Nuclear sensing of viral DNA, epigenetic regulation of herpes simplex virus infection, and innate immunity

AbstractHerpes simplex virus (HSV) undergoes a lytic infection in epithelial cells and a latent infection in neuronal cells, and epigenetic mechanisms play a major role in the differential gene expression under the two conditions. HSV viron DNA is not associated with histones but is rapidly loaded with heterochromatin upon entry into the cell. Viral proteins promote reversal of the epigenetic silencing in epithelial cells while the viral latency-associated transcript promotes additional heterochromatin in neuronal cells. The cellular sensors that initiate the chromatinization of foreign DNA have not been fully defined. IFI16 and cGAS are both essential for innate sensing of HSV DNA, and new evidence shows how they work together to initiate innate signaling. IFI16 also plays a role in the heterochromatinization of HSV DNA, and this review will examine how IFI16 integrates epigenetic regulation and innate sensing of foreign viral DNA to show how these two responses are related

Owen County Transportation Vulnerability Study

In this session we discuss the Transportation Vulnerability Assessment the Indiana Department of Natural Resources and the Polis Center completed for Owen County, Indiana. The results were presented to state and community officials in a public meeting held on December 7, 2015. A focus analysis of the vulnerable assets will be performed, including developing engineering hydraulic models for the site, flood depth grids, fluvial erosion mapping, and cost estimates for suggested mitigation

Disruption of the UL41 gene in the herpes simplex virus 2 dl5-29 mutant increases its immunogenicity and protective capacity in a murine model of genital herpes

AbstractThe herpes simplex virus 2 dl5-29 replication-defective mutant virus has been shown to induce protective immunity in mice and both prophylactic and therapeutic immunity in guinea pigs. In an attempt to improve the efficacy of dl5-29 we disrupted its UL41 gene, producing the triple mutant virus dl5-29-41L. dl5-29-41L has a decreased ability to inhibit host cell protein synthesis and a reduced cytopathic effect on cultured cells. When used to immunize mice, dl5-29-41L elicited significantly stronger neutralizing antibody responses and significantly stronger CD4+ and CD8+ cellular immune responses than dl5-29. The enhanced immune responses corresponded with increased protective capacity in a murine model of genital herpes. The protective immunity elicited by either virus was very durable, protecting mice for at least 7 months. Furthermore, we show that cell lysate preparations of both viruses were significantly more efficacious than the corresponding extracellular virus preparations

Kinetics of Facultative Heterochromatin and Polycomb Group Protein Association with the Herpes Simplex Viral Genome during Establishment of Latent Infection

ABSTRACT The herpes simplex virus (HSV) genome is associated with heterochromatic histone modifications, including trimethylation of the lysine 27 residue of histone H3 (H3K27me3), during latent infection of neurons. Here we have examined the kinetics of general chromatin and H3K27me3 association with the viral genome during establishment of latent infection. Using both wild-type virus and a mutant virus that is unable to undergo replication in neurons, we found that histone H3 associates with viral gene promoters by 7 days postinfection (dpi). Levels of H3K27me3 were low at 7 dpi but increased dramatically by 14 dpi. Hence, general chromatin association and/or other factors may play a key role(s) in the initial silencing of lytic genes, and H3K27me3 may play a role in further suppression of the genome and/or the maintenance of latency. A component of Polycomb repressive complex 2 (PRC2), which mediates the addition of K27me3 to histone H3 (Suz12), was also recruited by 14 dpi. We have shown previously that the levels of H3K27me3 during latent infection are increased in the presence of the latency-associated transcript (LAT). However, the initial targeting of PRC2 was not found to be dependent on the LAT. We found that a component of the PRC1 complex (Bmi1), which binds to H3K27me3, was not enriched at promoters found previously to be enriched for H3K27me3. Our results are consistent with (i) chromatinization of viral DNA or other mechanisms causing the initial silencing of HSV lytic genes and (ii) facultative heterochromatin maintaining that silencing during latent infection of neurons

Role for A-Type Lamins in Herpesviral DNA Targeting and Heterochromatin Modulation

Posttranslational modification of histones is known to regulate chromatin structure and transcriptional activity, and the nuclear lamina is thought to serve as a site for heterochromatin maintenance and transcriptional silencing. In this report, we show that the nuclear lamina can also play a role in the downregulation of heterochromatin and in gene activation. Herpes simplex virus DNA initiates replication in replication compartments near the inner edge of the nucleus, and histones are excluded from these structures. To define the role of nuclear lamins in HSV replication, we examined HSV infection in wild-type and A-type lamin–deficient (Lmna−/−) murine embryonic fibroblasts (MEFs). In Lmna−/− cells, viral replication compartments are reduced in size and fail to target to the nuclear periphery, as observed in WT cells. Chromatin immunoprecipitation and immunofluorescence studies demonstrate that HSV DNA is associated with increased heterochromatin in Lmna−/− MEFs. These results argue for a functional role for A-type lamins as viral gene expression, DNA replication, and growth are reduced in Lmna−/− MEFs, with the greatest effect on viral replication at low multiplicity of infection. Thus, lamin A/C is required for targeting of the viral genome and the reduction of heterochromatin on viral promoters during lytic infection. The nuclear lamina can serve as a molecular scaffold for DNA genomes and the protein complexes that regulate both euchromatin and heterochromatin histone modifications

Regional variation in suicide rates in Sri Lanka between 1955 and 2011:a spatial and temporal analysis

Abstract Background Between 1955 and 2011 there were marked fluctuations in suicide rates in Sri Lanka; incidence increased six-fold between 1955 and the 1980s, and halved in the early 21st century. Changes in access to highly toxic pesticides are thought to have influenced this pattern. This study investigates variation in suicide rates across Sri Lanka’s 25 districts between 1955 and 2011. We hypothesised that changes in the incidence of suicide would be most marked in rural areas due to the variation in availability of highly toxic pesticides in these locations during this time period. Methods We mapped district-level suicide rates in 1955, 1972, 1980 and 2011. These periods preceded, included and postdated the rapid rise in Sri Lanka’s suicide rates. We investigated the associations between district-level variations in suicide rates and census-derived measures of rurality (population density), unemployment, migration and ethnicity using Spearman’s rank correlation and negative binomial models. Results The rise and fall in suicide rates was concentrated in more rural areas. In 1980, when suicide rates were at their highest, population density was inversely associated with area variation in suicide rates (r = −0.65; p < 0.001), i.e. incidence was highest in rural areas. In contrast the association was weakest in 1950, prior to the rise in pesticide suicides (r = −0.10; p = 0.697). There was no strong evidence that levels of migration or ethnicity were associated with area variations in suicide rates. The relative rates of suicide in the most rural compared to the most urban districts before (1955), during (1980) and after (2011) the rise in highly toxic pesticide availability were 1.1 (95% CI 0.5 to 2.4), 3.7 (2.0 to 6.9) and 2.1 (1.6 to 2.7) respectively. Conclusions The findings provide some support for the hypothesis that changes in access to pesticides contributed to the marked fluctuations in Sri Lanka’s suicide rate, but the impact of other factors cannot be ruled out

Is Google Trends a useful tool for tracking mental and social distress during a public health emergency? A time–series analysis

Background: Google Trends data are increasingly used by researchers as an indicator of population mental health, but few studies have investigated the validity of this approach during a public health emergency.Methods: Relative search volumes (RSV) for the topics depression, anxiety, self-harm, suicide, suicidal ideation, loneliness, and abuse were obtained from Google Trends. We used graphical and time-series approaches to compare daily trends in searches for these topics against population measures of these outcomes recorded using validated self-report scales (PHQ-9; GAD-7; UCLA-3) in a weekly survey (n=~70,000) of the impact COVID-19 on psychological and social experiences in the UK population (12/03/2020 to 21/08/ 2020).Results: Self-reported levels of depression, anxiety, self-harm/suicidal ideation, self-harm, loneliness and abuse decreased during the period studied. There was no evidence of an association between self-reported anxiety, self-harm, abuse and RSV on Google Trends. Trends in Google topic RSV for depression and suicidal ideation were inversely associated with self-reports of these outcomes (p=0.03 and p=0.04 respectively). However, there was statistical and graphical evidence that self-report and Google searches for loneliness (p<0.001) tracked one another. Limitations: No age/sex breakdown of Google Trends data are available. Survey respondents were not representative of the UK population and no pre-pandemic data were available. Conclusion: Google Trends data do not appear to be a useful indicator of changing levels of population mental health during a public health emergency, but may have some value as an indicator of loneliness. Keywords: Mental Health, Pandemic, Suicide, Depression, Loneliness, Anxiety, Domestic violenc

Persistent Elevated Expression of Cytokine Transcripts in Ganglia Latently Infected with Herpes Simplex Virus in the Absence of Ganglionic Replication or Reactivation

AbstractInfection of mouse trigeminal ganglia by herpes simplex virus induces cytokine expression that persists long after infectious virus or viral antigens become undetectable. To examine mechanisms underlying this phenomenon, we used a thymidine kinase mutant, dlsptk, which fails to replicate in ganglia and does not reactivate upon ganglionic explant. Using quantitative reverse transcriptase–polymerase chain reaction assays, we found that levels of interferon-γ and tumor necrosis factor-α transcripts in dlsptk-infected ganglia were lower than those in wild type-infected ganglia, but were significantly (eight- to 10-fold) higher than those in mock-infected ganglia from Day 3 to Day 100 postinfection. We also studied latency-associated transcript (LAT) negative mutants that exhibit increased expression of productive cycle transcripts in ganglia. Ganglia infected with these mutants contained levels of cytokine transcripts similar to those in wild type-infected ganglia; any increases in viral antigen expression mediated by the LAT deletion were not accompanied by increased cytokine expression. Thus, neither viral replication, the ability to reactivate, nor LAT expression in ganglia is required for persistent elevated cytokine expression. The results provide indirect evidence that low-level expression of viral productive cycle genes in neurons can provide signals that elicit cytokine expression