Texas Biomed Science Report 2011-2012 - Texas Biomedical ...

Robert A. Davey, Ph.D.
Scientist, Virology and Immunology
Drugs work together with vaccines to protect us against disease. Drugs
are particularly effective for short to mid-term protection or when people
are in areas where a recent outbreak has occurred or vaccination is not
possible. Drug identification in the pharmaceutical industry has relied on
testing large sets of chemicals, often in the millions, to block replication
of virus or bacterial pathogens. After finding several thousand chemicals
that work weakly, organic chemists modify and improve some of them
to make more effective compounds and to ensure low toxicity and side
effects to the patient. To handle so many chemicals is difficult and relies
on robotics and other complex equipment. Unfortunately, this equipment
is large, expensive and dangerous and requires continuous maintenance
making it impractical to house in the high-containment laboratory.
The BSL-4 maximum containment laboratory in the department of
Virology and Immunology offers the perfect environment to develop and
optimize an alternative workflow for identification of drugs for high
containment pathogens. We have developed semi-automated approaches
to drug screening that are safe, efficient and work at high containment.
These include a microscope system that can automatically take photos of
infected cells in 96 and 384-well plates as well as computer software that
we have customized to automatically identify infected cells and determine
drug efficacy. To ensure safety, our lab personnel are still heavily involved
in hands on work but we can drastically reduce the time to finding
effective drugs by 90 percent over more traditional methods by using this
approach. Still, testing millions of chemicals would take a very long time
but we have developed systems that can be used at low containment to
Left to right: Manu Anantpadma,
Janelle Bentz, Robert Davey,
Robert Maldonado, Olena Shtanko
2011–2012 Scientific Report
“The fight against viral pathogens is ongoing and we cannot afford to let our guard down. We have dodged a
number of bullets just over the last 10 years between naturally evolving and emergent pathogens as well as those
made and released intentionally. The problem is that few facilities are capable of handling the type of pathogens
that cause severe human disease, let alone to find drugs to combat them, because of the hazard posed to
laboratory workers. My goal is to identify new drugs that can be used to combat these pathogens.”
Staff
Publications
• Chen Z, Kolokoltsov AA, Wang J, Adhikary S, Lorinczi M, Elferink L, Davey RA (2011) GRB2
interaction with the ecotropic murine leukemia virus receptor, mCAT-1, controls virus entry
and is stimulated by virus binding. J Virol. Accepted for publication.
• Eaves-Pyles T, Bu HF, Tan XD, Cong Y, Patel J, Davey RA, Strasser JE (2011) Luminal-applied
flagellin is internalized by polarized intestinal epithelial cells and elicits immune responses
via the TLR5 dependent mechanism. PLoS One 6:e24869.
• Kolokoltsov AA, Adhikary S, Garver J, Johnson L, Davey RA, Vela EM (2011) Inhibition of
Lassa virus and Ebola virus infection in host cells treated with the kinase inhibitors genistein
and tyrphostin. Arch Virol Sep 25. [Epub ahead of print].
• Kondratowicz AS, Lennemann NJ, Sinn PL, Davey RA, Hunt CL, Moller-Tank S, Meyerholz
DK, Rennert P, Mullins RF, Brindley M, Sandersfeld LM, Quinn K, Weller M, McCray PB Jr,
Chiorini J, Maury W (2011). T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor
for Zaire Ebolavirus and Lake Victoria Marburgvirus. Proc Natl Acad Sci USA, May 2.
• Hunt, CL, Kolokoltsov AA, Davey RA, Maury W (2010) The Tyro3 receptor kinase Axl
enhances macropinocytosis of Zaire ebolavirus. J Virol 85:334-47.
• Saeed MF, Kolokoltsov AA, Albrecht T, Davey RA (2010) Cellular entry of Ebola virus
involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through
early and late endosomes. PLoS Pathog 6 pii: e1001110.
help narrow down targets to a few thousand chemicals which can be
tested in a few weeks. Presently we are engaged in an ongoing project with
a major drug screening facility at the National Institutes of Health. Our
goal of this project is to identify new drugs against Marburg (cousin of
Ebola virus) and Lassa fever viruses. The hits from this screen will be
testing and optimized in the BSL-4 lab at Texas Biomedical Research
Institute. We are also working with other labs in the department to help
analysis of data and assays and are already reaping the benefits in time
and cost savings.
E For more information, please visit www.txbiomed.org/departments/
virology/virology-staff-bio?u=185
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