Defining nervous system susceptibility during acute and latent herpes simplex virus-1 infection

Menendez, Chandra M.; Carr, Daniel J.J.

doi:10.1016/j.jneuroim.2017.02.020

Cited by 46 publications

(35 citation statements)

References 87 publications

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“…), and from NI littermate controls (n = 3 per group, age and sex matched). (Figure legend continues) through the OB, as the mechanism of viral entry to the CNS (51,52). HSV-1 virus titer was especially high in the TG and BSC of moribund Rel C307X mice.…”

Section: Discussionmentioning

confidence: 99%

Rel-Dependent Immune and Central Nervous System Mechanisms Control Viral Replication and Inflammation during Mouse Herpes Simplex Encephalitis

Mancini

Caignard

Charbonneau

et al. 2019

The Journal of Immunology

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Herpes simplex encephalitis (HSE), caused by HSV type 1 (HSV-1) infection, is an acute neuroinflammatory condition of the CNS and remains the most common type of sporadic viral encephalitis worldwide. Studies in humans have shown that susceptibility to HSE depends in part on the genetic make-up of the host, with deleterious mutations in the TLR3/type I IFN axis underlying some cases of childhood HSE. Using an in vivo chemical mutagenesis screen for HSV-1 susceptibility in mice, we identified a susceptible pedigree carrying a causal truncating mutation in the Rel gene (Rel C307X), encoding for the NF-kB transcription factor subunit c-Rel. Like Myd88 2/2 and Irf3 2/2 mice, Rel C307X mice were susceptible to intranasal HSV-1 infection. Reciprocal bone marrow transfers into lethally irradiated hosts suggested that defects in both hematopoietic and CNS-resident cellular compartments contributed together to HSE susceptibility in Rel C307X mice. Although the Rel C307X mutation maintained cell-intrinsic antiviral control, it drove increased apoptotic cell death in infected fibroblasts. Moreover, reduced numbers of CD4 + CD25 + Foxp3 + T regulatory cells, and dysregulated NK cell and CD4 + effector T cell responses in infected Rel C307X animals, indicated that protective immunity was also compromised in these mice. In the CNS, moribund Rel C307X mice failed to control HSV-1 viral replication in the brainstem and cerebellum, triggering cell death and elevated expression of Ccl2, Il6, and Mmp8 characteristic of HSE neuroinflammation and pathology. In summary, our work implicates c-Rel in both CNS-resident cell survival and lymphocyte responses to HSV-1 infection and as a novel cause of HSE disease susceptibility in mice.

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Section: Discussionmentioning

confidence: 99%

Rel-Dependent Immune and Central Nervous System Mechanisms Control Viral Replication and Inflammation during Mouse Herpes Simplex Encephalitis

Mancini

Caignard

Charbonneau

et al. 2019

The Journal of Immunology

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“…For example, Herpes simplex virus-1 (HSV-1), a DNA virus, has a high seroprevalence in the human population [ 32 ]. When infecting the central nervous system, HSV-1 causes herpes simplex encephalitis, the leading cause of viral encephalitis [ 33 ]. The initial study found that STING deficient mice were extremely susceptible to intravenous infection of HSV-1 [ 34 ].…”

Section: Tmem173 Alleles In Human Healthmentioning

confidence: 99%

TMEM173 variants and potential importance to human biology and disease

Patel

Jin

2018

Genes Immun

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TMEM173 gene encodes the protein STING (stimulator of interferon genes), a key player in host defense against pathogens. Mutations in the human TMEM173 gene cause a life-threatening auto-inflammatory disease called SAVI (STING-associated vasculopathy with onset in infancy). Human STING is also a promising therapeutic target for cancers and infectious diseases. Recently, Aduro Biotech and Novartis announced a $250M-plus initiative to develop STING-targeting cancer immunotherapies. Thus, understanding the genetics of the human TMEM173 gene is important for both basic and translational research. The human TMEM173 gene has great heterogeneity and population stratification. R232 of STING is the most common human TMEM173 allele. However, >50% of Americans are not R232/R232. HAQ (R71H-G230A-R293Q) is the second most common human TMEM173 allele. While R232/R232 is the dominant TMEM173 genotype in Europeans, R232/HAQ is the most common TMEM173 genotype in East Asians. Importantly, recent studies suggested that HAQ and H232 are likely loss-of-function TMEM173 alleles. In all, ~30% of East Asians and ~10% of Europeans are HAQ/HAQ, HAQ/H232 or H232/H232. Here, we reviewed human TMEM173 alleles, mutations and their potential impact on human health and medicine.

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“…Using a modified ex vivo tissue explant reactivation assay (i.e., the dissociation method instead of the classical mincing method), Chen et al achieved efficient recovery from the brain stem, olfactory bulb, and frontal cortex but not from the hippocampus, demonstrating that CNS can be a site of latency for HSV-1 ( 26 ). Recent studies have provided evidence that HSV-1 can establish latency in CNS neurons ( 17 , 27 – 29 ). However, it is uncertain whether neurons constitute the only reservoir of latent HSV-1 in the CNS.…”

Section: Discussionmentioning

confidence: 99%

Patterns of Herpes Simplex Virus 1 Infection in Neural Progenitor Cells

Zheng

Klammer

Naciri

et al. 2020

J Virol

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HSV-1 can induce damage in brain regions that include the hippocampus and associated limbic structures. These neurogenic niches are important because they are associated with memory formation and are highly enriched with neural progenitor cells (NPCs). The susceptibility and fate of HSV-1 infected NPCs is largely unexplored. We differentiated human induced pluripotent stem cells (iPSCs) into NPCs to generate two-dimensional (2D) and three-dimensional (3D) culture models to examine the interaction of HSV-1 with NPCs. Here, we show that: i) NPCs can be efficiently infected by HSV-1, but infection does not result in cell death of most NPCs, even at high multiplicity of infections (MOIs); ii) limited HSV-1 replication and gene expression can be detected in the infected NPCs; iii) a viral silencing mechanism is established in NPCs exposed to antivirals (E)-5-(2-bromovinyl)-2′-deoxyuridine (5BVdU) and interferon-α (IFN-α). When the antivirals are removed, spontaneous reactivation can occur at low frequency; iv) HSV-1 impairs the ability of NPCs to migrate in a dose-dependent fashion in the presence of 5BVdU + IFN-α; and v) 3D cultures of NPCs are less susceptible to HSV-1 infection than 2D cultures, yet still retain latent genomes. These results suggest that NPC pools could be sites of HSV-1 reactivation in the CNS. Finally, our results highlight the potential value of iPSC 3D cultures to model HSV-1-NPCs interaction. IMPORTANCE This study employed human induced pluripotent stem cells (hiPSCs) to model the interaction of HSV-1 with NPCs, which reside in the neurogenic niches of the CNS and play a fundamental role in adult neurogenesis. Herein, we provide evidence that in NPCs infected at an MOI as low as 0.001 HSV-1 can establish a latent state, suggesting that i) HSV-1 latency is not only restricted to mature neurons, but it can be established during earlier stages of neuronal differentiation; ii) neurogenic niches in the brain may constitute additional HSV-1 latent reservoirs. Lytic HSV-1 infections impaired NPCs migration, which represents a critical step in neurogenesis. Difference in susceptibility to HSV-1 infection between two-dimensional (2D) and three-dimensional (3D) NPC cultures was observed, highlighting the potential value of 3D cultures for modeling host-pathogen interactions. Together, our results are relevant in light of observations relating HSV-1 infection to post-encephalitic cognitive dysfunction.

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Defining nervous system susceptibility during acute and latent herpes simplex virus-1 infection

Cited by 46 publications

References 87 publications

Rel-Dependent Immune and Central Nervous System Mechanisms Control Viral Replication and Inflammation during Mouse Herpes Simplex Encephalitis

Rel-Dependent Immune and Central Nervous System Mechanisms Control Viral Replication and Inflammation during Mouse Herpes Simplex Encephalitis

TMEM173 variants and potential importance to human biology and disease

Patterns of Herpes Simplex Virus 1 Infection in Neural Progenitor Cells

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