other cytokines.…”

Section: Discussionmentioning

confidence: 99%

Type I interferon-dependent CCL4 is induced by a cGAS/STING pathway that bypasses viral inhibition and protects infected tissue, independent of viral burden

Parekh

Krouse

Reider

et al. 2019

Preprint

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Type I interferons (T1-IFN) are critical in the innate immune response, acting upon infected and uninfected cells to initiate an antiviral state by expressing genes that inhibit multiple stages of the lifecycle of many viruses. T1-IFN triggers the production of Interferon-Stimulated Genes (ISGs), activating an antiviral program that reduces virus replication. The importance of the T1-IFN response is highlighted by the evolution of viral evasion strategies to inhibit the production or action of T1-IFN in virus-infected cells. T1-IFN is produced via activation of pathogen sensors within infected cells, a process that is targeted by virus-encoded immunomodulatory molecules. This is probably best exemplified by the prototypic poxvirus, Vaccinia virus (VACV), which uses at least 6 different mechanisms to completely block the production of T1-IFN within infected cells in vitro. Yet, mice lacking aspects of T1-IFN signaling are often more susceptible to infection with many viruses, including VACV, than wild-type mice. How can these opposing findings be rationalized? The cytosolic DNA sensor cGAS has been implicated in immunity to VACV, but has yet to be linked to the production of T1-IFN in response to VACV infection. Indeed, there are two VACV-encoded proteins that effectively prevent cGAS-mediated activation of T1-IFN. We find that the majority of VACV-infected cells in vivo do not produce T1-IFN, but that a small subset of VACV-infected cells in vivo utilize cGAS to sense VACV and produce T1-IFN to protect infected mice. The protective effect of T1-IFN is not mediated via ISG-mediated control of virus replication. Rather, T1-IFN drives expression of CCL4, which recruits inflammatory monocytes that constrain the VACV lesion in a virus replication-independent manner by limiting spread within the tissue.Our findings have broad implications in our understanding of pathogen detection and viral evasion in vivo, and highlight a novel immune strategy to protect infected tissue. SummaryThe recognition of virus infection leads to a quick and robust antiviral response mediated by type I interferons (T1-IFN). Nearly all viruses have acquired genes that block the induction or action of T1-IFN in order to attain a replicative advantage. Some viruses thwart the T1-IFN response so thoroughly, that cells infected in vitro do not produce any T1-IFN. And yet, animal models with defects in T1-IFN signaling are more sensitive to infection with these viruses than their wild-type counterparts. In this study, we find evidence to explain these otherwise contradicting findings. We show that a small population of infected cells in vivo are able to utilize a pathogen-sensing pathway that is completely blocked in vitro. T1-IFN produced by these specialized cells protects mice by recruiting inflammatory monocytes that restrict the spread of virus within infected tissue, independent of viral burden. Our findings have a direct impact on our understanding of how viruses are detected in infected tissue, and present a novel strategy of the immune syst...

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ISG15 governs mitochondrial function in macrophages following vaccinia virus infection

Cited by 76 publications

References 88 publications

Interferon-Independent Innate Responses to Cytomegalovirus

Interferon-Independent Innate Responses to Cytomegalovirus

Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages

Type I interferon-dependent CCL4 is induced by a cGAS/STING pathway that bypasses viral inhibition and protects infected tissue, independent of viral burden

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