Host chromatin assembly can function as a barrier to viral infection. Epstein-Barr virus (EBV) establishes latent infection as
Although ICP4 is the only essential transcription activator of herpes simplex virus 1 (HSV-1), its mechanisms of action are still only partially understood. We and others propose a model in which HSV-1 genomes are chromatinized as a cellular defense to inhibit HSV-1 transcription. To counteract silencing, HSV-1 would have evolved proteins that prevent or destabilize chromatinization to activate transcription. These proteins should act as HSV-1 transcription activators. We have shown that HSV-1 genomes are organized in highly dynamic nucleosomes and that histone dynamics increase in cells infected with wild type HSV-1. We now show that whereas HSV-1 mutants encoding no functional ICP0 or VP16 partially enhanced histone dynamics, mutants encoding no functional ICP4 did so only minimally. Transient expression of ICP4 was sufficient to enhance histone dynamics in the absence of other HSV-1 proteins or HSV-1 DNA. The dynamics of H3.1 were increased in cells expressing ICP4 to a greater extent than those of H3.3. The dynamics of H2B were increased in cells expressing ICP4, whereas those of canonical H2A were not. ICP4 preferentially targets silencing H3.1 and may also target the silencing H2A variants. In infected cells, histone dynamics were increased in the viral replication compartments, where ICP4 localizes. These results suggest a mechanism whereby ICP4 activates transcription by disrupting, or preventing the formation of, stable silencing nucleosomes on HSV-1 genomes.
We have performed a genomic characterization of a kinetoplastid protist living within the amoebozoan Neoparamoeba pemaquidensis. The genome of this "Ichthyobodo-related organism" was found to be unexpectedly large, with at least 11 chromosomes between 1.0 and 3.5 Mbp and a total genome size of at least 25 Mbp.Kinetoplastids are an important group of eukaryotic microbes named by virtue of their shared possession of a conspicuous mass of DNA-the "kinetoplast"-inside the mitochondrion (21, 31). They are remarkable for their bizarre suite of biochemical features (e.g., spliced leader [SL] trans splicing and mitochondrial RNA editing) (1,5,21) and are best known as pathogens: the so-called "tritryps" are responsible for mass mortality and morbidity in humans and other animals (1, 14, 31). The kinetoplastids also contain a variety of other parasites, such as the fish pathogen Cryptobia, as well as many free-living groups (e.g., Bodo) (31). Phylogenetic studies suggest that within kinetoplastids, parasitic lineages have evolved from free-living ones on at least four occasions (31). Despite many genomics-enabled advances for the tritryp pathogens (e.g., see references 2, 14, and 18), a comprehensive evolutionary framework for understanding the biology of these important pathogens is currently lacking.The kinetoplastid endosymbiont of Neoparamoeba pemaquidensis, an amoebozoan that causes disease in fish (e.g., Atlantic salmon) and invertebrates such as lobster (20,27), represents an apparent example of "recent" adaptation to intracellularity. We refer to this enigmatic endosymbiont as the "Ichthyobodo-related organism" (IRO) based on 18S ribosomal DNA (rDNA) analyses showing its close affinity to Ichthyobodo (6,(10)(11)(12). In this study we characterized genes from N. pemaquidensis and its kinetoplastid endosymbiont and carried out the first investigation of the chromosomes of both organisms using pulsed-field gel electrophoresis (PFGE) and Southern blotting.N. pemaquidensis strains CCAP 1560/4 and 1560/5 and Neoparamoeba branchiphila AFSM3/II were cultured as described previously (13). Using standard transmission electron microscopy (TEM) and 4Ј,6-diamidino-2-phenylindole (DAPI) staining protocols, N. pemaquidensis strain 1560/4 was mostly found to possess 1 (and only occasionally 2) oval or round IRO per cell, each 4 to 6 m in diameter. The IRO was typically very closely associated with the host cell nucleus, with their surfaces often appearing to be in direct contact (Fig. 1A and C). This is consistent with previous reports based on studies of multiple strains of Neoparamoeba (e.g., see references 10, 12, 13, and 17). Within the IRO, a single mitochondrion was found to occupy more than half of the endosymbiont cell volume, with its distinctive kinetoplast DNA (kDNA) appearing as a complex fibrillar structure in TEM micrographs (Fig. 1A and B). The close proximity of the IRO to the amoeba host nucleus was also apparent under DAPI staining (Fig. 1C). The IRO nucleus stained weakly with DAPI relative to the amoeba nucle...
Gombos RB, Brown JC, Teefy J, Gibeault RL, Conn KL, Schang LM, Hemmings DG. Vascular dysfunction in young ec50, mid-aged and aged mice with latent cytomegalovirus infections. Am J Physiol Heart Circ Physiol 304: H183-H194, 2013. First published November 2, 2012; doi:10.1152/ajpheart.00461.2012.-Human cytomegalovirus (HCMV) is associated with vascular diseases in both immunosuppressed and immunocompetent individuals. CMV infections cycle between active and latent phases throughout life. We and others have shown vascular dysfunction during active mouse CMV (mCMV) infections. Few studies have examined changes in physiology during latent CMV infections, particularly vascular responses or whether the negative effects of aging on vascular function and fertility will be exacerbated under these conditions. We measured vascular responses in intact mesenteric and uterine arteries dissected from young, mid-aged, and aged latently mCMV-infected (mCMV genomes are present but infectious virus is undetectable) and agematched uninfected mice using a pressure myograph. We tested responses to the ␣ 1-adrenergic agonist phenylephrine, the nitric oxide donor sodium nitroprusside, and the endothelium-dependent vasodilator methacholine. In young latently mCMV-infected mice, vasoconstriction was increased and vasodilation was decreased in mesenteric arteries, whereas both vasoconstriction and vasodilation were increased in uterine arteries compared with those in age-matched uninfected mice. In reproductively active mid-aged latently infected mice, mesenteric arteries showed little change, whereas uterine arteries showed greatly increased vasoconstriction. These vascular effects may have contributed to the decreased reproductive success observed in mid-aged latently mCMV-infected compared with age-matched uninfected mice (16.7 vs. 46.7%, respectively). In aged latently infected mice, vasodilation is increased in mesenteric and uterine arteries likely to compensate for increased vasoconstriction to mediators other than phenylephrine. The novel results of this study show that even when active mCMV infections become undetectable, vascular dysfunction continues and differs with age and artery origin. uterine arteries; mesenteric arteries; infertility; vascular function; pressure myograph HUMAN CYTOMEGALOVIRUS (HCMV) is a member of the -Herpesviridae family (50). In the human population, it infects 40 to 80% of individuals (10). Although in the general population it is thought to be mostly asymptomatic, infection has been associated with tumorigenesis, transplant rejection, vascular diseases such as atherosclerosis and restenosis, and increased mortality and hypertension (9,19,23,26,33,62,64). The mechanisms whereby HCMV infections result in vasculopathy are still unclear.
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