Interplay of Murine Gammaherpesvirus 68 with NF-kappaB Signaling of the Host

Cieniewicz, Brandon; Santana, Alexis; Minkah, Nana; Krug, Laurie T.

doi:10.3389/fmicb.2016.01202

Cited by 18 publications

(23 citation statements)

References 292 publications

(463 reference statements)

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“…Within two weeks of intranasal infection with MHV68, virus replication in the lung is resolved and the virus transits to the spleen where it establishes latency, predominantly in B lymphocytes [ 22 , 25 , 26 ]. Peak splenic latency occurs between 14 and 18 dpi and coincides with splenomegaly, a process driven by lymphocyte expansion in response to the infection [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice

et al. 2018

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Gammaherpesviruses encode proteins with homology to the cellular purine metabolic enzyme formyl-glycinamide-phosphoribosyl-amidotransferase (FGARAT), but the role of these viral FGARATs (vFGARATs) in the pathogenesis of a natural host has not been investigated. We report a novel role for the ORF75A vFGARAT of murine gammaherpesvirus 68 (MHV68) in infectious virion production and colonization of mice. MHV68 mutants with premature stop codons in orf75A exhibited a log reduction in acute replication in the lungs after intranasal infection, which preceded a defect in colonization of multiple host reservoirs including the mediastinal lymph nodes, peripheral blood mononuclear cells, and the spleen. Intraperitoneal infection rescued splenic latency, but not reactivation. The 75A.stop virus also exhibited defective replication in primary fibroblast and macrophage cells. Viruses produced in the absence of ORF75A were characterized by an increase in the ratio of particles to PFU. In the next round of infection this led to the alteration of early events in lytic replication including the deposition of the ORF75C tegument protein, the accelerated kinetics of viral gene expression, and induction of TNFα release and cell death. Infecting cells to deliver equivalent genomes revealed that ORF75A was required for initiating early events in infection. In contrast with the numerous phenotypes observed in the absence of ORF75A, ORF75B was dispensable for replication and pathogenesis. These studies reveal that murine rhadinovirus vFGARAT family members ORF75A and ORF75C have evolved to perform divergent functions that promote replication and colonization of the host.

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Section: Resultsmentioning

confidence: 99%

Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice

et al. 2018

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“…Persistent human gammaherpesvirus infection is associated with the development of malignancies such as Burkitt's lymphoma, Hodgkin's disease, and Kaposi's sarcoma (Mesri et al, 2014 ). Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are host (human)-specific and therefore lack a tractable in vivo infection model (Cieniewicz et al, 2016 ; Habison et al, 2017 ). The discovery of MHV68 provided what is now a much studied laboratory model for investigating virus reactivation from latency as well as host mechanisms of immune control, and the genetic basis of viral fitness in different cell types and tissues (Rajčáni and Kúdelová, 2007 ; Sattler et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Tick-Borne Transmission of Murine Gammaherpesvirus 68

Hajnická

Kúdelová

Štibrániová

et al. 2017

Front. Cell. Infect. Microbiol.

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Herpesviruses are a large group of DNA viruses infecting mainly vertebrates. Murine gammaherpesvirus 68 (MHV68) is often used as a model in studies of the pathogenesis of clinically important human gammaherpesviruses such as Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. This rodent virus appears to be geographically widespread; however, its natural transmission cycle is unknown. Following detection of MHV68 in field-collected ticks, including isolation of the virus from tick salivary glands and ovaries, we investigated whether MHV68 is a tick-borne virus. Uninfected Ixodes ricinus ticks were shown to acquire the virus by feeding on experimentally infected laboratory mice. The virus survived tick molting, and the molted ticks transmitted the virus to uninfected laboratory mice on which they subsequently fed. MHV68 was isolated from the tick salivary glands, consistent with transmission via tick saliva. The virus survived in ticks without loss of infectivity for at least 120 days, and subsequently was transmitted vertically from one tick generation to the next, surviving more than 500 days. Furthermore, the F1 generation (derived from F0 infected females) transmitted MHV68 to uninfected mice on which they fed, with MHV68 M3 gene transcripts detected in blood, lung, and spleen tissue of mice on which F1 nymphs and F1 adults engorged. These experimental data fulfill the transmission criteria that define an arthropod-borne virus (arbovirus), the largest biological group of viruses. Currently, African swine fever virus (ASFV) is the only DNA virus recognized as an arbovirus. Like ASFV, MHV68 showed evidence of pathogenesis in ticks. Previous studies have reported MHV68 in free-living ticks and in mammals commonly infested with I. ricinus, and neutralizing antibodies to MHV68 have been detected in large mammals (e.g., deer) including humans. Further studies are needed to determine if these reports are the result of tick-borne transmission of MHV68 in nature, and whether humans are at risk of infection.

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“…Macrophages appear to be cells that are immediately infected upon transmission [ 61 ] and host both lytic and latent viruses in vivo [ 62 , 63 ]. Considering the fact that lytic replication plays a critical role in seeding the latent splenic reservoir [ 63 , 64 ], and that RTA [ 63 , 65 , 66 ], IFN-γ [ 67 ], and NF-κB [ 68 , 69 ] are important interacting players in MHV-68 viral latency and reactivation, our finding of a “controlled viral escape” might offer a reasonable explanation for how virus-host interactions, reach this balanced status, to facilitate viral intra-host spreading and transmission. The involvement of TLR3 in viral immune invasion has been previously reported.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of murine herpesvirus-68 replication by IFN-gamma in macrophages is counteracted by the induction of SOCS1 expression

et al. 2018

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Gamma interferon (IFN-γ) is known to negatively regulate murine gammaherpesvirus-68 (MHV-68 or γHV-68) replication. This process involves the suppression of the viral gene replication and transcription activator (RTA) promoter, as well as activation of signal transducers and activators of transcription (STAT1). Notably, this effect is gradually attenuated during MHV-68 infection of bone marrow-derived macrophages (BMMs), which raised the possibility that the virus may utilize a mechanism that counteracts the antiviral effect of IFN-γ. By identifying the cellular factors that negatively regulate JAK-STAT1 signaling, we revealed that the infection of BMMs by MHV-68 induces the expression of suppressor of cytokine signaling 1 (SOCS1) and that depletion of SOCS1 restores the inhibitory effect of IFN-γ on virus replication. Moreover, we demonstrated that the expression of SOCS1 was induced as a result of the Toll-like receptor 3 (TLR3) mediated activation of the NF-κB signaling cascade. In conclusion, we report that TLR3-TRAF-NF-κB signaling pathway play a role in the induction of SOCS1 that counteracts the antiviral effect of IFN-γ during MHV-68 infection. This process is cell type-specific: it is functional in macrophages, but not in epithelial cells or fibroblasts. Our study reveals a mechanism that balances the immune responses and the escape of a gamma-herpesvirus in some antigen-presenting cells.

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Interplay of Murine Gammaherpesvirus 68 with NF-kappaB Signaling of the Host

Cited by 18 publications

References 292 publications

Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice

Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice

Tick-Borne Transmission of Murine Gammaherpesvirus 68

Inhibition of murine herpesvirus-68 replication by IFN-gamma in macrophages is counteracted by the induction of SOCS1 expression

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