2004 Denali Biomedical Research Workshop

Emerging Pathogens at High Latitudes

Final Report

Executive Summary:

The 2004 Denali

 Biomedical Workshop was held August 27-29 at the Denali Princess Lodge.  It was designed for intellectual reconnaissance and planning as Alaska INBRE and others in the University of Alaska expand research on infectious agents that impact animals and people in the state.

Conclusions and action items include:

o The University of Alaska and the INBRE program, working in partnership with other bioresearch entities in Alaska and in the nation, should continue to develop research programs in zoonotic and other infectious diseases.

o A Center for Zoonotic Disease Studies could be established to build capacity on pathogenesis, ecology, and host-parasite relationships, with particular attention to: West Nile virus, Brucella sp. Francisella tularensis, rabies and related viruses, Clostridium botulinum, and avian influenza.  [Post-Denali meetings are sharpening our focus on Francisella and Brucella.]

o Research on microbial ecology should be vigorously pursued, including the enteric pathogens from sewerage, transport of pathogens by migratory birds and mammals, and the ecological niches of pathogens.

o The association between infectious and chronic diseases deserves investigation in Alaskan communities.  One potential research area is the relationship between Helicobacter infection and gastric cancer.  The approaches should include host genetics, pathogen genotyping, epidemiology, environmental reservoirs, and animal reservoirs.

o We should establish prospective monitoring of arthropod and other vectors in Alaska.  Potential collaborators include the Department of Defense (military reservations), the Alaska Native Science Commission, state agencies, and federal agencies.

o Research on human influenza strains should include retrospective analyses from specimens archived sera and tissues.  These projects will involve collaborations among state health labs, federal agencies, the Armed Forces Institute of Pathology, the UAF Supercomputing Center, UAF bioinformatics and genetics faculty, and Alaska Native health entities.  Other specific influenza projects on modeling of antigen-receptor binding and avian influenza surveillance are described in more detail in the attached report from Break-out Session. #1.

o Research on infectious agents should be expanded in the future to include immunology, immunogenetics, and immunotoxicology.

o A number of participants in the workshop asked whether we would consider holding another such topical meeting or meetings in the coming years to refine and expand the general planning begun as a part of this Workshop.  The possibility of Workshops in future years will be considered by the INBRE administration, the INBRE External Advisory Committee and the INBRE State Steering Committee. 

Participants:

The invited scientific participants included 15 Outside research scientists as well as 24 Alaskans (14 from the university and  9 from other research and health delivery entities).

Scientists from Outside Alaska
Carol Blair, PhD	Colorado State University
Nancy Cox, PhD	CDC, Atlanta,
Ron DiGiacomo, VMD, MPH	University of Washington
Philip Elzer., PhD	Louisiana State University
Julie Fox, PhD	University of Calgary
Rona Hirschberg, PhD	NIAID, NIH, Bethesda
Anders Johansson, MD	University of Umea, Sweden
Scott Layne, MD	UCLA
Robbin Lindsay, PhD	Health Canada, Winnepeg
Samuel Miller, MD	University of Washington
Norman Neumann, PhD	University of Calgary
Richard Race, DVM	NIAID, NIH, Hamilton, MT
David Swayne, DVM, PhD	USDA, Athens, GA
Jeff Taubenberger , MD, PhD	Armed Forces Institute of Pathology, Washington
Masahisa Watari, PhD	Obihiro University, Hokkaido, Japan
University of Alaska
John Blake, DVM, MS	Fairbanks
George Happ, Ph.D	Fairbanks
Carol Jones, PhD	Anchorage
Andrew Lang, PhD	Fairbanks
Thomas Marr, PhD	Fairbanks
Kevin McCracken, PhD	Fairbanks
Todd O’Hara, DVM, PhD	Fairbanks
Karen Perdue, BS	Fairbanks
Amanda Read, PhD	Fairbanks
Jon Runstadler, DVM, PhD	Fairbanks
Dennis Valenzeno, PhD	Anchorage
Sigrid Vogl, DVM	Fairbanks
Kevin Winker, PhD	Fairbanks
Tony Yeo, PhD	Anchorage
Other Alaskans
James Berner, MD	Alaska Native Tribal Health Consortium
Jay Butler, MD	Arctic Investigations Program, CDC
Louisa Castrodale, DVM, MPH	Alaska State Epidemiology Program
Robert Gerlach, DVM	Alaska State Veterinarian
Bernard Jilly, PhD	Alaska State Public Health Laboratory
Lynne Lucher, PhD	Alaska State Public Health Laboratory
Thomas Nighswander, MD	Alaska Native Health Physician
Ellen Provost, DO, MPH	Alaska Native Medical Center
Alan Parkinson, PhD	Artic Investigations Program, CDC

The Program:

Informal discussions began in Fairbanks on Thursday, September 27^th  among some of the Outside participants and faculty from UAA and UAF in Fairbanks.  In addition, Rona Hirschberg (NIAID) presented a seminar on “The NIH Grant Process” to faculty, students, and staff.

After arrival at Denali and an informal reception on Friday evening, the Saturday program on September 28 included five formal sessions interspersed with questions and general discussion.

Session 1 - Alaska Context and Federal Priorities.

Jay Butler, George Happ, Rona Hirschberg, Sam Miller, speakers

James Berner, Louisa Castrodale, Bernd Jilly, Lynne Lucher, Thomas Nighswander, and Alaska Parkinson, panel discussants

Session 2 -  Influenza

Nancy Cox and Jeff Taubenberger, speakers

David Swayne, Scott Layne, Julie Fox, Thomas Marr, Kevin McCracken, and Kevin Winker, panel discussants

Session 3 - Arbovirus

Julie Fox, Robbin Lindsay, and Carol Blair, speakers

Session 4 - Transmission, Virulence, and Pathogenesis

Richard Race, Masahisa Watarai, Philip Elzer, Samuel Miller, and Jay Butler, speakers

Session 5 - Ecology and Epidemiology

Anders Johansson, Norman Neumann, and Alan Parkinson, speakers.

Late Saturday afternoon was devoted to discussion of the topics for breakout sessions.

The formal sessions on Sunday consisted four break-out groups.  The goals were to define prime research target themes and  to describe and develop specific research projects.  The reports from the breakout groups follow this overall summary. :

1) Influenza. - Tom Marr, convener

2) Relation of infection to the development of adult chronic disease  - James Berner, convener

3) Interaction of contaminants, susceptibility to infection, and chronic disease  - Todd O’Hara, convener

4) The impact of climate change on infectious disease  - Jay Butler convener

Informal discussions continued on Sunday afternoon and evening, during a workshop bus trip into Denali Park, over dinner Sunday evening, and on Monday and Tuesday at UAF. 

Acknowledgements:

In closing this report, the participants want to gratefully acknowledge the careful, creative, and energetic program planning, logistic planning, and staff support of Nora Kelly, Project Administrator of INBRE and EPSCoR, and also of Dottie Moss, who coordinated the travel for the meeting and provided help in the on-site conduct of the workshop.

Funding for this workshop was provided by Alaska INBRE (P20 RR016466 from the National Center for Research Resources of the National Institutes of Health) and by a planning grant from DEPSCoR. 

This summary was prepared by George Happ (george.happ@alaska.edu).

Breakout Group 1 - Influenza subcommittee:

Summarized by Jeff Taubenberger, MD/PhD and Tom Marr, PhD

Influenza projects:

1. Human
1. Retrospective genomics analysis of human influenza strains with special emphasis on older isolates (1960’s – 1980’s)
2. Proposal to obtain full-genomic sequences of several hundred strains from the State lab collection over this period
3. Example hypotheses to be tested include:

i. Dating the emergence of the 1968 H3 by sequence analysis of pre-1968 H2N2 viruses and early post-1968 viruses

ii. Prediction of HA receptor-binding patterns from primary isolates without significant egg-adaptation

iii. Evolution of post-1977 H1N1 viruses with emphasis on parallel evolution of core protein genes between pre-1968 H2N2 and post-1968 H3N2 and post-1977 H1N1 viruses

iv. Reassortment between H3N2 and H1N1 viruses after 1977

4. Collaboration between state lab, UAF, and federal labs would require an MOU on sharing data
5. Sequencing analysis to be done collaboratively by AFIP, UAF and state health lab
6. Bioinformatics analysis of data to be done via the UAF Supercomputing Center.
1. Human retrospective seroarcheology survey:
1. Proposal to determine whether H3 viruses circulated before 1918 in humans
2. Native health serum collection from pre-1968 to be analyzed for H3 antibodies in collaboration with CDC – Jay Butler (Anchorage) and Nancy Cox (Atlanta) labs comparing results from sera collected from people of known ages (i.e. less than 50 years old and greater than 50 years old in 1968)
2. Animal influenza projects:
1. Retrospective genomics analysis using archived avian influenza samples from collection of Professor Richard Slemons at Ohio State University – genomic sequence analysis to be performed as above collaboratively between UAF, AFIP, and Ohio State.
2. Would require MOU for data sharing with UAF
3. Prospective surveillance for avian influenza invlving UAF investigators in collaboration with Professor Slemons on birds in Alaska, the Pacific rim, and South America
4. Genomic sequence analysis of prospectively collected avian strains as above with collaborating groups based on retrospective genomics project.
5. Develop direct molecular subtyping protocols to allow genomic sequencing and hemagglutinin (HA) and neuraminidase (NA) gene subtyping without antigenic characterization
6. Development of a universal influenza genotyping chip using the genomics data obtained from human and avian influenza sequences
7. Example hypotheses to be tested:

i. Are Eurasian avian influenza strains brought to North America via Alaska?

ii. Do the Eurasian and North American lineages mix in Alaska?

iii. Are particular influenza subtypes or strains host-species adapted?

iv. How much reassortment is there in wild avian influenza?

v. Is there phylogenetic support for the 15 HA and 9 NA antigenic subtypes? More? Less?

4. Modeling receptor-binding of influenza HA receptor-binding to sialic acid sugars of different configurations and different HA protein sequences using 3D-modeling capabilities of UAF supercomputing center and Ian Wilson and James Stevens of Scripps Research Institute and Jeff Taubenberger lab at AFIP
1. Recent resolved crystal structures of influenza H1, H3, and H5 subtypes make it possible to model receptor changes critical to human adaptation of avian influenza viruses
2. Scripps investigators developed and have used a glycan array to measure binding affinity of different HA proteins with known receptor-pocket sequences
3. Collaboration could extend these observations by computer modeling of the interaction between HA and target sugars
4. AFIP lab could correlate this to lectin-histochemistry studies on human, and animal respiratory tissues to model how influenza pandemic strains emerge

Above projects would lead to collaborative research grant applications to NIH, NSF, and other possible funding sources. An example is potential funding available via the State Department for US/Russian influenza collaborations (e.g., supporting prospective avian influenza surveillance in Siberia and Alaska).

Breakout Group 2: Interaction of contaminants, susceptibility to infection, chronic disease

            Prepared by Todd O’Hara

            The group believes that future research in the state should be directed toward assessing the impact of contaminants on immune function, in humans as well as in marine and terrestrial wildlife.  The specific recommendation of the group is that the university strive to hire an immunotoxicologist.

Breakout Group 3 -  Infection/Chronic Disease

            Prepared by James Berner

Many well-documented associations between infection and chronic disease exist.  Clear associations exist between infection and cancer, atherosclerotic disease, and autoimmune disease.  As a suggested research area, the relationship between infection with Helicobacter pylori and gastric cancer was selected.  The infection is endemic in rural Alaska Natives, and is also found in non-Natives in Alaska.  Alaska Natives have an increased risk for gastric cancer.

Research questions that must be addressed:

1. Genetic factors in host susceptibility to infection.
2. Genetic factors associated with development of gastric cancer.
3. Genetic factors in H. pylori virulence (includes H.pylori strains associated with gastric cancer.)
4. Mechanisms of H.pylori spread in families, communities.
5. Environmental reservoirs for H. pylori.
6. Animal reservoirs.

Breakout Group 4:  The effect of climate change on microbial ecology and infectious diseases of animals and man

            Prepared by Jay Butler

The group identified six diseases/agents of concern, based on interest of potential funding agencies and health importance in Alaska:

1. West Nile virus
2. Brucella sp.
3. Francisella tularensis
4. Rabies (+/- other lyssaviruses and vesiculoviruses)
5. Clostridium botulinum
6. Avian influenza

A Center for Zoonotic Diseases Studies could be established to build capacity from multiple funding sources.  The potential influence of climate change on each of these organisms may provide opportunity to do basic research into the pathogenesis, ecology, and host-parasite relationship of each.

There is great need to develop data sets.  The UAF Supercomputing Center and the expertise of Dr. Marr provide a great bioinformatics resource.  However, data for modeling the effect of climate change are limited and planning collection of such data should be a component of many future projects relating to climate change.

General areas discussed included study of the effect of climate change on:

• The  interface between microbes and their ecologic niches (e.g., the role of free-living protozoa in supporting F. tularensis in various climates)
• Aquatic microbial ecology
• Sewerage disposal and dispersal of enteric pathogens in the environment
• Migratory patterns and the spread of zoonotic pathogens (e.g, rabies, echinococcus, Brucella sp.)

Specific Project: conduct follow-up surveys of earlier studies of arthropod vector ranges (mosquitoes and ticks of particular interest) and establish prospective monitoring of vectors in select areas of Alaska

• Discussion bullets:
• Will require increasing the current level of entomological expertise at the University
• Will require extensive field work
• Potential collaborators:
• Department of Defense: have been conducting limited mosquito pool surveys on military reservations in Alaska
• Alaska Native Science Foundation: potential utilization of subsistence hunters in specimen collection

Further discussion of specific project ideas would be greatly facilitated by obtaining more information on who is doing what in related areas (e.g., Alaska Department of Fish and Game, Alaska Department of Environmental Conservation, US Fish and Wildlife Service, other departments at UAF)