David A. Ornelles, PhD
David A. Ornelles, Ph.D., Associate Professor
Dr. Ornelles received a Bachelor’s Degree in Electrical Engineering from the University of Hawaii. He attended graduate school at MIT where he received a Ph.D. in Biochemistry in 1987. Following a postdoctoral fellowship in molecular virology at Princeton University, Dr. Ornelles joined the faculty of WFSM in the Department of Microbiology and Immunology in 1993.
SYNOPSIS OF AREA OF INTEREST:
1. Cellular restrictions imposed on adenovirus replication. We study the mechanisms by which adenovirus oncoproteins overcome a cell-cycle-linked restriction imposed on virus replication and how these oncoproteins both defeat and replace cell-cycle checkpoint controls.
2. Rational development of adenovirus for cancer therapy. We seek to understand how key oncoproteins of adenovirus dictate the oncolytic nature of adenovirus and apply this information to the development of an improved therapy for cancer.
3. DNA alterations associated with leukemia. Adenovirus has the power to elicit mutations in a hit-and-run fashion. We discovered that the leukemia-associated RUNX1 gene suppresses adenovirus replication. We seek to understand the relationship between RUNX1 and adenovirus and determine if prenatal adenovirus infection can contribute to the development of mutations associated with childhood leukemia.
4. Adenovirus and bacterial otitis media. We seek to understand how the common respiratory adenoviruses promote the development of bacterial otitis media in an animal model.
DETAILED AREA OF INTEREST:
Products of the adenovirus E1B and E4 genes act in concert to promote efficient expression of viral genes, to block the export of cellular mRNA from the nucleus, and to inactivate key host cell proteins that regulate cell growth and DNA repair. Mutant adenoviruses that cannot express the E1B-55K (55K) gene replicate most efficiently in cells that are rapidly dividing. Consequently, 55K-mutant adenoviruses are used to treat cancer even though the basis for their selective growth in cancer cells remains poorly understood.
Research on the E4 region of adenovirus has shed light on the tumor-selective nature of the 55K-mutant virus. Surprisingly, the E4orf1 protein suppresses late viral gene expression at the level of translation and limits the oncolytic efficiency of the 55K-mutant adenoviruses.
Deletion of the highly conserved E4orf3 gene in the 55K-mutant background gives rise to a double-mutant virus that replicates very poorly but kills certain human tumor cells with stunning efficiency. This double-mutant virus is unable to block host cell protein synthesis and fails to suppress the cellular DNA-damage response. This leads to the hypothesis that tumor cells with a heightened intrinsic level of DNA damage signaling will be especially susceptible to killing by this virus.
Another line of study, seeking to identify cellular factors targeted by the 55K and E4orf6 proteins, has identified RUNX1 as a targeted cellular gene. Interestingly, RUNX1, also known as AML1, is the most frequently disrupted gene in acute childhood leukemia. This line of study may identify an important regulator of immune and bone cell development as an important cellular target for adenovirus with potentially far-reaching implications for this apparently mild human pathogen. Translocations between RUNX1 and ETV6 arise in as many as 1% of all children before birth. Adenovirus appears to infect 5% of all children before both. Ongoing work seeks to determine if there is a connection between prenatal adenovirus infection and the presence of pre-leukemic mutations that can be detected at birth.
Chronic or recurrent otitis media is a problem of great economic and sociological significance. Bacteria normally resident in the nasopharynx can cause otitis media. However, otitis media may be more accurately considered a polymicrobial disease resulting from the interplay of bacterial and viral pathogens. Because species C adenoviruses are among the most frequently detected viral pathogens in children with chronic or recurrent otitis media, in collaboration with Dr. Ed Swords, we seek to identify the unique properties of adenovirus that promote bacterial ascension and the development of otitis media.