The latency-associated transcript locus of herpes simplex virus 1 is a virulence determinant in human skin

Autor: Phillip Sung, Ann M. Arvin, Leigh Zerboni, Dongmei Liu, Andrew J. Davison, Emilia A. H. Vanni, Jennifer F. Moffat, Marvin Sommer, Joseph W. Foley
Jazyk: angličtina
Rok vydání: 2020
Předmět:
viruses
Human skin
Pathogenesis
Herpesvirus 1
Human
Skin infection
Pathology and Laboratory Medicine
medicine.disease_cause
Mice
Medical Conditions
Gene expression
Medicine and Health Sciences
Biology (General)
Skin
Viral Genomics
0303 health sciences
Virulence
integumentary system
Genomics
Infectious Diseases
Lytic cycle
Medical Microbiology
Viral Pathogens
Viruses
Heterografts
Pathogens
Anatomy
Integumentary System
Research Article
Skin Infections
Virulence Factors
QH301-705.5
Immunology
Locus (genetics)
Dermatology
Microbial Genomics
Biology
Genome Complexity
Skin Diseases
Microbiology
03 medical and health sciences
Virology
Genetics
medicine
Animals
Humans
Microbial Pathogens
Molecular Biology
030304 developmental biology
030306 microbiology
Organisms
Intron
Biology and Life Sciences
Computational Biology
Herpes Simplex
RC581-607
medicine.disease
Introns
Viral Replication
MicroRNAs
Herpes simplex virus
nervous system
Genetic Loci
Parasitology
Immunologic diseases. Allergy
Zdroj: PLoS Pathogens, Vol 16, Iss 12, p e1009166 (2020)
PLoS Pathogens
ISSN: 1553-7374
1553-7366
Popis: Herpes simplex virus 1 (HSV-1) infects skin and mucosal epithelial cells and then travels along axons to establish latency in the neurones of sensory ganglia. Although viral gene expression is restricted during latency, the latency-associated transcript (LAT) locus encodes many RNAs, including a 2 kb intron known as the hallmark of HSV-1 latency. Here, we studied HSV-1 infection and the role of the LAT locus in human skin xenografts in vivo and in cultured explants. We sequenced the genomes of our stock of HSV-1 strain 17syn+ and seven derived viruses and found nonsynonymous mutations in many viral proteins that had no impact on skin infection. In contrast, deletions in the LAT locus severely impaired HSV-1 replication and lesion formation in skin. However, skin replication was not affected by impaired intron splicing. Moreover, although the LAT locus has been implicated in regulating gene expression in neurones, we observed only small changes in transcript levels that were unrelated to the growth defect in skin, suggesting that its functions in skin may be different from those in neurones. Thus, although the LAT locus was previously thought to be dispensable for lytic infection, we show that it is a determinant of HSV-1 virulence during lytic infection of human skin.
Author summary Herpes simplex virus type 1 (HSV-1) infects and destroys the outer layer of skin cells, producing lesions known as cold sores. Although these lesions heal, the virus persists in the host for the lifetime and can reactivate to cause new lesions. This is possible because the virus enters the axons of neurones in the skin and moves to their cell bodies located in spinal or cranial nerve bundles called ganglia, where the virus becomes dormant (latent). The most abundant viral RNAs expressed during this state are the latency associated transcripts (LATs), which have been considered a hallmark of HSV-1 latency. Here, we studied HSV-1 infection and spread in human skin. Unexpectedly, we found that the LAT locus is necessary for lesion formation in skin. HSV-1 viruses that were genetically mutated to delete the start of the locus could not spread in skin, whereas viruses with many other genetic mutations had this capacity. Our results suggest that an antiviral drug that inhibits transcripts from this region of the viral genome could block viral spread in skin, or a vaccine could possibly be produced by genetically modifying the virus at the LAT locus and by doing so, limit the virus’ ability become latent in neurones.
Databáze: OpenAIRE
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