Mechanism of herpesvirus UL24 protein regulating viral immune escape and virulence

Ruan, Peilin; Wang, Mingshu; Cheng, Anchun; Zhao, Xinxin; Yang, Qiao; Wu, Ying; Zhang, Shaqiu; Tian, Bin; Huang, Juan; Ou, Xumin; Gao, Qun; Sun, Di; He, Yu; Wu, Zhen; Zhu, Dekang; Jia, Renyong; Chen, Shun; Liu, Mafeng

doi:10.3389/fmicb.2023.1268429

Cited by 7 publications

(2 citation statements)

References 169 publications

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“…One unexpected pattern of expression was the downregulation of several ORFs upon transition from infected to replicating. Most notable of these were ORFs 14–18 , which appear to be US22 family whose homologues ( U2 and U3 for HHV-6, UL23–25 for HCMV) have diverse roles in tegument-mediated transactivation, control of type I IFN response, and modulating cell cycle ( 147 – 150 ). This could suggest that these genes contribute to initiation of lytic infection in different cell types.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection

Belean,

Xue,

Cisneros

et al. 2024

Front. Immunol.

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IntroductionHerpesviruses, including the roseoloviruses, have been linked to autoimmune disease. The ubiquitous and chronic nature of these infections have made it difficult to establish a causal relationship between acute infection and subsequent development of autoimmunity. We have shown that murine roseolovirus (MRV), which is highly related to human roseoloviruses, induces thymic atrophy and disruption of central tolerance after neonatal infection. Moreover, neonatal MRV infection results in development of autoimmunity in adult mice, long after resolution of acute infection. This suggests that MRV induces durable immune dysregulation.MethodsIn the current studies, we utilized single-cell RNA sequencing (scRNAseq) to study the tropism of MRV in the thymus and determine cellular processes in the thymus that were disrupted by neonatal MRV infection. We then utilized tropism data to establish a cell culture system.ResultsHerein, we describe how MRV alters the thymic transcriptome during acute neonatal infection. We found that MRV infection resulted in major shifts in inflammatory, differentiation and cell cycle pathways in the infected thymus. We also observed shifts in the relative number of specific cell populations. Moreover, utilizing expression of late viral transcripts as a proxy of viral replication, we identified the cellular tropism of MRV in the thymus. This approach demonstrated that double negative, double positive, and CD4 single positive thymocytes, as well as medullary thymic epithelial cells were infected by MRV in vivo. Finally, by applying pseudotime analysis to viral transcripts, which we refer to as “pseudokinetics,” we identified viral gene transcription patterns associated with specific cell types and infection status. We utilized this information to establish the first cell culture systems susceptible to MRV infection in vitro.ConclusionOur research provides the first complete picture of roseolovirus tropism in the thymus after neonatal infection. Additionally, we identified major transcriptomic alterations in cell populations in the thymus during acute neonatal MRV infection. These studies offer important insight into the early events that occur after neonatal MRV infection that disrupt central tolerance and promote autoimmune disease.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection

Belean,

Xue,

Cisneros

et al. 2024

Front. Immunol.

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“…This complete protection can be attributed to the strong neutralizing antibody response induced by ΔUL24/TK/gp2 vaccination. UL24, a highly conserved core protein of herpesvirus, has been demonstrated to act on multiple immune signaling pathways in herpes simplex virus type 1(HSV-1) and pseudorabies virus (PRV), thereby participating in immune escape from the host antiviral response ( 46 ). However, the role of UL24 in immune escape of EqAHV1 has not yet been established.…”

Section: Discussionmentioning

confidence: 99%

Development of a live attenuated vaccine candidate for equid alphaherpesvirus 1 control: a step towards efficient protection

Hu,

Wu,

Jia

et al. 2024

Front. Immunol.

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Equid alphaherpesvirus 1 (EqAHV1) is a viral pathogen known to cause respiratory disease, neurologic syndromes, and abortion storms in horses. Currently, there are no vaccines that provide complete protection against EqAHV1. Marker vaccines and the differentiation of infected and vaccinated animals (DIVA) strategy are effective for preventing and controlling outbreaks but have not been used for the prevention of EqAHV1 infection. Glycoprotein 2 (gp2), located on the envelope of viruses (EqAHV1), exhibits high antigenicity and functions as a molecular marker for DIVA. In this study, a series of EqAHV1 mutants with deletion of gp2 along with other virulence genes (TK, UL24/TK, gI/gE) were engineered. The mutant viruses were studied in vitro and then in an in vivo experiment using Golden Syrian hamsters to assess the extent of viral attenuation and the immune response elicited by the mutant viruses in comparison to the wild-type (WT) virus. Compared with the WT strain, the YM2019 Δgp2, ΔTK/gp2, and ΔUL24/TK/gp2 strains exhibited reduced growth in RK-13 cells, while the ΔgI/gE/gp2 strain exhibited significantly impaired proliferation. The YM2019 Δgp2 strain induced clinical signs and mortality in hamsters. In contrast, the YM2019 ΔTK/gp2 and ΔUL24/TK/gp2 variants displayed diminished pathogenicity, causing no observable clinical signs or fatalities. Immunization with nasal vaccines containing YM2019 ΔTK/gp2 and ΔUL24/TK/gp2 elicited a robust immune response in hamsters. In particular, compared with the vaccine containing the ΔTK/gp2 strain, the vaccine containing the ΔUL24/TK/gp2 strain demonstrated enhanced immune protection upon challenge with the WT virus. Furthermore, an ELISA for gp2 was established and refined to accurately differentiate between infected and vaccinated animals. These results confirm that the ΔUL24/TK/gp2 strain is a safe and effective live attenuated vaccine candidate for controlling EqAHV1 infection.

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Duck plague virus UL24 protein initiates K48/K63-linked IRF7 polyubiquitination to antagonize the innate immune response

Ruan,

Chen,

Wang

et al. 2024

Poultry Science

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Mechanism of herpesvirus UL24 protein regulating viral immune escape and virulence

Cited by 7 publications

References 169 publications

Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection

Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection

Development of a live attenuated vaccine candidate for equid alphaherpesvirus 1 control: a step towards efficient protection

Duck plague virus UL24 protein initiates K48/K63-linked IRF7 polyubiquitination to antagonize the innate immune response

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