A Novel Cre Recombinase Imaging System for Tracking Lymphotropic Virus Infection In Vivo

Dutia, Bernadette M.; Reid, Stuart; Drummond, Derek D.; Ligertwood, Yvonne; Bennet, Ian; Rietberg, Willard; Silvia, O.J.; Jarvis, Michael A.; Nash, Anthony

doi:10.1371/journal.pone.0006492

Cited by 11 publications

(8 citation statements)

References 35 publications

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“…1B), which is consistent with previous observations using cells harvested from peripheral sites (36,41). Together, these results confirm previous reports (7,12,13,41) and clearly indicate that latent infection of bone marrow cells is a stable feature of chronic MHV68 infection.…”

supporting

confidence: 92%

“…KSHV has also been detected in the bone marrow of transplant recipients (22). Similarly, MHV68 is detectable in the bone marrow during chronic infection (7,12,13,41). Consistent with latent gammaherpesvirus infection of the bone marrow, EBV-positive B cell lines spontaneously arise from long-term bone marrow cultures derived from both healthy donors (4,5,28) and hematologic patients (26), perhaps suggesting the presence of latently infected progenitor cells in the bone marrow since primary B cells would not be expected to survive long-term in vitro culture (26).…”

mentioning

confidence: 97%

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Immature and Transitional B Cells Are Latency Reservoirs for a Gammaherpesvirus

Coleman

Nealy

Tibbetts

2010

J Virol

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The human gammaherpesviruses Epstein-Barr virus (EBV)and Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 ) are ubiquitous human pathogens that are associated with the development of numerous types of malignancies, including B cell lymphomas. Murine gammaherpesvirus 68 (MHV68) is genetically related to EBV and KSHV and causes lymphoma and lymphoproliferative disease in mice, providing a useful small-animal model for mechanistic in vivo studies of the virus-host relationship. Both the human and murine viruses subvert the antiviral immune response to establish lifelong latent infections in mature B cells. However, it is not clearly understood how these viruses gain access to specific mature B cell subsets or whether latent infection of these subsets is actively maintained over time. One intriguing possibility is that gammaherpesviruses gain entry to the circulating mature B cell compartment via infection of B cell progenitors. Mature B cells arise via a highly regulated, multistep developmental process that results in the daily generation of thousands of new cells. Thus, any developing B cell subsets could provide a potential access point for recurrent entry of the virus into the long-lived mature B cell reservoir.

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supporting

confidence: 92%

mentioning

confidence: 97%

Immature and Transitional B Cells Are Latency Reservoirs for a Gammaherpesvirus

Coleman

Nealy

Tibbetts

2010

J Virol

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“…Prior to and concomitant with colonization of the spleen, MHV68 is detected both in the mediastinal lymph nodes (MLN) that survey the lymph exiting the lungs and in peripheral blood mononuclear cells (PBMCs) [ 21 – 24 ]. Given the severity of acute replication in the lungs, we investigated the ability of 75A.stop viruses to infect these intermediate reservoirs.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, the acute phase of infection after intranasal inoculation seems to promote the efficient seeding of the latent splenic reservoir. MHV68 replicates in alveolar epithelial cells of the lung [ 47 ], and is detected in the MLN prior to, and concomitant, with infection of peripheral blood mononuclear cells [ 21 – 24 , 48 ]. These observations support a model whereby the virus gains access to B cells in the lymph nodes that survey sites of acute infection, and then traffics to the spleen via the blood.…”

Section: Discussionmentioning

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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“…However, care must be taken to avoid disruption of neighboring genes. Current loci used include the genomic region left of M1 (37), between ORF11 and the gene for mK3 (17), ORF27-ORF29 (disrupting the nonessential gene ORF28) (43,44,60,63), and ORF57-ORF58 (26,61). Additional nontranscribed regions between convergent annotated ORF transcripts that might prove suitable for transgene insertion were located in the ORF11-ORF12 and ORF51-ORF52 intergenic regions (Fig.…”

Section: Discussionmentioning

confidence: 99%

Tiled Microarray Identification of Novel Viral Transcript Structures and Distinct Transcriptional Profiles during Two Modes of Productive Murine Gammaherpesvirus 68 Infection

Cheng

Zhi

Santana

et al. 2012

J Virol

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cWe applied a custom tiled microarray to examine murine gammaherpesvirus 68 (MHV68) polyadenylated transcript expression in a time course of de novo infection of fibroblast cells and following phorbol ester-mediated reactivation from a latently infected B cell line. During de novo infection, all open reading frames (ORFs) were transcribed and clustered into four major temporal groups that were overlapping yet distinct from clusters based on the phorbol ester-stimulated B cell reactivation time course. High-density transcript analysis at 2-h intervals during de novo infection mapped gene boundaries with a 20-nucleotide resolution, including a previously undefined ORF73 transcript and the MHV68 ORF63 homolog of Kaposi's sarcoma-associated herpesvirus vNLRP1. ORF6 transcript initiation was mapped by tiled array and confirmed by 5= rapid amplification of cDNA ends. The ϳ1.3-kb region upstream of ORF6 was responsive to lytic infection and MHV68 RTA, identifying a novel RTA-responsive promoter. Transcription in intergenic regions consistent with the previously defined expressed genomic regions was detected during both types of productive infection. We conclude that the MHV68 transcriptome is dynamic and distinct during de novo fibroblast infection and upon phorbol ester-stimulated B cell reactivation, highlighting the need to evaluate further transcript structure and the context-dependent molecular events that govern viral gene expression during chronic infection. Murine gammaherpesvirus 68 (MHV68; also known as ␥HV68 or murid herpesvirus 4) infection of mice is a model pathogenesis system for gammaherpesviruses such as Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/ HHV-8) and Epstein-Barr virus (EBV) (5, 20). The life cycles of these lymphotropic and transforming viruses in the host involve the initial transit across a mucosal barrier to gain access to and establish latency in a leukocyte reservoir, followed by intermittent reactivation and dissemination to the mucosal surfaces for spread to new hosts (32,74,77,82).Replication at the site of primary infection impacts MHV68 dissemination and latency establishment in secondary lymphoid tissues of mice. The absence of proteins essential for lytic replication, such as the viral transactivator ORF50/mRTA (61) and the ORF6/single-stranded DNA-binding protein (ssDBP) (49), or the inhibition of viral DNA replication by the administration of cidofovir (62) impairs the establishment of latency in the splenic B cell compartment. In addition, virus replication at the mucosa triggers the innate and adaptive immune responses critical for host control (6,45,72,73). These responses might play a critical role in the recruitment and activation of target cells such as dendritic cells that precede dissemination to distal reservoirs, such as splenic B cells and peritoneal macrophages (5, 25). Thus, the lytic gene expression program in newly infected cells that are permissive for productive infection is an important aspect of pathogenesis.Reactivation from latency is a...

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A Novel Cre Recombinase Imaging System for Tracking Lymphotropic Virus Infection In Vivo

Cited by 11 publications

References 35 publications

Immature and Transitional B Cells Are Latency Reservoirs for a Gammaherpesvirus

Immature and Transitional B Cells Are Latency Reservoirs for a Gammaherpesvirus

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

Tiled Microarray Identification of Novel Viral Transcript Structures and Distinct Transcriptional Profiles during Two Modes of Productive Murine Gammaherpesvirus 68 Infection

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