Winter 2013 - Hauptman Woodward Institute

The UMLAND and SCHULTZ LABS Receive a DOD Grant
Drs. Timothy C. Umland and L. Wayne Schultz have received a
grant from the Department of Defense to study the transmission of
emergent diseases from animals to humans.
Zoonoses are infectious diseases that are transmitted between
species. Typically, zoonotic pathogens are viruses, and they spread
from other vertebrate species to humans either by direct contact
with the animal or its excretions or via an arthropod (e.g. insect)
vector. The appearance of a pathogen in a new host species is
called “disease emergence”.
Zoonotic viruses are responsible for many of the most serious
infectious diseases confronting modern medicine. Examples include
avian influenza (H5N1), West Nile virus, several forms of encephalitis,
SARS (severe acute respiratory syndrome), Ebola and AIDS, to
name a few. The influenza virus alone accounted for several severe
pandemics in the 20th century including the “Spanish flu” of 1918,
the “Asian flu” of 1957, and the “Hong Kong flu” of 1968.
In animals and humans, the innate immune system provides the
main defense against novel viral attack. Host cells release proteins
called interferons in response to the presence of viruses or other
pathogens. “Interferons” (named after their ability to “interfere”
with viral replication within host cells) facilitate communication
between cells, triggering the immune system to eradicate the
microbial invaders.
In retaliation, viruses have evolved mechanisms for evading the
innate immune responses of their established (donor) host species.
Successful expansion to a new (recipient) host species would require
the ability to control the immune response in that species as well.
It is known that certain viral proteins impair the interferon activation
response through molecular interactions with specific host proteins,
thereby disrupting the intracellular signaling pathways of the host
species. Presumably, the ability of viral proteins to form similar
interactions with proteins in a potential recipient species would lower
the barrier to species jumping. However, little is known about the
actual conservation of virus-host protein interactions in donor and
recipient species or the extent of adaptation necessary for viruses
to form comparable complexes with similar proteins in new hosts.
The Umland/Schultz project. HWI Research Scientists Tim Umland
and Wayne Schultz have recently received a 3-year (with an
option to extend to a total of 5 years), $1.1M grant from the
Department of Defense to study the relationship between conserved
protein-protein interactions and successful host-range expansion.
Drs. Umland and Schultz will identify instances of conserved,
cross-species, virus-host protein interactions involving viruses with
histories of host jumps, especially to humans. In particular, they will
examine host proteins involved in the interferon response pathway
for such interactions.
The HWI scientists will define and characterize the virus-host,
protein-protein interfaces by using small-angle x-ray scattering
(SAXS) to create structural models. The amino acid residues
involved in forming the protein interfaces can then be identified.
Mutagenesis studies will be used to verify critical residues that must
be conserved for range expansion to occur.
Potential impact. The public is at risk from emerging infectious
diseases. This danger is particularly high for diseases that infect
animals of economic importance or common wildlife where
human contact and consumption create avenues of exposure. This
HWI-based investigation will provide knowledge of the relative
ease with which a given virus might adapt to a new species,
particularly humans. It will also provide specific molecular details
about common viral-host protein interactions that will be useful in
the design of potential broad-spectrum antiviral therapeutic agents.
New Collaborations for HWI Scientists
The successful pursuit of a scientific research project often
requires the complementary expertise of two or more scientists or
laboratories. At HWI, researchers focus on using x-ray crystallography
to determine the three-dimensional structures of
molecules. Since crystallography requires specialized training,
and the information it reveals is vital to many biologically related
studies, HWI scientists are often asked to collaborate on a variety
of studies. In fact, one HWI scientist recently received funding as
a subcontractor on a project originating in UB’s School of Medicine
and Biomedical Sciences, and two other HWI scientists
recently co-authored research results with a UB collaborator.
Designing Anti-HPV Drugs
Human Papilloma Virus (HPV) is the cause of several types of
cancer. Although currently available vaccines protect against
the most common HPV infections, this virus has more than 180
known variants or subtypes, and only four of these are
covered by the vaccines.
However, Dr. Thomas Melendy, a UB microbiologist, recently
identified a protein (known as E1) that occurs in all HPV subtypes
and might provide a basis for the first
broad-range HPV drug target. He has
been awarded a $1.65 million grant
by the National Institutes of Health to
try to develop such a drug.
Drs. Vivian Cody and
Thomas Melendy
The E1 protein is encoded by the viral
genome and interacts with human
proteins involved in DNA synthesis. As
a result, the human DNA synthetic
machinery is “reprogrammed” to
synthesize HPV genomes. Dr. Melendy
is particularly interested in the interaction
between E1 and the human
enzyme, Topoisomerase I (Topol). He
has identified the specific amino acids responsible for this interaction
and has found them to be conserved across all HPV subtypes.
Dr. Melendy’s new NIH grant funds efforts to analyze the E1-Topol
interaction and to design small molecules that will interfere with this
interaction. As part of this effort, Dr. Vivian Cody, a principal
research scientist at HWI, will attempt to co-crystallize E1 and Topol
and to visualize their interactions at the molecular level. Information
derived from her crystallographic studies will be used to fine-tune
the small-molecule inhibitors that show potential as anti-HPV drugs.
continued from page 2
Identifying New Drug Targets for
Drug-Resistant Bacteria
Acinetobacter baumannii is a bacterial species
that is responsible for a growing number of
hospital-acquired infections. It is difficult to
eradicate with common disinfectants, and
many strains are resistant to most, if not all,
anti-microbial drugs. It generally doesn’t affect
healthy people, but it poses an increasing
danger for people who have had surgeries,
soldiers with battlefield injuries, and the elderly.
Recently, Thomas A. Russo, MD, UB’s Departments
of Medicine, Microbiology and Immunology,
and his HWI colleagues, Timothy C.
Umland and L. Wayne Schultz, have
succeeded in identifying several potential drug
targets that may provide new ways for combatting
A. baumannii. Their work suggests that the
usual methods of studying bacteria in rich
laboratory media may not be the best way to
find new antimicrobial drug targets.
The UB/HWI collaborators recognized that
typical laboratory conditions are different
from the environment of the human body
where nutrients the bacteria need may be in
short supply and immune responses are
present. By growing the bacteria in human
ascites, a peritoneal fluid present in a variety
of pathological conditions, they discovered a
novel, previously unrecognized set of genes
essential for the growth of A. baumannii. The
proteins encoded by these genes represent
potential new drug targets since inhibition of
the respective functions of these proteins will
halt bacterial growth and reduce bacterial
survivability within a human host.
The researchers are now pursuing drug
discovery efforts focused on the newly identified
targets. Their research is being supported
by grants from UB, the US Army, and the
Department of Veterans Affairs.
Dr. Eaton Lattman, CEO’s Column
I recently received from one of Hauptman-Woodward's
most long-standing friends and supporters a thoughtful
letter that discussed our research programs. It said in
part "... A factor of importance is not just whether the
research is so-called basic, applied or perhaps considered
translational, but whether it is good, excellent, or
outstanding. ... but the fact that the Institute personnel
have been able to support their basic research for 50
years suggests that the quality and productivity of investigations
overall have been meritorious. ... In recent
years there has been somewhat more diversity the
sources from which support has been sought."
This letter was implicitly asking us what we are doing to stay outstanding, and
how we are finding new sources of support in the very difficult grant climate
that is causing great distress to many independent institutions like ours. Let me
share with you some of the comments (slightly expanded) that I made in my
response to our friend.
Dear friend,
Thank you both for your generous support, and for your thoughtful commentary on
HWI research. I agree very much with what you said, and I would like to respond
with a brief picture of how I see our future.
To be successful, a small, research Institute like Hauptman-Woodward has to do
something supremely well. We have had Herb's Nobel Prize work in crystallography;
we have had George DeTitta's creation of one of the world's first automated,
high-throughput crystallization laboratories. What do we do for an encore? We
have two directions in which I think we could attain the same kind of unique excellence
that characterized the work of Herb and George. One of these has to do with
the large NSF grant for which we are in the finals. There are 11 applicants left in the
pool, and the NSF will fund five or six. This is a multi-institutional effort to make use
of the new x-ray laser constructed at Stanford for structural biology. It will revolutionize
the field in the same way that synchrotron x-ray sources have done in the past.
This grant would bring many benefits, both scientific and institutional.
• The x-ray laser will allow us to use crystals a thousand times smaller than the ones
we use today. Nanocrystals will bring a whole new universe of proteins into the realm
of crystallography, and will also provide a new technology frontier that will bring our
high-throughput crystallization laboratory to a position of world leadership again.
• The grant is very prestigious, and will re-burnish HWI’s worldwide reputation.
• NSF regulations require that a degree-granting institution submit this type of
grant, and so our proposal was actually sponsored by UB. The grant would
provide for a much closer connection between the our two organizations.
The second of our new directions involves setting up a structure-based drug
design facility that will nucleate a wide variety of drug development projects at
UB and among local biotech companies, and will provide a new academic
paradigm for drug development. The idea is to mate the clinical and genetic
knowledge of a disease developed by more medically oriented investigators
with the deep molecular insights of HWI scientists.
These two directions represent only a part of the new opportunities that we are addressing.
I hope that you will feel excited and encouraged about the adventures that lie before
us, and about the potential for new coming decades of excellence for HWI.
Dr. E. Lattman
continued on page 3
Drs. L. Wayne Schultz, Thomas A. Russo and Timothy C. Umland
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