A new splice variant of the human guanylate‐binding protein 3 mediates anti‐influenza activity through inhibition of viral transcription and replication

Nordmann, Alexandra; Wixler, Ludmilla; Boergeling, Yvonne; Wixler, Viktor; Ludwig, Stephan

doi:10.1096/fj.11-189886

Cited by 85 publications

(88 citation statements)

References 32 publications

(55 reference statements)

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“…Upregulated DEGs that mapped to the remaining 8 GO terms were associated with nucleic acid metabolism (Fig. 9B) and play a role in splicing, e.g., splicing factor argi- nine/serine rich 12 (SFRS12, FC of 6) and formin binding protein 21 (FBP21, FC of 9) (70, 71), or antiviral defense, e.g., guanylate binding proteins 3 and 6 (GBP3 and GBP6, respectively; FCs of 3 and 5), which repress viral polymerases (72).…”

Section: Resultsmentioning

confidence: 99%

Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

Arnold

Girke

Sureshchandra

et al. 2016

J Virol

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Primary infection with varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, results in varicella. VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster. The relationship between VZV and its host during acute infection in the sensory ganglia is not well understood due to limited access to clinical specimens. Intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV) recapitulates the hallmarks of VZV infection in humans. We leveraged this animal model to characterize the host-pathogen interactions in the ganglia during both acute and latent infection by measuring both viral and host transcriptomes on days postinfection (dpi) 3, 7, 10, 14, and 100. SVV DNA and transcripts were detected in sensory ganglia 3 dpi, before the appearance of rash. CD4 and CD8 T cells were also detected in the sensory ganglia 3 dpi. Moreover, lung-resident T cells isolated from the same animals 3 dpi also harbored SVV DNA and transcripts, suggesting that T cells may be responsible for trafficking SVV to the ganglia. Transcriptome sequencing (RNA-Seq) analysis showed that cessation of viral transcription 7 dpi coincides with a robust antiviral innate immune response in the ganglia. Interestingly, a significant number of genes that play a critical role in nervous system development and function remained downregulated into latency. These studies provide novel insights into host-pathogen interactions in the sensory ganglia during acute varicella and demonstrate that SVV infection results in profound and sustained changes in neuronal gene expression. IMPORTANCEMany aspects of VZV infection of sensory ganglia remain poorly understood, due to limited access to human specimens and the fact that VZV is strictly a human virus. Infection of rhesus macaques with simian varicella virus (SVV), a homolog of VZV, provides a robust model of the human disease. Using this model, we show that SVV reaches the ganglia early after infection, most likely by T cells, and that the induction of a robust innate immune response correlates with cessation of virus transcription. We also report significant changes in the expression of genes that play an important role in neuronal function. Importantly, these changes persist long after viral replication ceases. Given the homology between SVV and VZV, and the genetic and physiological similarities between rhesus macaques and humans, our results provide novel insight into the interactions between VZV and its human host and explain some of the neurological consequences of VZV infection. V aricella-zoster virus (VZV) is a neurotropic alphaherpesvirus and the causative agent of varicella (chickenpox) (1). VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster (shingles), a painful disease that affects almost 1 million individuals in the United States alone (2). VZV is transmitted through the inhalation of virus-laden saliva droplets or by direct contact with the infectious fluid from vesicles...

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Section: Resultsmentioning

confidence: 99%

Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

Arnold

Girke

Sureshchandra

et al. 2016

J Virol

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“…The highest expression values obtained with the microarray analysis were the ones for the GIG2-like and GBP-3-like genes (83.55 and 71.61-fold change, respectively). GIG2 (grass carp reovirus-induced gene 2) is an interferon inducible gene specific of non-amniote organisms with no significant homology to any known genes in mammalian genomes (Zhang et al, 2013), and GBP3 is a guanylate binding protein belonging to the family of large GTPases (Nordmann et al, 2012). Both genes have been described as interferon inducible genes.…”

Section: Discussionmentioning

confidence: 99%

Zebrafish liver (ZFL) cells are able to mount an anti-viral response after stimulation with Poly (I:C)

Ruyra

Torrealba

Morera

et al. 2015

Comparative Biochemistry and Physiology Part B: Biochemistry an

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“…1A, 2A). Human GBPs were shown to play a role in controlling intracellular pathogens (31). Therefore, we first assessed whether endogenous human GBPs are recruited to T. gondii using indirect immunofluorescence (Fig.…”

Section: Human Gbps Are Recruited To T Gondii In An Atg16l1-dependenmentioning

confidence: 99%

Role of Mouse and Human Autophagy Proteins in IFN-γ–Induced Cell-Autonomous Responses against Toxoplasma gondii

Ohshima

Lee

Sasai

et al. 2014

The Journal of Immunology

112

127

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IFN-γ mediates cellular innate immunity against an intracellular parasite, Toxoplasma gondii, by inducing immunity-related GTPases such as p47 IFN-γ–regulated GTPases (IRGs) and p65 guanylate-binding proteins (GBPs), which also participate in antibacterial responses via autophagy. An essential autophagy protein, Atg5, was previously shown to play a critical role in anti–T. gondii cell-autonomous immunity. However, the involvement of other autophagy proteins remains unknown. In this study, we show that essential autophagy proteins differentially participate in anti–T. gondii cellular immunity by recruiting IFN-γ–inducible GTPases. IFN-γ–induced suppression of T. gondii proliferation and recruitment of an IRG Irgb6 and GBPs are profoundly impaired in Atg7- or Atg16L1-deficient cells. In contrast, cells lacking other essential autophagy proteins, Atg9a and Atg14, are capable of mediating the anti–T. gondii response and recruiting Irgb6 and GBPs to the parasites. Although IFN-γ also stimulates anti–T. gondii cellular immunity in humans, whether this response requires GBPs and human autophagy proteins remains to be seen. To analyze the role of human ATG16L1 and GBPs in IFN-γ–mediated anti–T. gondii responses, human cells lacking ATG16L1 or GBPs were generated by the Cas9/CRISPR genome-editing technique. Although both ATG16L1 and GBPs are dispensable for IFN-γ–induced inhibition of T. gondii proliferation in the human cells, human ATG16L1 is also required for the recruitment of GBPs. Taken together, human ATG16L1 and mouse autophagy components Atg7 and Atg16L1, but not Atg9a and Atg14, participate in the IFN-γ–induced recruitment of the immunity-related GTPases to the intracellular pathogen.

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A new splice variant of the human guanylate‐binding protein 3 mediates anti‐influenza activity through inhibition of viral transcription and replication

Cited by 85 publications

References 32 publications

Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

Zebrafish liver (ZFL) cells are able to mount an anti-viral response after stimulation with Poly (I:C)

Role of Mouse and Human Autophagy Proteins in IFN-γ–Induced Cell-Autonomous Responses against Toxoplasma gondii

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