Update on Herpes Virus Infections of the Nervous System

Steiner, Israel; Benninger, Felix

doi:10.1007/s11910-013-0414-8

Cited by 151 publications

(125 citation statements)

References 90 publications

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“…The virus uses multiple receptors for successful infection in a variety of cell types, including MEFs. Studies in animal models and in humans have shown that HSV-1 infection is not only the major cause of severe herpes infections on the mouth and lips, but also an important cause of fatal sporadic encephalitis (25,26). In the current study, we report that HSV-1 infection triggers RIP3/MLKL-dependent necrosis via an RHIMcontaining viral ribonucleotide reductase large subunit (ICP6).…”

mentioning

confidence: 64%

Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense

Wang

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

196

193

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The receptor-interacting kinase-3 (RIP3) and its downstream substrate mixed lineage kinase domain-like protein (MLKL) have emerged as the key cellular components in programmed necrotic cell death. Receptors for the cytokines of tumor necrosis factor (TNF) family and Toll-like receptors (TLR) 3 and 4 are able to activate RIP3 through receptor-interacting kinase-1 and Toll/IL-1 receptor domaincontaining adapter inducing IFN-β, respectively. This form of cell death has been implicated in the host-defense system. However, the molecular mechanisms that drive the activation of RIP3 by a variety of pathogens, other than the above-mentioned receptors, are largely unknown. Here, we report that human herpes simplex virus 1 (HSV-1) infection triggers RIP3-dependent necrosis. This process requires MLKL but is independent of TNF receptor, TLR3, cylindromatosis, and host RIP homotypic interaction motif-containing protein DNA-dependent activator of IFN regulatory factor. After HSV-1 infection, the viral ribonucleotide reductase large subunit (ICP6) interacts with RIP3. The formation of the ICP6-RIP3 complex requires the RHIM domains of both proteins. An HSV-1 ICP6 deletion mutant failed to cause effective necrosis of HSV-1-infected cells. Furthermore, ectopic expression of ICP6, but not RHIM mutant ICP6, directly activated RIP3/MLKL-mediated necrosis. Mice lacking RIP3 exhibited severely impaired control of HSV-1 replication and pathogenesis. Therefore, this study reveals a previously uncharacterized host antipathogen mechanism.programmed necrosis | HSV-1 | ICP6 | RIP3 | MLKL C ell death triggered by pathogens is a crucial component of mammalian host-defense system. Apoptosis, a predominant programmed cell death in mammals, functions as an effective host-defense mechanism for preventing pathogen replication. Apoptosis is initiated by either mitochondria or cell-death receptors, and it is executed by a group of cysteine proteases called caspases (1). The apoptotic pathway can be subverted by pathogen-encoded apoptotic suppressors such as caspase inhibitors (2). Recent studies have revealed that caspase inhibition can lead to alternative activation of necrosis, releasing the damage-associated molecular patterns (DAMPs) signal to trigger the activation of the host immune system (3, 4).Cytokines of the TNF family are classical inducers of programmed necrosis that are morphologically characterized by the swelling of intracellular organelles and disrupted plasma membranes. Programmed necrosis triggered by death cytokines such as TNF, also known as necroptosis (5-7), is tightly regulated by receptor-interacting kinase-1 (RIP1) (8), its deubiquitin enzyme cylindromatosis (CYLD) (9), and receptor-interacting kinase-3 (RIP3) (10-12). The RIP homotypic interaction motif (RHIM) domains of RIP1 and RIP3 are required for the formation of the RIP1-RIP3 complex that is called a necrosome (13). Recently, mixed lineage kinase domain-like (MLKL) protein has been identified as a functional substrate of RIP3 kinase (14, 15). Upon phosphorylation, ...

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mentioning

confidence: 64%

Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense

Wang

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

196

193

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“…The mortality of untreated HSV encephalitis is roughly 70 %, and 97 % of survivors will not return to their previous level of function [41,[154][155][156]. Clinical trials in the 1980s demons t r a t e d s i g n i f i c a n t l y i m p r o v e d o u t c o m e s w i t h intravenous aciclovir, as described above [103,104], and the 1-year mortality with current antivirals and supportive care is now in the range of 5-15 %, despite high rates of admission to the ICU [44,60,157].…”

Section: Discussionmentioning

confidence: 99%

“…A survey from 2005 to 2010 including Americans between 14 and 49 years of age in the USA estimated HSV-1 seropositivity at 54 % and HSV-2 seropositivity at~16 % [40]. While HSV-2 is also capable of causing encephalitis (particularly in the immunocompromised host), HSV-1 is responsible for~90 % of HSV encephalitis in adults and children, and is the focus of this review [41]. Despite only rarely manifesting as encephalitis in infected individuals, HSV-1 is consistently the single most common cause of sporadic encephalitis worldwide [42][43][44][45][46][47][48][49][50][51][52].…”

Section: Epidemiologymentioning

confidence: 99%

Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management

2016

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Herpetic infections have plagued humanity for thousands of years, but only recently have advances in antiviral medications and supportive treatments equipped physicians to combat the most severe manifestations of disease. Prompt recognition and treatment can be lifesaving in the care of patients with herpes simplex-1 virus encephalitis, the most commonly identified cause of sporadic encephalitis worldwide. Clinicians should be able to recognize the clinical signs and symptoms of the infection and familiarize themselves with a rational diagnostic approach and therapeutic modalities, as early recognition and treatment are key to improving outcomes. Clinicians should also be vigilant for the development of acute complications, including cerebral edema and status epilepticus, as well as chronic complications, including the development of autoimmune encephalitis associated with antibodies to the N-methyl-D-aspartate receptor and other neuronal cell surface and synaptic epitopes. Herein, we review the pathophysiology, differential diagnosis, and clinical and radiological features of herpes simplex virus-1 encephalitis in adults, including a discussion of the most common complications and their treatment. While great progress has been made in the treatment of this life-threatening infection, a majority of patients will not return to their previous neurologic baseline, indicating the need for further research efforts aimed at improving the long-term sequelae.

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“…HSE is the most common sporadic viral encephalitis in the Western world. This life-threatening disease strikes otherwise healthy children once (recurrence is rare) in the course of primary infection with the herpes simplex virus, which is ubiquitous and typically innocuous (111). The arguments against a genetic hypothesis and against a monogenic hypothesis in particular included the sporadic nature of the disease, with only four multiplex families having been reported since its first description in 1941 (112).…”

Section: Hse: a Model Diseasementioning

confidence: 99%

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

201

163

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This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

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Update on Herpes Virus Infections of the Nervous System

Cited by 151 publications

References 90 publications

Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense

Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense

Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management

Severe infectious diseases of childhood as monogenic inborn errors of immunity

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