Infection of Cattle with a Bovine Herpesvirus 1 Strain That Contains a Mutation in the Latency-Related Gene Leads to Increased Apoptosis in Trigeminal Ganglia during the Transition from Acute Infection to Latency

Lovato, Luciane Teresinha; Inman, Melissa; Henderson, Gail; Doster, Alan R.; Jones, Clinton

doi:10.1128/jvi.77.8.4848-4857.2003

Cited by 76 publications

(100 citation statements)

References 71 publications

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“…Consequently, LR-RNA sequences may promote the early phases of establishing latency by binding to bICP0 mRNA sequences, which would inhibit productive infection by reducing bICP0 levels and inducing an earlier IFN response. Our previous studies also indicate that expression of an LR protein promotes survival of infected neurons by inhibiting apoptosis (Ciacci-Zanella et al, 1999;Lovato et al, 2003). In conclusion, we propose that premature expression of LR-RNA by the LR mutant virus, in the absence of LR protein expression, leads to survival of a subset of infected neurons that can establish latency but are unable to reactivate from latency .…”

Section: Virussupporting

confidence: 62%

Premature expression of the latency-related RNA encoded by bovine herpesvirus type 1 correlates with higher levels of beta interferon RNA expression in productively infected cells

Pérez

Meyer

Saira

et al. 2008

Journal of General Virology

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Bovine herpesvirus type 1 (BHV-1) is an important pathogen that can initiate bovine respiratory disease complex. Like other members of the subfamily Alphaherpesvirinae, BHV-1 establishes latency in sensory neurons. The latency-related (LR) gene expresses a family of alternatively spliced transcripts in infected sensory neurons that have the potential to encode several LR proteins. An LR mutant virus that contains three stop codons near the 59 terminus of the first open reading frame in the LR gene does not express two LR proteins or reactivate from latency. In addition, the LR mutant virus induces higher levels of apoptosis in trigeminal ganglionic neurons and grows less efficiently in certain tissues of infected calves. In spite of the reduced pathogenesis, the LR mutant virus, wild-type BHV-1 and the LR rescued virus exhibit identical growth properties in cultured bovine cells. In this study, we demonstrated that during early phases of productive infection the LR mutant virus expressed higher levels of LR-RNA relative to the LR rescued virus or wt BHV-1. Bovine kidney cells infected with the LR mutant virus also induced higher levels of beta interferon RNA and interferon response genes. These results suggest that inappropriate expression of LR-RNA, in the absence of LR protein expression, may influence the latency-reactivation cycle and pathogenic potential of BHV-1.

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Section: Virussupporting

confidence: 62%

Premature expression of the latency-related RNA encoded by bovine herpesvirus type 1 correlates with higher levels of beta interferon RNA expression in productively infected cells

Pérez

Meyer

Saira

et al. 2008

Journal of General Virology

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“…Similar to our original studies with HSV-1 (Perng et al, 2000a), a BHV-1 LR mutant containing three stop codons inserted just downstream of the start of open reading frame 2 (ORF2) (the first ORF in LR; see Fig. 1C) has higher levels of apoptosis in TG neurons during the transition from acute infection to latency (establishment of latency) compared to wild-type or marker-rescued virus (Lovato et al, 2003). In transient transfection assays, plasmids expressing LR containing these alterations to ORF2 no longer inhibit apoptosis (Inman et al, 2001a).…”

Section: Introductionmentioning

confidence: 53%

The bovine herpesvirus-1 LR ORF2 is critical for this gene's ability to restore the high wild-type reactivation phenotype to a herpes simplex virus-1 LAT null mutant

Mott

Osório

Jin

et al. 2003

Journal of General Virology

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The bovine herpesvirus-1 LR ORF2 is critical for this gene's ability to restore the high wild-type reactivation phenotype to a herpes simplex virus-1 LAT null mutant During neuronal latency of herpes simplex virus (HSV)-1, the latency-associated transcript (LAT) is the only viral gene readily detectable. LAT is required for the high-level reactivation phenotype in animal models. LAT's anti-apoptotic activity was recently demonstrated by our group and it was proposed that LAT's anti-apoptotic function is involved in enhancing the reactivation phenotype. Recently, using chimeric virus CJLAT, it was shown that the reactivation phenotype of LAT " mutant dLAT2903 can be restored to wild-type levels by inserting the bovine herpes virus (BHV)-1 latency-related (LR) gene into the LAT locus of this HSV-1 LAT deletion mutant. Although transcription of the LR gene, like LAT, inhibits apoptosis, LR appears to be multifunctional. To investigate whether the LR gene's anti-apoptotic function was responsible for restoring the high-reactivation phenotype, a mutated BHV-1 LR gene was inserted into the LAT locus of HSV-1 generating the chimeric virus CJLATmut. This mutation consists of three stop codons inserted just after the ATG of the first LR open reading frame (ORF2). In plasmids and in a BHV-1 mutant, this mutation eliminated the LR gene's anti-apoptotic activity, strongly suggesting that ORF2 encodes a protein responsible for LR's anti-apoptotic activity. Reactivation of the CJLATmut virus, in both rabbits and mice, was significantly lower than in wild-type McKrae virus (P=0?0001 and P=0?0003, respectively) and CJLAT virus, containing wild-type LR in place of LAT (P<0?0001) and was similar to LAT " dLAT2903 (P=0?8 and P=0?7, respectively). Thus, disruption of BHV-1 LR ORF2 eliminated the high-reactivation phenotype. INTRODUCTIONOver 80 % of adults in the United States harbour latent herpes simplex virus type 1 (HSV-1). Following primary peripheral infection of the eye, HSV-1 travels along axons via antegrade transport to sensory neurons of the trigeminal ganglia (TG) where latency is established. The latent virus reactivates sporadically as a result of stress, UV exposure and other unknown stimuli. Reactivations can also occur in the absence of known stimuli, which we have operationally defined as spontaneous reactivation. Following reactivation, HSV-1 travels along axons in a retrograde direction to the initial infection site, where it can replicate and cause recurrent disease (Andreansky et al., 1998;Roizman & Whitley, 2001). Recurrent HSV-1 infection in the eye can cause corneal scarring leading to the loss of vision. As a result, HSV-1 is one of the leading infectious causes of corneal blindness in the developed world (Liesegang et al., 1989). The mechanism(s) by which the latent virus reactivates and causes disease are currently not completely understood.The only gene that is actively transcribed during HSV-1 neuronal latency is the latency-associated transcript (LAT) (Rock et al., 1987b; Stevens et al., 1987). A stab...

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“…The LRT mutants were shed at similar rates from the nasal cavity during the primary infection [80,158]. In latently infected neurons, reduced levels of viral DNA were detected [81] but higher levels of apoptosis occurred in trigeminal ganglion at the end of the acute infection [118]. The BoHV-1 LRT mutants were not re-excreted following a reactivation treatment with dexamethasone, which induced reactivation and re-excretion in all calves infected by either wild-type or LRT rescued virus [81].…”

Section: Latency and Reactivationmentioning

confidence: 93%

“…An immediate onset of apoptosis would decrease BoHV-1 replication at the entry site and prevent therefore its spread. It was also demonstrated that caspase 3, a key regulatory protein in the apoptotic pathway, is activated late during productive BoHV-1 infection [35,118]. BICP0 probably participates in this delayed induction of apoptosis by an indirect mechanism that stimulates caspase 3 cleavage [72].…”

Section: Replication At the Mucosal Portal Of Entrymentioning

confidence: 99%

Bovine herpesvirus 1 infection and infectious bovine rhinotracheitis

et al. 2007

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-Bovine herpesvirus 1 (BoHV-1), classified as an alphaherpesvirus, is a major pathogen of cattle. Primary infection is accompanied by various clinical manifestations such as infectious bovine rhinotracheitis, abortion, infectious pustular vulvovaginitis, and systemic infection in neonates. When animals survive, a life-long latent infection is established in nervous sensory ganglia. Several reactivation stimuli can lead to viral re-excretion, which is responsible for the maintenance of BoHV-1 within a cattle herd. This paper focuses on an updated pathogenesis based on a molecular characterization of BoHV-1 and the description of the virus cycle. Special emphasis is accorded to the impact of the latency and reactivation cycle on the epidemiology and the control of BoHV-1. Several European countries have initiated BoHV-1 eradication schemes because of the significant losses incurred by disease and trading restrictions. The vaccines used against BoHV-1 are described in this context where the differentiation of infected from vaccinated animals is of critical importance to achieve BoHV-1 eradication.

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Infection of Cattle with a Bovine Herpesvirus 1 Strain That Contains a Mutation in the Latency-Related Gene Leads to Increased Apoptosis in Trigeminal Ganglia during the Transition from Acute Infection to Latency

Abstract: Bovine herpesvirus 1 (BHV-1) is an important pathogen of cattle and infection is usually initiated via

Cited by 76 publications

References 71 publications

Premature expression of the latency-related RNA encoded by bovine herpesvirus type 1 correlates with higher levels of beta interferon RNA expression in productively infected cells

Premature expression of the latency-related RNA encoded by bovine herpesvirus type 1 correlates with higher levels of beta interferon RNA expression in productively infected cells

The bovine herpesvirus-1 LR ORF2 is critical for this gene's ability to restore the high wild-type reactivation phenotype to a herpes simplex virus-1 LAT null mutant

Bovine herpesvirus 1 infection and infectious bovine rhinotracheitis

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