| 1. |
- Hait, A. S., et al.
(författare)
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Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans
- 2020
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Ingår i: Science Immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 5:54
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Tidskriftsartikel (refereegranskat)abstract
- Recurrent herpesvirus infections can manifest in different forms of disease, including cold sores, genital herpes, and encephalitis. There is an incomplete understanding of the genetic and immunological factors conferring susceptibility to recurrent herpes simplex virus 2 (HSV2) infection in the central nervous system (CNS). Here, we describe two adult patients with recurrent HSV2 lymphocytic Mollaret's meningitis that each carry a rare monoallelic variant in the autophagy proteins ATG4A or LC3B2. HSV2-activated autophagy was abrogated in patient primary fibroblasts, which also exhibited significantly increased viral replication and enhanced cell death. HSV2 antigen was captured in autophagosomes of infected cells, and genetic inhibition of autophagy by disruption of autophagy genes, including ATG4A and LC3B2, led to enhanced viral replication and cell death in primary fibroblasts and a neuroblastoma cell line. Activation of autophagy by HSV2 was sensitive to ultraviolet (UV) irradiation of the virus and inhibited in the presence of acyclovir, but HSV2-induced autophagy was independent of the DNA-activated STING pathway. Reconstitution of wild-type ATG4A and LC3B2 expression using lentiviral gene delivery or electroporation of in vitro transcribed mRNA into patient cells restored virus-induced autophagy and the ability to control HSV2 replication. This study describes a previously unknown link between defective autophagy and an inborn error of immunity that can lead to increased susceptibility to HSV2 infection, suggesting an important role for autophagy in antiviral immunity in the CNS.
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| 2. |
- Bodda, C., et al.
(författare)
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HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection
- 2020
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 217:7
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Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex virus (HSV) is the main cause of viral encephalitis in the Western world, and the type I interferon (IFN) system is important for antiviral control in the brain. Here, we have compared Ifnb induction in mixed murine brain cell cultures by a panel of HSV1 mutants, each devoid of one mechanism to counteract the IFN-stimulating cGAS-STING pathway. We found that a mutant lacking the deubiquitinase (DUB) activity of the VP1-2 protein induced particularly strong expression of Ifnb and IFN-stimulated genes. HSV1 ΔDUB also induced elevated IFN expression in murine and human microglia and exhibited reduced viral replication in the brain. This was associated with increased ubiquitination of STING and elevated phosphorylation of STING, TBK1, and IRF3. VP1-2 associated directly with STING, leading to its deubiquitination. Recruitment of VP1-2 to STING was dependent on K150 of STING, which was ubiquitinated by TRIM32. Thus, the DUB activity of HSV1 VP1-2 is a major viral immune-evasion mechanism in the brain. © 2020 Bodda et al.
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| 3. |
- Paludan, Sören R, 1972, et al.
(författare)
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Constitutive immune mechanisms: mediators of host defence and immune regulation
- 2021
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Ingår i: Nature Reviews Immunology. - : Springer Science and Business Media LLC. - 1474-1733 .- 1474-1741. ; 21:3, s. 137-150
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Tidskriftsartikel (refereegranskat)abstract
- The immune system enables organisms to combat infections and to eliminate endogenous challenges. Immune responses can be evoked through diverse inducible pathways. However, various constitutive mechanisms are also required for immunocompetence. The inducible responses of pattern recognition receptors of the innate immune system and antigen-specific receptors of the adaptive immune system are highly effective, but they also have the potential to cause extensive immunopathology and tissue damage, as seen in many infectious and autoinflammatory diseases. By contrast, constitutive innate immune mechanisms, including restriction factors, basal autophagy and proteasomal degradation, tend to limit immune responses, with loss-of-function mutations in these pathways leading to inflammation. Although they function through a broad and heterogeneous set of mechanisms, the constitutive immune responses all function as early barriers to infection and aim to minimize any disruption of homeostasis. Supported by recent human and mouse data, in this Review we compare and contrast the inducible and constitutive mechanisms of immunosurveillance. Constitutive innate immune mechanisms, such as restriction factors, RNA interference, antimicrobial peptides, basal autophagy and proteasomal degradation, exert early host defence activities that also aim to minimize tissue damage and homeostatic disruption by limiting the activation of inducible innate immunity.
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| 4. |
- Carter-Timofte, M. E., et al.
(författare)
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RNA Polymerase III as a Gatekeeper to Prevent Severe VZV Infections
- 2018
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Ingår i: Trends in Molecular Medicine. - : Elsevier BV. - 1471-4914. ; 24:10, s. 904-915
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Tidskriftsartikel (refereegranskat)abstract
- In most individuals, varicella zoster virus (VZV) causes varicella upon primary infection and zoster during reactivation. However, in a subset of individuals, VZV may cause severe disease, including encephalitis. Host genetics is believed to be the main determinant of exacerbated disease manifestations. Recent studies have demonstrated that defects in the DNA sensor RNA polymerase III (POL III) confer selective increased susceptibility to VZV infection, thus providing fundamental new insight into VZV immunity. Here we describe the roles of POL III in housekeeping and immune surveillance during VZV infection. We present the latest knowledge on the role of POL III in VZV infection and discuss outstanding questions related to the role of POL III in VZV immunity, and how this insight can be translated into clinical medicine.
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| 5. |
- Paludan, Sören R, 1972, et al.
(författare)
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Constitutive and latent immune mechanisms exert 'silent' control of virus infections in the central nervous system
- 2021
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Ingår i: Current Opinion in Immunology. - : Elsevier BV. - 0952-7915. ; 72, s. 190-198
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Tidskriftsartikel (refereegranskat)abstract
- Viral infections in the central nervous system (CNS) can lead to severe disease manifestations often mediated by a combination of viral cytopathic effects and immunopathology. Moreover, neuronal tissue and brain activities are highly sensitive to excessive inflammation that disturb homeostasis. Immune responses to virus infections in the CNS should therefore be tightly balanced and limited in magnitude and duration to avoid immunopathology and tissue damage. Recent data from genetic studies of patients with viral infections in the CNS as well as experimental cell and animal models have provided evidence of non-redundant roles for constitutive and latent immune mechanisms, which mediate a first line of antiviral control without significantly triggering inflammatory activities. Collectively, accumulating data suggest the existence of a layer of immune mechanisms in the CNS exerting immediate control of infection, hence buffering the need for activation of more potent immune reactions with inherent potential to induce immunopathology and disease.
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