Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Virology Journal
Published in: Virology Journal 1/2020

Open Access 01-12-2020 | Research

Longitudinal transcriptomic characterization of viral genes in HSV-1 infected tree shrew trigeminal ganglia

Authors: Erlin Wang, Yunshuang Ye, Ke Zhang, Jinlong Yang, Daohua Gong, Jianhua Zhang, Renjun Hong, Huan Zhang, Lihong Li, Guijun Chen, Liping Yang, Jianmei Liu, Hanyu Cao, Ting Du, Nigel W. Fraser, Le Cheng, Xia Cao, Jumin Zhou

Published in: Virology Journal | Issue 1/2020

Login to get access

Abstract

Background

Following acute infection, Herpes Simplex virus-1 (HSV-1) establishes lifelong latency and recurrent reactivation in the sensory neurons of trigeminal ganglia (TG). Infected tree shrew differs from mouse and show characteristics similar to human infection. A detailed transcriptomic analysis of the tree shrew model could provide mechanistic insights into HSV-1 infection in humans.

Methods

We sequenced the transcriptome of infected TGs from tree shrews and mice, and 4 human donors, then examined viral genes expression up to 58 days in infected TGs from mouse and tree shrew, and compare the latency data with that in human TGs.

Results

Here, we found that all HSV-1 genes could be detected in mouse TGs during acute infection, but 22 viral genes necessary for viral transcription, replication and viral maturation were not expressed in tree shrew TGs during this stage. Importantly, during latency, we found that LAT could be detected both in mouse and tree shrew, but the latter also has an ICP0 transcript signal absent in mouse but present in human samples. Importantly, we observed that infected human and tree shrew TGs have a more similar LAT region transcription peak. More importantly, we observed that HSV-1 spontaneously reactivates from latently infected tree shrews with relatively high efficiency.

Conclusions

These results represent the first longitudinal transcriptomic characterization of HSV-1 infection in during acute, latency and recurrent phases, and revealed that tree shrew infection has important similar features with human infection.
Appendix
Available only for authorised users
Literature
1.
Roizman B, Knipe DM, Whitely R: Herpes Simplex Viruses. In Fields Virology (Knipe, Fields Virology)-2 Volume Set). Edited by David M K, Peter H; 2013: 1823-1897.
2.
Valyi-Nagy T, Deshmane S, Dillner A, Fraser NW. Induction of cellular transcription factors in trigeminal ganglia of mice by corneal scarification, herpes simplex virus type 1 infection, and explantation of trigeminal ganglia. J Virol. 1991;65:4142–52.PubMedPubMedCentral
3.
Stevens JG, Cook ML. Latent herpes simplex virus in spinal ganglia of mice. Science. 1971;173:843–5.PubMed
4.
Cook ML, Bastone VB, Stevens JG. Evidence that neurons harbor latent herpes simplex virus. Infect Immun. 1974;9:946–51.PubMedPubMedCentral
5.
Li L, Li Z, Wang E, Yang R, Xiao Y, Han H, Lang F, Li X, Xia Y, Gao F, et al. Herpes simplex virus 1 infection of tree shrews differs from that of mice in the severity of acute infection and viral transcription in the peripheral nervous system. J Virol. 2015;90:790–804.PubMedPubMedCentral
6.
Honess RW, Roizman B. Regulation of herpesvirus macromolecular synthesis: sequential transition of polypeptide synthesis requires functional viral polypeptides. Proc Natl Acad Sci U S A. 1975;72:1276–80.PubMedPubMedCentral
7.
Honess RW, Roizman B. Regulation of herpesvirus macromolecular synthesis. I. Cascade regulation of the synthesis of three groups of viral proteins. J Virol. 1974;14:8–19.PubMedPubMedCentral
8.
Umbach JL, Kramer MF, Jurak I, Karnowski HW, Coen DM, Cullen BR. MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature. 2008;454:780–3.PubMedPubMedCentral
9.
Kramer MF, Jurak I, Pesola JM, Boissel S, Knipe DM, Coen DM. Herpes simplex virus 1 microRNAs expressed abundantly during latent infection are not essential for latency in mouse trigeminal ganglia. Virology. 2011;417:239–47.PubMed
10.
Stevens JG, Wagner EK, Devi-Rao GB, Cook ML, Feldman LT. RNA complementary to a herpesvirus alpha gene mRNA is prominent in latently infected neurons. Science. 1987;235:1056–9.PubMed
11.
Shen W, Sa e Silva M, Jaber T, Vitvitskaia O, Li S, Henderson G, Jones C: Two small RNAs encoded within the first 1.5 kilobases of the herpes simplex virus type 1 latency-associated transcript can inhibit productive infection and cooperate to inhibit apoptosis. J Virol 2009, 83:9131–9139.
12.
Rowe AM, St Leger AJ, Jeon S, Dhaliwal DK, Knickelbein JE, Hendricks RL. Herpes keratitis. Prog Retin Eye Res. 2013;32:88–101.PubMed
13.
Fatahzadeh M, Schwartz RA. Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management. J Am Acad Dermatol. 2007;57:737–63 quiz 764-736.PubMed
14.
Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, Gyorgy B, Breakefield XO, Tanzi RE, Moir RD. Alzheimer's disease-associated beta-amyloid is rapidly seeded by Herpesviridae to protect against brain infection. Neuron. 2018;99:56–63 e53.PubMedPubMedCentral
15.
Ezzat K, Pernemalm M, Palsson S, Roberts TC, Jarver P, Dondalska A, Bestas B, Sobkowiak MJ, Levanen B, Skold M, et al. The viral protein corona directs viral pathogenesis and amyloid aggregation. Nat Commun. 2019;10:2331.PubMedPubMedCentral
16.
Darai G, Schwaier A, Komitowski D, Munk K. Experimental infection of Tupaia belangeri (tree shrews) with herpes simplex virus types 1 and 2. J Infect Dis. 1978;137:221–6.PubMed
17.
Darai G, Koch HG, Flugel RM, Gelderblom H. Tree shrew (Tupaia) herpesviruses. Dev Biol Stand. 1982;52:39–51.PubMed
18.
Fan Y, Huang ZY, Cao CC, Chen CS, Chen YX, Fan DD, He J, Hou HL, Hu L, Hu XT, et al. Genome of the Chinese tree shrew. Nat Commun. 2013;4:1426.PubMed
19.
Li L, Li Z, Li X, Wang E, Lang F, Xia Y, Fraser NW, Gao F, Zhou J. Reactivation of HSV-1 following explant of tree shrew brain. J Neuro-Oncol. 2016;22:293–306.
20.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.PubMedPubMedCentral
21.
22.
Watson RJ, Clements JB. A herpes simplex virus type 1 function continuously required for early and late virus RNA synthesis. Nature. 1980;285:329–30.PubMed
23.
DeLuca NA, Schaffer PA. Activation of immediate-early, early, and late promoters by temperature-sensitive and wild-type forms of herpes simplex virus type 1 protein ICP4. Mol Cell Biol. 1985;5:1997–2008.PubMedPubMedCentral
24.
Sampath P, Deluca NA. Binding of ICP4, TATA-binding protein, and RNA polymerase II to herpes simplex virus type 1 immediate-early, early, and late promoters in virus-infected cells. J Virol. 2008;82:2339–49.PubMed
25.
Dremel SE, DeLuca NA. Genome replication affects transcription factor binding mediating the cascade of herpes simplex virus transcription. Proc Natl Acad Sci U S A. 2019;116:3734–9.PubMedPubMedCentral
26.
DeLuca NA, Courtney MA, Schaffer PA. Temperature-sensitive mutants in herpes simplex virus type 1 ICP4 permissive for early gene expression. J Virol. 1984;52:767–76.PubMedPubMedCentral
27.
Wang L, Feng Z, Wang X, Wang X, Zhang X. DEGseq: an R package for identifying differentially expressed genes from RNA-seq data. Bioinformatics. 2010;26:136–8.PubMed
28.
Farrell MJ, Dobson AT, Feldman LT. Herpes simplex virus latency-associated transcript is a stable intron. Proc Natl Acad Sci U S A. 1991;88:790–4.PubMedPubMedCentral
29.
Krummenacher C, Zabolotny JM, Fraser NW. Selection of a nonconsensus branch point is influenced by an RNA stem-loop structure and is important to confer stability to the herpes simplex virus 2-kilobase latency-associated transcript. J Virol. 1997;71:5849–60.PubMedPubMedCentral
30.
Peng W, Vitvitskaia O, Carpenter D, Wechsler SL, Jones C. Identification of two small RNAs within the first 1.5-kb of the herpes simplex virus type 1-encoded latency-associated transcript. J Neuro-Oncol. 2008;14:41–52.
31.
Feldman LT, Ellison AR, Voytek CC, Yang L, Krause P, Margolis TP. Spontaneous molecular reactivation of herpes simplex virus type 1 latency in mice. Proc Natl Acad Sci U S A. 2002;99:978–83.PubMedPubMedCentral
32.
Margolis TP, Elfman FL, Leib D, Pakpour N, Apakupakul K, Imai Y, Voytek C. Spontaneous reactivation of herpes simplex virus type 1 in latently infected murine sensory ganglia. J Virol. 2007;81:11069–74.PubMedPubMedCentral
33.
Wagner EK, Flanagan WM, Devi-Rao G, Zhang YF, Hill JM, Anderson KP, Stevens JG. The herpes simplex virus latency-associated transcript is spliced during the latent phase of infection. J Virol. 1988;62:4577–85.PubMedPubMedCentral
34.
Wagner EK, Devi-Rao G, Feldman LT, Dobson AT, Zhang YF, Flanagan WM, Stevens JG. Physical characterization of the herpes simplex virus latency-associated transcript in neurons. J Virol. 1988;62:1194–202.PubMedPubMedCentral
35.
Thompson RL, Sawtell NM. The herpes simplex virus type 1 latency-associated transcript gene regulates the establishment of latency. J Virol. 1997;71:5432–40.PubMedPubMedCentral
36.
Perng GC, Slanina SM, Yukht A, Ghiasi H, Nesburn AB, Wechsler SL. The latency-associated transcript gene enhances establishment of herpes simplex virus type 1 latency in rabbits. J Virol. 2000;74:1885–91.PubMedPubMedCentral
37.
Ahmed M, Lock M, Miller CG, Fraser NW. Regions of the herpes simplex virus type 1 latency-associated transcript that protect cells from apoptosis in vitro and protect neuronal cells in vivo. J Virol. 2002;76:717–29.PubMedPubMedCentral
38.
Carpenter D, Hsiang C, Jiang X, Osorio N, BenMohamed L, Jones C, Wechsler SL. The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) protects cells against cold-shock-induced apoptosis by maintaining phosphorylation of protein kinase B (AKT). J Neuro-Oncol. 2015;21:568–75.
39.
Tormanen K, Allen S, Mott KR, Ghiasi H. The Latency-Associated Transcript Inhibits Apoptosis via Downregulation of Components of the Type I Interferon Pathway during Latent Herpes Simplex Virus 1 Ocular Infection. J Virol. 2019;93(10):e00103–19.
40.
Kent JR, Kang W, Miller CG, Fraser NW. Herpes simplex virus latency-associated transcript gene function. J Neuro-Oncol. 2003;9:285–90.
41.
Nicoll MP, Hann W, Shivkumar M, Harman LE, Connor V, Coleman HM, Proenca JT, Efstathiou S. The HSV-1 latency-associated transcript functions to repress latent phase lytic gene expression and suppress virus reactivation from latently infected neurons. PLoS Pathog. 2016;12:e1005539.PubMedPubMedCentral
42.
Leib DA, Bogard CL, Kosz-Vnenchak M, Hicks KA, Coen DM, Knipe DM, Schaffer PA. A deletion mutant of the latency-associated transcript of herpes simplex virus type 1 reactivates from the latent state with reduced frequency. J Virol. 1989;63:2893–900.PubMedPubMedCentral
43.
Leib DA, Nadeau KC, Rundle SA, Schaffer PA. The promoter of the latency-associated transcripts of herpes simplex virus type 1 contains a functional cAMP-response element: role of the latency-associated transcripts and cAMP in reactivation of viral latency. Proc Natl Acad Sci U S A. 1991;88:48–52.PubMedPubMedCentral
44.
Mador N, Braun E, Haim H, Ariel I, Panet A, Steiner I. Transgenic mouse with the herpes simplex virus type 1 latency-associated gene: expression and function of the transgene. J Virol. 2003;77:12421–9.PubMedPubMedCentral
45.
Trousdale MD, Steiner I, Spivack JG, Deshmane SL, Brown SM, MacLean AR, Subak-Sharpe JH, Fraser NW. In vivo and in vitro reactivation impairment of a herpes simplex virus type 1 latency-associated transcript variant in a rabbit eye model. J Virol. 1991;65:6989–93.PubMedPubMedCentral
46.
Bloom DC, Devi-Rao GB, Hill JM, Stevens JG, Wagner EK. Molecular analysis of herpes simplex virus type 1 during epinephrine-induced reactivation of latently infected rabbits in vivo. J Virol. 1994;68:1283–92.PubMedPubMedCentral
47.
Perng GC, Dunkel EC, Geary PA, Slanina SM, Ghiasi H, Kaiwar R, Nesburn AB, Wechsler SL. The latency-associated transcript gene of herpes simplex virus type 1 (HSV-1) is required for efficient in vivo spontaneous reactivation of HSV-1 from latency. J Virol. 1994;68:8045–55.PubMedPubMedCentral
48.
Perng GC, Ghiasi H, Slanina SM, Nesburn AB, Wechsler SL. The spontaneous reactivation function of the herpes simplex virus type 1 LAT gene resides completely within the first 1.5 kilobases of the 8.3-kilobase primary transcript. J Virol. 1996;70:976–84.PubMedPubMedCentral
49.
Watson ZL, Washington SD, Phelan DM, Lewin AS, Tuli SS, Schultz GS, Neumann DM, Bloom DC. In Vivo Knockdown of the Herpes Simplex Virus 1 Latency-Associated Transcript Reduces Reactivation from Latency. J Virol. 2018;92(16):e00812–18.
50.
Hill JM, Nolan NM, McFerrin HE, Clement C, Foster TP, Halford WP, Kousoulas KG, Lukiw WJ, Thompson HW, Stern EM, Bhattacharjee PS. HSV-1 latent rabbits shed viral DNA into their saliva. Virol J. 2012;9:221.PubMedPubMedCentral
51.
Hill JM, Sedarati F, Javier RT, Wagner EK, Stevens JG. Herpes simplex virus latent phase transcription facilitates in vivo reactivation. Virology. 1990;174:117–25.PubMed
52.
Jarman RG, Loutsch JM, Devi-Rao GB, Marquart ME, Banaszak MP, Zheng X, Hill JM, Wagner EK, Bloom DC. The region of the HSV-1 latency-associated transcript required for epinephrine-induced reactivation in the rabbit does not include the 2.0-kb intron. Virology. 2002;292:59–69.PubMed
53.
Bloom DC, Hill JM, Devi-Rao G, Wagner EK, Feldman LT, Stevens JG. A 348-base-pair region in the latency-associated transcript facilitates herpes simplex virus type 1 reactivation. J Virol. 1996;70:2449–59.PubMedPubMedCentral
54.
Kang W, Mukerjee R, Gartner JJ, Hatzigeorgiou AG, Sandri-Goldin RM, Fraser NW. Characterization of a spliced exon product of herpes simplex type-1 latency-associated transcript in productively infected cells. Virology. 2006;356:106–14.PubMed
55.
Devi-Rao GB, Goodart SA, Hecht LM, Rochford R, Rice MK, Wagner EK. Relationship between polyadenylated and nonpolyadenylated herpes simplex virus type 1 latency-associated transcripts. J Virol. 1991;65:2179–90.PubMedPubMedCentral
56.
Zwaagstra JC, Ghiasi H, Slanina SM, Nesburn AB, Wheatley SC, Lillycrop K, Wood J, Latchman DS, Patel K, Wechsler SL. Activity of herpes simplex virus type 1 latency-associated transcript (LAT) promoter in neuron-derived cells: evidence for neuron specificity and for a large LAT transcript. J Virol. 1990;64:5019–28.PubMedPubMedCentral
57.
Mitchell WJ, Lirette RP, Fraser NW. Mapping of low abundance latency-associated RNA in the trigeminal ganglia of mice latently infected with herpes simplex virus type 1. J Gen Virol. 1990;71(Pt 1):125–32.PubMed
58.
Chen SH, Lee LY, Garber DA, Schaffer PA, Knipe DM, Coen DM. Neither LAT nor open reading frame P mutations increase expression of spliced or intron-containing ICP0 transcripts in mouse ganglia latently infected with herpes simplex virus. J Virol. 2002;76:4764–72.PubMedPubMedCentral
59.
Maillet S, Naas T, Crepin S, Roque-Afonso AM, Lafay F, Efstathiou S, Labetoulle M. Herpes simplex virus type 1 latently infected neurons differentially express latency-associated and ICP0 transcripts. J Virol. 2006;80:9310–21.PubMedPubMedCentral
60.
Chen Q, Lin L, Smith S, Huang J, Berger SL, Zhou J. CTCF-dependent chromatin boundary element between the latency-associated transcript and ICP0 promoters in the herpes simplex virus type 1 genome. J Virol. 2007;81:5192–201.PubMedPubMedCentral
61.
Beishline K, Vladimirova O, Tutton S, Wang Z, Deng Z, Lieberman PM. CTCF driven TERRA transcription facilitates completion of telomere DNA replication. Nat Commun. 2017;8:2114.PubMedPubMedCentral
62.
Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12:357–60.PubMedPubMedCentral
63.
Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.PubMed
64.
Liao Y, Smyth GK, Shi W. The subread aligner: fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Res. 2013;41:e108.PubMedPubMedCentral
65.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 2001;25:402–8.PubMed
66.
Wang Y, Song F, Zhu J, Zhang S, Yang Y, Chen T, Tang B, Dong L, Ding N, Zhang Q, et al. GSA: genome sequence archive<sup/>. Genomics Proteomics Bioinformatics. 2017;15:14–8.PubMedPubMedCentral
67.
Members BIGDC. The BIG data center: from deposition to integration to translation. Nucleic Acids Res. 2017;45:D18–24.
68.
Council. NR. Guide for the care and use of laboratory animals. Washington, DC: National Academy Press; 1996.
Metadata
Title
Longitudinal transcriptomic characterization of viral genes in HSV-1 infected tree shrew trigeminal ganglia
Authors
Erlin Wang
Yunshuang Ye
Ke Zhang
Jinlong Yang
Daohua Gong
Jianhua Zhang
Renjun Hong
Huan Zhang
Lihong Li
Guijun Chen
Liping Yang
Jianmei Liu
Hanyu Cao
Ting Du
Nigel W. Fraser
Le Cheng
Xia Cao
Jumin Zhou
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Virology Journal / Issue 1/2020
Electronic ISSN: 1743-422X
DOI
https://doi.org/10.1186/s12985-020-01344-8

Other articles of this Issue 1/2020

Virology Journal 1/2020 Go to the issue

Research

Effective inactivation of Nipah virus in serum samples for safe processing in low-containment laboratories

Research

Viral metagenomic analysis of chickens with runting-stunting syndrome in the Republic of Korea

Short report

Comparative neutralizing potencies of antibodies suggest conservation as well as mechanistic differences in human cytomegalovirus entry into epithelial and endothelial cells

Research

Assessment of a multiplex PCR and Nanopore-based method for dengue virus sequencing in Indonesia

Research

Identification of protein inhibitor of activated STAT 4, a novel host interacting partner that involved in bovine viral diarrhea virus growth

Research

The USP18 cysteine protease promotes HBV production independent of its protease activity

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24 to hear Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits