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Results for “ADENOVIRUS INFECTIONS”
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[Contribution to the study of type 1 adenovirus infections].
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Adenovirus infections of the eye in London.
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Experimental adenovirus infection of the mouse adrenal gland. I. Light microscopic observations.
A murine type of adenovirus has been found to have a highly selective affinity for the adrenal of its natural host. In view of the adrenal pathology in Addison's disease, which consists of cortical atrophy and focal lymphocytic infiltration, the possibility of a viral causation is an attractive hypothesis. The striking adrenotropism of this agent offers, theoretically, a potential experimental animal model for investigation of this possibility. Most of our information about the acute biologic action of adenoviruses has been gained from study of virus-infected tissue culture cells. The sharply focused and severe attack of the murine agent upon a prime target organ facilitates correlative in vivo studies of the cytopathology of adenovirus infection at levels of light and electron microscopy.
Serological evidence of adenovirus infection in cats.
The widespread presence of adenoviruses in various species makes it probable that infection and the carrier state also exist in cats. On the basis of these considerations, investigations were carried out to find antibodies against adenovirus in sera from different cat populations kept under different conditions. For the antibody detection, purified adenovirus was used in an indirect ELISA. To produce positive serum, SPF cats were immunized with a purified hexon preparation. Altogether 632 field sera of different origin were tested. Among field samples, adenovirus seropositivity varied between 10-26%.
Comparison of enteric adenovirus infection in various human cell lines.
Growth of the fastidious enteric adenoviruses 40 and 41 was compared in different human cell lines. Purified virions were used to infect the following cell lines: A549; KB; Chang's conjunctiva; 293; HeLa. Both types of enteric adenovirus were infectious for each cell line, with the exception of adenovirus 40 in HeLa cells. Relatively low infectious titers were obtained from each cell type following infection with adenovirus 40 (TCID50 average = 10(-1.5)), whereas adenovirus 41 replicated to significantly higher titer (TCID50 average = 10(-3.0)). For both viruses, the highest infectious titers were obtained with A549 and KB cells. A time course experiment performed to quantitate the amount of hexon present in A549 and KB cells infected with each virus indicated that while the kinetics of accumulation were similar for both viruses, the concentration of type 41 hexon was significantly greater than that for type 40 in either cell line. The concentration of type 41 hexon was similar in each cell type; for type 40, a greater concentration of hexon was obtained in the A549 cell line than in the KB cells. The results indicate the distinct replication characteristics exhibited by adenovirus 40 are not due to a restriction in a specific host cell, and, because purified virions were used, not attributable to interference that might occur with co-infection from multiple viruses present in the same clinical specimen. We conclude the differences observed in the replication of these viruses are independent of host cell type and are associated, uniquely, with each virus.
Fatal disseminated adenovirus infection in a renal transplant recipient.
A 61 year old woman died of diffuse interstitial adenovirus pneumonia 55 days after receiving a cadaveric renal allograft. The adenovirus was serologically distinct from the 33 known human adenovirus serotypes and appears to represent a new human adenovirus. Pathologic and virological findings indicate that the pneumonia was only one manifestation of a disseminated infection, the source of which may have been a latent adenovirus infection preexisting in the donor kidney. The establishment of the etiologic diagnosis in this case, which was complicated by the presence of oculocutaneous and esophageal herpes simplex virus infection as well as focal pulmonary aspergillosis, required coordinated histopathologic and virological investigation. Our findings demonstrate that severe viral infections in transplant recipients are not caused exclusively by members of the herpesvirus group.
p53-dependent cell death/apoptosis is required for a productive adenovirus infection.
The p53 tumor suppressor protein binds to both cellular and viral proteins, which influence its biological activity. One such protein is the large E1b tumor antigen (E1b58kDa) from adenoviruses (Ads), which abrogates the ability of p53 to transactivate various promoters. This inactivation of p53 function is believed to be the mechanism by which E1b58kDa contributes to the cell transformation process. Although the p53-E1b58kDa complex occurs during infection and is conserved among different serotypes, there are limited data demonstrating that it has a role in virus replication. However, loss of p53 expression occurs after adenovirus infection of human cells and an E1b58kDa deletion mutant (Onyx-015, also called dl 1520) selectively replicates in p53-defective cells. These (and other) data indicate a plausible hypothesis is that loss of p53 function may be conducive to efficient adenovirus replication. However, wild-type (wt) Ad5 grows more efficiently in cells expressing a wt p53 protein. These studies indicate that the hypothesis may be an oversimplification. Here, we show that cells expressing wt p53, as well as p53-defective cells, allow adenovirus replication, but only cells expressing wt p53 show evidence of virus-induced cytopathic effect. This correlates with the ability of adenovirus to induce cell death. Our data indicate that p53 plays a necessary part in mediating cellular destruction to allow a productive adenovirus infection. In contrast, p53-deficient cells are less sensitive to the cytolytic effects of adenovirus and as such raise questions about the use of E1b58kDa-deficient adenoviruses in tumor therapy.
The role of nuclear factor-kappa B activation in airway inflammation following adenovirus infection and COPD.
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[Neurologic changes in adenovirus infection in children].
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The amino-terminal portion of CD1 of the adenovirus E1A proteins is required to induce susceptibility to tumor necrosis factor cytolysis in adenovirus-infected mouse cells.
Previous work by our laboratory and others has shown that mouse cells normally resistant to tumor necrosis factor can be made sensitive to the cytokine by the expression of adenovirus E1A. The E1A gene can be introduced by either infection or transfection, and either of the two major E1A proteins, 289R or 243R, can induce this sensitivity. The E1A proteins are multifunctional and modular, with specific domains associated with specific functions. Here, we report that the CD1 domain of E1A is required to induce susceptibility to tumor necrosis factor cytolysis in adenovirus-infected mouse C3HA fibroblasts. Amino acids C terminal to residue 60 and N terminal to residue 36 are not necessary for this function. This conclusion is based on 51Cr-release assays for cytolysis in cells infected with adenovirus mutants with deletions in various portions of E1A. These E1A mutants are all in an H5dl309 background and therefore they lack the tumor necrosis factor protection function provided by the 14.7-kilodalton (14.7K) protein encoded by region E3. Western blot (immunoblot) analysis indicated that most of the mutant E1A proteins were stable in infected C3HA cells, although with certain large deletions the E1A proteins were unstable. The region between residues 36 and 60 is included within but does not precisely correlate with domains in E1A that have been implicated in nuclear localization, enhancer repression, cellular immortalization, cell transformation in cooperation with ras, induction of cellular DNA synthesis and proliferation, induction of DNA degradation, and binding to the 300K protein and the 105K retinoblastoma protein.
Pharmacological interference with dimerization of human neuronal nitric-oxide synthase expressed in adenovirus-infected DLD-1 cells.
A recombinant adenovirus containing the cDNA of human neuronal nitric-oxide synthase (nNOS) was constructed to characterize the interaction of nNOS with N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazole-1-yl)pyrimidin-4-yl]-4-(methoxycarbonyl)-piperazine-2-acetamide (BBS-1), a potent inhibitor of inducible NOS dimerization [Proc Natl Acad Sci USA 97:1506-1511, 2000]. BBS-1 inhibited de novo expression of nNOS activity in virus-infected cells at a half-maximal concentration (IC(50)) of 40 +/- 10 nM in a reversible manner. Low-temperature gel electrophoresis showed that BBS-1 attenuated the formation of SDS-resistant nNOS dimers with an IC(50) of 22 +/- 5.2 nM. Enzyme inhibition progressively decreased with increasing time of addition after infection. BBS-1 did not significantly inhibit dimeric nNOS activity (IC(50) > 1 mM). Long-term incubation with BBS-1 of human embryonic kidney cells stably transfected with nNOS or endothelial NOS revealed a slow time- and concentration-dependent decrease of NOS activity with half-lives of 30 and 43 h and IC(50) values of 210 +/- 30 nM and 12 +/- 0.5 microM, respectively. These results establish that BBS-1 interferes with the assembly of active nNOS dimers during protein expression. Slow inactivation of constitutively expressed NOS in intact cells may reflect protein degradation and interference of BBS-1 with the de novo synthesis of functionally active NOS dimers. As time-dependent inhibitors of NOS dimerization, BBS-1 and related compounds provide a promising strategy to develop a new class of selective and clinically useful NOS inhibitors.
[Significance of adenovirus infections in infancy and early childhood].
Of 418 stool specimens of infants tested, 45 specimens contained adenoviruses, mainly the types 1 and 2, 40 and 41. Infections by these types caused symptoms of the gastrointestinal and the respiratory tract to varying degrees: adenoviruses 40 and 41 frequently caused gastroenteritis, adeno 2 was often associated with diarrhoea, adeno 1 mostly caused illness of the respiratory tract necessitating hospitalization of the infants. As adenoviruses may produce--especially during the first years of life--severe diseases of the respiratory and the gastro-intestinal tract, their detection will be of major importance to the pediatrician, the more so as today's methods of detection of adenoviruses are easier and less time-consuming than in the past.
Translational control by adenovirus: lack of virus-associated RNAI during adenovirus infection results in phosphorylation of initiation factor eIF-2 and inhibition of protein synthesis.
The dl331 mutant of adenovirus serotype 5 fails to produce virus-associated (VA) RNAI, and cells infected with this mutant do not synthesize proteins efficiently at late times in infection. The translational defect occurs at the level of polypeptide chain initiation, and cell-free extracts prepared from dl331-infected cells exhibit the defect observed in vivo. Addition of either eukaryotic initiation factor 2 (eIF-2) or guanine nucleotide exchange factor (GEF) to these cell-free extracts restores translational activity, with GEF functioning more efficiently in this regard. These results suggest that cells infected with the dl331 mutant develop a translational block at the level of GEF-catalyzed guanine nucleotide exchange and that this block is most likely established through phosphorylation of the alpha subunit of eIF-2. In the present investigation we show that endogenous HeLa cell GEF activity is significantly reduced in cells infected with the dl331 mutant. Further, in contrast to cells infected with wild-type serotype 2 adenovirus, dl331-infected cells contain increased eIF-2 alpha kinase activity. These results indicate that VA RNAI plays a role in suppressing eIF-2 alpha kinase activity during adenovirus infection of HeLa cells.
YB-1 relocates to the nucleus in adenovirus-infected cells and facilitates viral replication by inducing E2 gene expression through the E2 late promoter.
The adenovirus early proteins E1A and E1B-55kDa are key regulators of viral DNA replication, and it was thought that targeting of p53 by E1B-55kDa is essential for this process. Here we have identified a previously unrecognized function of E1B for adenovirus replication. We found that E1B-55kDa is involved in targeting the transcription factor YB-1 to the nuclei of adenovirus type 5-infected cells where it is associated with viral inclusion bodies believed to be sites of viral transcription and replication. We show that YB-1 facilitates E2 gene expression through the E2 late promoter thus controlling E2 gene activity at later stages of infection. The role of YB-1 for adenovirus replication was demonstrated with an E1-minus adenovirus vector containing a YB-1 transgene. In infected cells, AdYB-1 efficiently replicated and produced infectious progeny particles. Thus, adenovirus E1B-55kDa protein and the host cell factor YB-1 act jointly to facilitate adenovirus replication in the late phase of infection.
Processing of vimentin occurs during the early stages of adenovirus infection.
Evidence is presented that a fraction of vimentin, a component of cytoskeleton recently found to be associated with intracytoplasmic, migrating adenovirus type 2 (Ad2), is processed into smaller polypeptides at early times after infection. The extent of vimentin cleavage appears to depend upon both the multiplicity of infection and the adenovirus serotype. Ad2, Ad5, Ad4, and Ad9 induced similar vimentin cleavage in infected cells, whereas Ad3, Ad7, and Ad12, for which most infecting particles are found sequestered within phagosomes, induced very little, if any, vimentin breakdown. This suggests that vimentin processing is in some way related to the number of virus particles migrating through the cytoplasm. Experiments performed in vitro and in vivo with adenovirus temperature-sensitive mutants H2 ts1 and H2 ts112 and UV-inactivated wild-type Ad2 indicated that vimentin processing is due to a nonvirion, cytoskeleton-associated, proteolytic enzyme activated by adenovirus and sharing characteristics with the protease described by Nelson and Traub (W.J. Nelson and P. Traub, J. Cell Sci. 57:25-49, 1982). The activity of this protease appears to be required for productive infection by adenovirus serotypes 2 and 5 (subgroup C), 4 (subgroup E), and 9 (subgroup D) but not by the oncogenic serotypes 3 and 7 (subgroup B) and 12 (subgroup A).
Deletion of the fiber gene induces the storage of hexon and penton base proteins in PML/Sp100-containing inclusions during adenovirus infection.
The present study has documented changes in the in situ distribution of viral DNA and capsid proteins in 293 cells infected with fiber gene-deleted adenoviruses. It shows that infection results in the intense production of progeny viruses which appear morphologically intact although they are devoid of fiber-coding sequence in their genome and hence of fiber protein in their capsid. The data confirm, therefore, that fiber protein is not essential for the assembly of progeny viruses. The main contribution of our observations concerns specific intranuclear structures induced by infection with either wild-type or fiber gene-deleted viruses. These clear amorphous inclusions contain two cellular proteins, PML and Sp100, which in non-infected cells co-localize to a special type of nuclear bodies. PML and Sp100 nuclear bodies appear to directly modulate or to be altered in a wide variety of situations including viral infections, cell death and transformation. In cells infected with fiber gene-deleted viruses, the clear amorphous inclusions now accumulate non-used hexon and penton base proteins, whereas the absence of fiber protein prevents the assembly of capsid proteins in crystallin arrays. Taken together, the data suggest that the clear amorphous inclusions may correspond to storage sites of structural and regulatory proteins. Consequently, these virus-induced structures may promote the productive cycle of adenoviruses by regulating the amount of over-produced viral proteins and the shutoff of the host cell metabolism.
Persistent adenovirus infections of nonpermissive monkey cells.
Persisten infections of monkey cells have been established by using two serotypes of human adenovirus. The persistently infected cells show no morpho logical changes, but continue ot produce low titers of infectious adenovirus. The inapparent infection can, at any time, be converted to a cytolytic productive one by superinfection with simian virus 40. Persistence in this system does not appear to result from multiple rounds of lytic infection, nor is it mediated by production of defective interfering particles. The persistently infected cells do not possess the characteristics of oncogenic transformation. Results of these studies also whow that the nonpermissiveness of monkey cells to adenovirus replication can be partially overcome by infection at high multiplicity.