Quantitative Trait Locus Based Virulence Determinant Mapping of the HSV-1 Genome in Murine Ocular Infection: Genes Involved in Viral Regulatory and Innate Immune Networks Contribute to Virulence

Kolb, Aaron W.; Lee, Kyubin; Larsen, Inna V.; Craven, Mark; Brandt, Curtis R.

doi:10.1371/journal.ppat.1005499

Cited by 36 publications

(44 citation statements)

References 72 publications

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“…ICP27 affects pre-mRNA processing of >200 genes in ICP27-transfected cells involved in important cellular pathways, implying a broad program of ICP27-mediated cellular modification to favor the virus, and helping to explain the observation that ICP27 expression is toxic to the cell and is both required for efficient virus growth and for severe symptoms (43)(44)(45). Of the affected genes, >30, including PML, STING, TRAF6, PPP6C, MAP3K7, FBXW11, IFNAR2, NFKB1, RELA, and CREBP, are related to innate immunity pathways, which is consistent with ICP27's known role in regulating innate immunity (46)(47)(48)(49).…”

Section: Splicing Inhibition Mediated By Icp27 and Cytosine-rich Sequmentioning

confidence: 99%

Herpes simplex virus ICP27 regulates alternative pre-mRNA polyadenylation and splicing in a sequence-dependent manner

Tang

Patel

Krause

2016

Proc. Natl. Acad. Sci. U.S.A.

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The herpes simplex virus (HSV) infected cell culture polypeptide 27 (ICP27) protein is essential for virus infection of cells. Recent studies suggested that ICP27 inhibits splicing in a gene-specific manner via an unknown mechanism. Here, RNA-sequencing revealed that ICP27 not only inhibits splicing of certain introns in <1% of cellular genes, but also can promote use of alternative 5′ splice sites. In addition, ICP27 induced expression of pre-mRNAs prematurely cleaved and polyadenylated from cryptic polyadenylation signals (PAS) located in intron 1 or 2 of ∼1% of cellular genes. These previously undescribed prematurely cleaved and polyadenylated pre-mRNAs, some of which contain novel ORFs, were typically intronless, <2 Kb in length, expressed early during viral infection, and efficiently exported to cytoplasm. Sequence analysis revealed that ICP27-targeted genes are GC-rich (as are HSV genes), contain cytosine-rich sequences near the 5′ splice site, and have suboptimal splice sites in the impacted intron, suggesting that a common mechanism is shared between ICP27-mediated alternative polyadenylation and splicing. Optimization of splice site sequences or mutation of nearby cytosines eliminated ICP27-mediated splicing inhibition, and introduction of C-rich sequences to an ICP27-insensitive splicing reporter conferred this phenotype, supporting the inference that specific gene sequences confer susceptibility to ICP27. Although HSV is the first virus and ICP27 is the first viral protein shown to activate cryptic PASs in introns, we suspect that other viruses and cellular genes also encode this function. (ICP27), an immediate early (IE) gene (among those first expressed after virus enters the cells) that is required for expression of some early and late viral genes as well as for virus growth, is highly conserved between HSV-1 and -2, two closely related neurotropic herpesviruses (1). ICP27 has a role in transcriptional regulation through association with the C-terminal domain of RNA polymerase II (2, 3), forms homodimers (4, 5), interacts with U1 small nuclear ribonucleoprotein (snRNP) through its C-terminal domain, and colocalizes with U1 and U2 snRNPs (6, 7). It also interacts with splicing factors such as SRSF3, SRSF1, SRSF7, and SRSF2 (8-11), and is involved in nuclear export of some viral transcripts (12, 13). The role of ICP27 in regulating pre-mRNA splicing remains controversial. Early studies indicated that, in an in vitro pre-mRNA splicing system, ICP27 may nonspecifically inhibit host pre-mRNA splicing, impairing spliceosome assembly as a result of interaction with SR protein kinase 1 (SRPK1) through ICP27's N-terminal RGG RNA-binding motif and/or interaction with spliceosome-association protein 145 (SAP145 or SF3B2) through ICP27's C-terminal domain (8, 11). A recent communication reported that HSV-1 does not inhibit cotranscriptional splicing and proposed that previous reports of ICP27-induced splicing inhibition were artifacts, due to misinterpretation of run-on transcription (14). Indeed, splicing of ...

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Section: Splicing Inhibition Mediated By Icp27 and Cytosine-rich Sequmentioning

confidence: 99%

Herpes simplex virus ICP27 regulates alternative pre-mRNA polyadenylation and splicing in a sequence-dependent manner

Tang

Patel

Krause

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Multiple studies, beginning in the 1950s, have reported HSV-1 recombinants with a wide range of plaque and virulence phenotypes (13)(14)(15)(16), suggesting epistatic interactions are involved. Epistatic interactions between host genes affecting susceptibility to HSV-1 latency have been identified (17).…”

mentioning

confidence: 99%

“…Several host gene mapping studies in mice have identified factors influencing the severity of general clinical disease (35), resistance and reactivation (25), mortality (12), encephalitis (36,37), and viral spread to the brain (38). Recently, quantitative trait locus (QTL) analysis has been used to map replication-associated loci in tomato yellow leaf curl virus (39), and we have described an alternative approach to investigate the genetics of viral virulence in ocular infections (16). We performed QTL-based analysis of the HSV-1 genome, which we termed virulence QTL mapping (vQTLmap), to identify viral genes involved in blepharitis and stromal keratitis (corneal clouding).…”

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confidence: 99%

Mapping Murine Corneal Neovascularization and Weight Loss Virulence Determinants in the Herpes Simplex Virus 1 Genome and the Detection of an Epistatic Interaction between the UL and IRS/US Regions

Lee

Kolb

Larsen

et al. 2016

J Virol

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Herpes simplex virus 1 (HSV-1) most commonly causes recrudescent labial ulcers; however, it is also the leading cause of infectious blindness in developed countries. Previous research in animal models has demonstrated that the severity of HSV-1 ocular disease is influenced by three main factors: host innate immunity, host immune response, and viral strain. We have previously shown that mixed infection with two avirulent HSV-1 strains (OD4 and CJ994) results in recombinants with a wide range of ocular disease phenotype severity. Recently, we developed a quantitative trait locus (QTL)-based computational approach (vQTLmap) to identify viral single nucleotide polymorphisms (SNPs) predicted to influence the severity of the ocular disease phenotypes. We have now applied vQTLmap to identify HSV-1 SNPs associated with corneal neovascularization and mean peak percentage weight loss (MPWL) using 65 HSV-1 OD4-CJ994 recombinants. The vQTLmap analysis using Random Forest for neovascularization identified phenotypically meaningful nonsynonymous SNPs in the ICP4, UL41 (VHS), UL42, UL46 (VP11/ 12), UL47 (VP13/14), UL48 (VP22), US3, US4 (gG), US6 (gD), and US7 (gI) coding regions. The ICP4 gene was previously identified as a corneal neovascularization determinant, validating the vQTLmap method. Further analysis detected an epistatic interaction for neovascularization between a segment of the unique long (UL) region and a segment of the inverted repeat short (IRS)/unique short (US) region. Ridge regression was used to identify MPWL-associated nonsynonymous SNPs in the UL1 (gL), UL2, UL4, UL49 (VP22), UL50, and ICP4 coding regions. The data provide additional insights into virulence gene and epistatic interaction discovery in HSV-1. IMPORTANCEHerpes simplex virus 1 (HSV-1) typically causes recurrent cold sores; however, it is also the leading source of infectious blindness in developed countries. Corneal neovascularization is critical for the progression of blinding ocular disease, and weight loss is a measure of infection severity. Previous HSV-1 animal virulence studies have shown that the severity of ocular disease is partially due to the viral strain. In the current study, we used a recently described computational quantitative trait locus (QTL) approach in conjunction with 65 HSV-1 recombinants to identify viral single nucleotide polymorphisms (SNPs) involved in neovascularization and weight loss. Neovascularization SNPs were identified in the ICP4, VHS, UL42, VP11/12, VP13/14, VP22, gG, US3, gD, and gI genes. Further analysis revealed an epistatic interaction between the UL and US regions. MPWL-associated SNPs were detected in the UL1 (gL), UL2, UL4, VP22, UL50, and ICP4 genes. This approach will facilitate future HSV virulence studies. Herpes simplex virus 1 (HSV-1) is most commonly responsible for recurrent vesicular lesions of the oral mucosa; however, HSV-1 is increasingly found in genital infections, and it is the leading cause of infectious blindness and sporadic encephalitis in developed countries (1-4). The ...

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“…Moreover, enzymes involved in the oxidative stress response were increased, probably due to a higher respiration rate leading to the elevated reactive oxygen species (ROS) production (15). Since thermotolerance is most probably polygenic, there is the possibility that the other genes contributing to high temperature growth would still be involved in pathways that affect virulence (16).…”

Section: Thermotolerancementioning

confidence: 99%

Molecular Insights into Pathogenesis and Infection with Aspergillus fumigatus

Ghazaei¹

2017

MJMS

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The virulence of fungi is dependent on multiple factors, including the immune status of patients and biological features of fungi. In particular, the virulence of Aspergillus fumigatus is due to the complex interaction among various molecules involved in thermotolerance (such as ribosomal biogenesis proteins, α-mannosyltransferase and heat shock proteins), pigment production (DHN-melanin), immune evasion (like melanin and hydrophobin) and nutrient uptake (such as siderophores and zinc transporters). Other molecules also play important roles in the virulence of A. fumigatus, including cell wall components and those which maintain its integrity (for instance β-1-3 glucan, α-1-3 glucan, chitin, galactomannan and mannoproteins) and adhesion (such as hydrophobins), as well as various hydrolytic enzymes (such as serine and aspartic protease, phospholipases, metalloproteinase and dipeptidyl peptidases). Signalling molecules (including G-protein, cAMP, Ras protein and calcineurin) also increase the virulence through altering the metabolic response to stress conditions and toxins (such as gliotoxin, fumitremorgins, fumagatin and helvolic acid).

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Quantitative Trait Locus Based Virulence Determinant Mapping of the HSV-1 Genome in Murine Ocular Infection: Genes Involved in Viral Regulatory and Innate Immune Networks Contribute to Virulence

Cited by 36 publications

References 72 publications

Herpes simplex virus ICP27 regulates alternative pre-mRNA polyadenylation and splicing in a sequence-dependent manner

Herpes simplex virus ICP27 regulates alternative pre-mRNA polyadenylation and splicing in a sequence-dependent manner

Mapping Murine Corneal Neovascularization and Weight Loss Virulence Determinants in the Herpes Simplex Virus 1 Genome and the Detection of an Epistatic Interaction between the UL and IRS/US Regions

Molecular Insights into Pathogenesis and Infection with Aspergillus fumigatus

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