The phenotype of the RABV glycoprotein determines cellular and global virus load in the brain and is decisive for the pace of the disease

Bertoune, Mirjam; Nickl, Bernadette; Krieger, Teresa G; Wohlers, L.; Bonaterra, Gabriel A.; Dietzschold, Bernhard; Weihe, Eberhard; Bette, Michael

doi:10.1016/j.virol.2017.08.019

Cited by 6 publications

(2 citation statements)

References 62 publications

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“…The infected regions included areas enriched with α7 nAChRs, specifically the motor cortex, amygdala, and hippocampus. While the rabies viral load in the human CNS during any stage of infection is poorly studied, using mice showing robust clinical signs of rabies and qt-PCR, the CNS viral titer has been estimated to be 1.6 - 8.3 x 10 7 viral genomes per μg of total RNA, depending on the viral strain ( Bertoune et al., 2017 ). It is worth noting that viral loads differ by brain regions, viral type, and stages of infection ( Laothamatas et al., 2008 ; Zhang et al., 2022 ).…”

Section: Discussionmentioning

confidence: 99%

The human alpha7 nicotinic acetylcholine receptor is a host target for the rabies virus glycoprotein

O’Brien,

Thao,

Weber

et al. 2024

Front. Cell. Infect. Microbiol.

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The rabies virus enters the nervous system by interacting with several molecular targets on host cells to modify behavior and trigger receptor-mediated endocytosis of the virion by poorly understood mechanisms. The rabies virus glycoprotein (RVG) interacts with the muscle acetylcholine receptor and the neuronal α4β2 subtype of the nicotinic acetylcholine receptor (nAChR) family by the putative neurotoxin-like motif. Given that the neurotoxin-like motif is highly homologous to the α7 nAChR subtype selective snake toxin α-bungarotoxin (αBTX), other nAChR subtypes are likely involved. The purpose of this study is to determine the activity of the RVG neurotoxin-like motif on nAChR subtypes that are expressed in brain regions involved in rabid animal behavior. nAChRs were expressed in Xenopus laevis oocytes, and two-electrode voltage clamp electrophysiology was used to collect concentration-response data to measure the functional effects. The RVG peptide preferentially and completely inhibits α7 nAChR ACh-induced currents by a competitive antagonist mechanism. Tested heteromeric nAChRs are also inhibited, but to a lesser extent than the α7 subtype. Residues of the RVG peptide with high sequence homology to αBTX and other neurotoxins were substituted with alanine. Altered RVG neurotoxin-like peptides showed that residues phenylalanine 192, arginine 196, and arginine 199 are important determinants of RVG peptide apparent potency on α7 nAChRs, while serine 195 is not. The evaluation of the rabies ectodomain reaffirmed the observations made with the RVG peptide, illustrating a significant inhibitory impact on α7 nAChR with potency in the nanomolar range. In a mammalian cell culture model of neurons, we confirm that the RVG peptide binds preferentially to cells expressing the α7 nAChR. Defining the activity of the RVG peptide on nAChRs expands our understanding of basic mechanisms in host-pathogen interactions that result in neurological disorders.

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Section: Discussionmentioning

confidence: 99%

The human alpha7 nicotinic acetylcholine receptor is a host target for the rabies virus glycoprotein

O’Brien,

Thao,

Weber

et al. 2024

Front. Cell. Infect. Microbiol.

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“…While activation of microglia has been observed during RABV infection in vitro and in vivo [155][156][157][158][159], the detection of viral antigen in infected microglia in vivo has been assumed to be the result of microglial phagocytosis of infected neurons [128]. Ray and colleagues provided some evidence that human microglia are susceptible to RABV infection in vitro [127].…”

Section: Microgliamentioning

confidence: 99%

Innate Immune Signaling and Role of Glial Cells in Herpes Simplex Virus- and Rabies Virus-Induced Encephalitis

Feige

Zaeck

Sehl-Ewert

et al. 2021

Viruses

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The environment of the central nervous system (CNS) represents a double-edged sword in the context of viral infections. On the one hand, the infectious route for viral pathogens is restricted via neuroprotective barriers; on the other hand, viruses benefit from the immunologically quiescent neural environment after CNS entry. Both the herpes simplex virus (HSV) and the rabies virus (RABV) bypass the neuroprotective blood–brain barrier (BBB) and successfully enter the CNS parenchyma via nerve endings. Despite the differences in the molecular nature of both viruses, each virus uses retrograde transport along peripheral nerves to reach the human CNS. Once inside the CNS parenchyma, HSV infection results in severe acute inflammation, necrosis, and hemorrhaging, while RABV preserves the intact neuronal network by inhibiting apoptosis and limiting inflammation. During RABV neuroinvasion, surveilling glial cells fail to generate a sufficient type I interferon (IFN) response, enabling RABV to replicate undetected, ultimately leading to its fatal outcome. To date, we do not fully understand the molecular mechanisms underlying the activation or suppression of the host inflammatory responses of surveilling glial cells, which present important pathways shaping viral pathogenesis and clinical outcome in viral encephalitis. Here, we compare the innate immune responses of glial cells in RABV- and HSV-infected CNS, highlighting different viral strategies of neuroprotection or Neuroinflamm. in the context of viral encephalitis.

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Viruses in connectomics: Viral transneuronal tracers and genetically modified recombinants as neuroscience research tools

Ugolini

2020

Journal of Neuroscience Methods

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The phenotype of the RABV glycoprotein determines cellular and global virus load in the brain and is decisive for the pace of the disease

Cited by 6 publications

References 62 publications

The human alpha7 nicotinic acetylcholine receptor is a host target for the rabies virus glycoprotein

The human alpha7 nicotinic acetylcholine receptor is a host target for the rabies virus glycoprotein

Innate Immune Signaling and Role of Glial Cells in Herpes Simplex Virus- and Rabies Virus-Induced Encephalitis

Viruses in connectomics: Viral transneuronal tracers and genetically modified recombinants as neuroscience research tools

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