Mutation of UL24 impedes the dissemination of acute herpes simplex virus 1 infection from the cornea to neurons of trigeminal ganglia

Abstract

Herpes simplex virus 1 (human herpesvirus 1) initially infects epithelial cells of the mucosa and then goes on to infect sensory neurons leading ultimately to a latent infection in trigeminal ganglia (TG). UL24 is a core herpesvirus gene that has been identified as a determinant of pathogenesis in several Alphaherpesvirinae, although the underlying mechanisms are unknown. In a mouse model of ocular infection, a UL24-deficient virus exhibited a reduction in viral titres in tear films of 1 log 10 , whilst titres in TG are often below the level of detection. Moreover, the efficiency of reactivation from latency was also severely reduced. Herein, we investigated how UL24 contributed to acute infection of TG. Our results comparing the impact of UL24 on viral titres in eye tissue versus in tear films did not reveal a general defect in virus release from the cornea. We also found that the impairment of replication seen in mouse primary embryonic neurons with a UL24-deficient virus was not more severe than that observed in an epithelial cell line. Rather, in situ histological analyses revealed that infection with a UL24-deficient virus led to a significant reduction in the number of acutely infected neurons at 3 days post-infection (p.i.). Moreover, there was a significant reduction in the number of neurons positive for viral DNA at 2 days p.i. for the UL24-deficient virus as compared with that observed for WT or a rescue virus. Our results supported a model whereby UL24 functions in the dissemination of acute infection from the cornea to neurons in TG.

Genotypic and Phenotypic Diversity of Herpes Simplex Virus 2 within the Infected Neonatal Population

“…Conversely, the UL24 V93A variant, which was observed only in SEM-derived isolates and is relatively rare among adult HSV-2 isolates as well, could be a potential example of a spread-limiting variation. UL24 function is required to disperse nucleolin during lytic HSV-1 infection (90, 91), and mutation of UL24 has been associated with a loss of neuroinvasion in animal models (75–77). Further research will be needed to build stronger genetic associations with additional neonatal isolates and to expand upon prior studies by testing these specific genetic variations in animal models.…”

Genotypic and phenotypic diversity within the neonatal HSV-2 population

“…UL24-null mutants form small plaques in culture (55), and result in decreased neuronal infection as compared to wild-type virus following ocular challenge in mice (60)(61)(62). A variant in UL20 (P129L) was found to be uniquely associated with both isolates causing CNS disease in the context of disseminated infection (DISS14 and DISS29).…”

“…http://dx.doi.org/10.1101/262055 doi: bioRxiv preprint first posted online Feb. 8, 2018; these coding variations that correlate with neonatal CNS disease phenotypes impact viral proteins known to modulate cell-to-cell spread (52)(53)(54)(55)(56) and/or contribute to neurovirulence in mouse models of CNS infection (54,(57)(58)(59)(60)(61)(62)(63) (Figure 7 and Table S2), however, their role in human disease has not been described. Additional variants in proteins not known to be associated with neurovirulence were also found to be associated with neonatal CNS disease.…”

G-Quadruplexes: More Than Just a Kink in Microbial Genomes

“…In HHVs, putative promoter regions have higher G4 densities than the coding regions, suggesting a regulatory role for G4s in gene expression [44]. G4s in the promoters of UL2, UL24, and K18, all of which have previously established roles in virulence, were found to be negative regulators of promoter activity ( Figure 4A) [45][46][47][48]. Herpesvirus genes are divided into immediate early (IE), early (E), and late (L) based on the time at which they are expressed in the replication cycle.…”