Role of early genes in pathogenesis of adenovirus pneumonia.

Abstract

Intranasal inoculation of type 5 adenovirus into the cotton rat Sigmodon hispidus produces a pneumonia pathologically similar to that in humans, and it, therefore, provides an excellent animal model to investigate the pathogenesis of this disease. The goal of this study was to test the hypothesis that accumulation of viral structural proteins is responsible for a major portion of the cell-damage-producing disease. Since viral DNA replication is essential for synthesis of the viral structural proteins, which are products of late genes, the hypothesis was tested using mutants defective in genes required for DNA synthesis. Most experiments were done with the conditionally lethal temperature-sensitive (ts) mutant H5ts125, which contains a mutation in the early region 2A When cotton rats were infected with 1 x 1080-plaque-forming units of wild-type adenovirus type 5 or HMts125, the pneumonias that followed were pathologically similar; in the latter phases, however, wild-type virus produced slightly more extensive pneumonia than did HSts125, probably because its replication permitted infection of more susceptible cells.The discovery of adenoviruses (1, 2), an important human pathogen whose 42 viral types produce a variety of diseases, led to extensive studies into the virion structure, the viral structural proteins, the nature of the viral genome, and the biochemical and molecular events in the sequential biosynthesis of the viral gene products (3). During type 5 adenovirus (Ad5) replication, host cell DNA synthesis is completely blocked about 12 hr after infection with AdS (4, 5), and host RNA and protein syntheses are blocked about 18-20 hr after infection (5-7). In addition, only about 10% of the viral DNA and structural proteins synthesized are actually packaged into mature virions whereas the remainder accumulate in the nuclei ofinfected cells forming inclusion bodies (8-11). These findings led to the hypothesis that the combination of shut-off of biosynthesis of host macromolecules and the intranuclear accumulation of large amounts of viral DNA and structural proteins leads to cell death and production of disease (5). Indeed, the purified fiber protein inhibited viral multiplication when added to adenovirus-infected KB cells, and it was shown to inhibit incorporation of [3H]thymidine into cellular DNA in cell extracts in vitro (12, 13).The objective of the study to be described was to test the hypothesis that production of an excess of late viral proteins is responsible for the molecular events essential for the pathogenesis of adenovirus disease. Thus, if synthesis of the late structural proteins were blocked, disease should not develop. This possibility was readily tested since mutants unable to synthesize viral DNA cannot produce late structural proteins, and such mutants had been isolated (14). H5ts125 (14) and H5ts149 (15) are conditionally lethal temperature-sensitive (ts) mutants that cannot replicate their DNA at their nonpermissive temperature of 39.50C, which fortunately is close to the body te...

Diversity of airway epithelial cell targets for in vivo recombinant adenovirus-mediated gene transfer.

“…In this re- One caveat regarding this conclusion comes from the knowledge that the airway epithelium of the cotton rats (S. hispidus, a rodent that has similarities to rat and hamster) is not identical to that of the human. The cotton rats were used in these studies because of the extensive data suggesting the cotton rat is similar to the human in regard to sensitivity to adenovirus airway infection (39). However, like other rodents and most other experimental animals, the cotton rat large airway epithelium differs from the human in that the cotton rat has significantly higher proportions of surface secretory cells and lower proportions of submucosal glands (40,41 for bronchioles.…”

Inhibition of Chemokine Expression by Adenovirus Early Region Three (E3) Genes

“…Other work using Ad with E3 deletions in a pneumonia pathogenesis model has suggested a role for E3 in affecting the composition and extent of lung inflammatory cell infiltrates (16,17,38).…”

Tumor necrosis factor-α activation by adenovirus E1A 13S CR3 occurs in a cell-dependent and cell-independent manner

“…Expression of adenovirus early genes may be important in mediation of inflammation by adenovirus, as infection in animal models with nonreplicating virus results in inflammation that is quantitatively similar to active infection (10,11,25). Tumor necrosis factor (TNF)-␣ is elevated in lung homogenates of these animals, suggesting that induction of this cytokine is important in the inflammatory response to adenovirus (11).…”