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Micronutrients and Infectious Diseases: Cellular and Molecular Immunomodulatory Mechanisms


Micronutrients And Infectious Diseases:
Cellular And Molecular Immunomodulatory Mechanisms

September 16-17, 1999
Bethesda, MD


Objectives:

  • To create a forum for the exchange of ideas between basic scientists, nutritionists, infectious disease specialists and clinical epidemiologists.
  • To strongly encourage the "bench to bedside" concept, i.e. to stimulate hypothesis-driven translational studies based on current understanding of the role of micronutrients in the predisposition, prevention and modulation of infectious diseases.
  • To examine the current mechanisms involved in the pathogenesis and clinical manisfestations of infectious diseases, including an understanding of the immunology, molecular biology, and potential direct interactions between micronutrients and pathogens.
  • To examine current strategies of intervention.
  • To obtain a summary of research gap areas and new directions for future research 

General Description and Background:

Studies in humans as well as experimental animal models have shown that nutritional deficiencies can alter the ability of the host immune system to respond to a variety of parasitic and bacterial infections. Furthermore, some infectious diseases alter the nutritional status of the hosts and the ability to absorb micronutrients. It is important that micronutrient studies have a clear testable hypothesis and designed to understand basic mechanisms involved. A major problem associated with the development of effective prevention strategies is the lack of understanding of the basic mechanisms involved in the alteration of host responses. It is anticipated that this mechanistic approach will bring scientific rigor to the field of micronutrients which is clearly of major significance to the manifestation of infectious diseases. Large micronutrient distribution programs should benefit from studies designed to understand the mechanisms by which micronutrients influence the expression of tropical infectious diseases. This would make rational intervention more feasible. NIH has a clear leadership responsibility to provide research guidance in this area.
 

Program Agenda

8:30 Welcome and Opening Remarks - NIH Staff
Plenary Talk
8:40 "Nutritional Modulation of Resistance to Infectious Diseases"
Dr. Kirk Klasing, Univ. of California, Davis
Micronutrient Effects on Innate Immunity and Hematopoiesis
Moderator, Dr. Adrianne Bendich, Smith Kline Beecham, Parsippany, NJ
9:10 "Micronutrients and Non-specific Immunity"
Dr. Kent Erickson, Univ. California, Davis
9:35 "Modulation of Human Monocyte Function by Dietary Carotenoids"
Dr. David Hughes, Norwich Research Park, UK
10:00 "Important Adaptive Changes made in Lymphopoiesis and Myelopoiesis During Zinc Deficiency"
Dr. Pamela Fraker, Michigan State Univ., East Lansing, MI
10:25 - 10:45
Break
 
Micronutrient Effects on Adaptive Immunity
Moderator, Dr. Donald Bundy, World Bank, Washington, DC
 
10:45 "Vitamin A-Induced Modulation of Antibody Responses"
Dr. Richard Semba, Johns Hopkins Univ., Baltimore, MD
11:10 "Immune Responses in a Vitamin A Deficiency State: Changes in Cellularity and Antibody Responses"
Dr. A. Catharine Ross, Penn State University, University Park, PA
11:35 "Micronutrients and Malaria: Changes in Antibody and Cytokine Production"
Dr. Anuraj Shankar, Johns Hopkins Univ., Baltimore, MD
12:00 - 12:30
General Discussion/ Critical Questions
List of "Suggested" Critical Questions
  1. Most studies of mechanisms look at one specific nutrient. Is there any evidence of synergy (or antagonism) between different micronutrients in terms of immunomodulation?
  2. What is the influence of disease on the absorption of micronutrients and on micronutrient status?
  3. A reduction of plasma retinol, zinc and iron are a consequence of Infection. Why does this happen? Low plasma iron stimulates greater activity of macrophage nitric oxide synthase activity which is bacteriocidal. Is the reduction in retinol a device to reduce losses of urinary retinol which are associated with fever? Alternatively, does low retinol increase immunocompetance?
  4. How does Vitamin A (or other micronutrients) affect the number and differentiation of bone marrow progenitors? Are significant effects seen with a moderate deficiency of the particular micronutrient in question?
  5. What is the interaction of vitamin A and acute phase response to infection/injury? When is this interaction "beneficial" to the host and when does it represent maladaptation? 
12:30 - 1:30
Lunch
PM SESSION DAY 1
 
Micronutrients and Gene Expression
Moderator, Dr. Richard Deckelbaum, Columbia University, NY
 
1:30 "Zinc Deficiency Alters Th2 Immune Response to Gut Nematodes"
Dr. Marilyn Scott, McGill Univ, Canada
1:55 "Vitamin A and gut Immunity"
Dr. David Thurnham, Univ. of Ulster, N. Ireland
2:20  "The Effect of Stress and Starvation on Bacterial Virulence Strategies"
Dr. John Alverdy, Univ. of Chicago, Chicago, Illinois
2:45 - 3:00
Break
 
Micronutrients and Gene Expression
Moderator, Dr. Richard Deckelbaum, Columbia University, NY
 
3:00 "Expression of Cysteine-Rich Intestinal Protein, a Zinc Finger Protein, Affects Th1/Th2 Cytokine Balance"
Dr. Robert Cousins, Univ. of Fl., Gainesville, FL
3:25 "Zinc and Apoptosis in Respiratory Epithelium"
Dr. Peter Zalewski, Univ. Adelaide, Woodville, Australia
3:50 "Influence of Antioxidant Nutrients on Viral Infection"
Dr. Melinda Beck, Univ. N. Carolina, Chapel Hill, NC
4:15 "Retinol-Binding Protein, Retinoid Transport and Immunity"
Dr. William Blaner, Columbia Univ., New York, NY)
 
4:40 - 5:00
General Discussion/ Critical questions
List of "Suggested" Critical Questions
  1. How can researchers make the best use of the many emerging transgenic and gene-deletion (knock-out) mice? 
  2. What animal models are particularly suited for evaluating the immunomodulatory effects of nutrients on the maturation, activation and effector functions of the various immune cells types and tissues? Which biomarkes, in vivo tests, provide the best insights when considering the modulatory influences of nutrients on immunocompetence.
  3. What molecular studies can be done to address micronutrient modulation of immune function during infection in humans? How do we bridge the large gap between molecular biology and nutritional epidemiology?
  4. When, where and how do the pathways of retinoic acid and cytokine signaling intersect? Do Th1 type cytokines markedly enhance Th2 responses in vitamin A (or other micronutrient) deficiency? Are there key intermediates, such as IRF, STAT or JAK/TYK signaling pathways?
  5. Why is plasma zinc moved to the liver in infection? Is it just to reduce losses via the gut in diarrhoea or does low plasma Zn upregulate aspects of the immune system?
 
6:30 Speakers Dinner at Jean-Michel Restaurant, Old Georgetown Road/Democracy Blvd
AM SESSION DAY 2
8:15 - 8:35 Summary of Day 1
 
Micronutrient Effects on Intracellular Signalling Pathways
Moderator, Dr. Kent Erickson, Univ. California, Davis
 
8:35 "Effects of Dietary Fatty Acids on T cell Activation, a T Cell Receptor (TcR)-Mediated Signaling in a Murine Model"
Dr. David McMurray, Texas A & M, College Station, TX
8:50 "Dietary Omega-3 Fatty Acids Adversly Effects IL-12 and IFNg Responses During Murine Listeriosis"
Dr. Kevin Fritsche, Univ. of Missouri, Columbia, MO
9:15 "Giardia lamblia - the Life-Cycle of a Primitive Eukaryote is Modulated by its Lipid Environment"
Dr. Richard Deckelbaum, Columbia Univ., NY, and Dr. Ted Nash, NIAID
9:40 - 9:55
Break
 
Modulation of Cytokine Responses by Micronutrients
Moderator, Dr. David Hughes, Norwich Research Park, UK
 
9:55 "Effects of Zinc on Th1 and Th2 Cytokine Shifts"
Dr. Ananda Prasad, Wayne State Univ., Detroit, MI
10:20 "Effects on Selenium Deficiency on Cytokine Responses"
Dr. Marianna Baum, Univ. of Miami, Miami, FL
10:45 "Effects of Inadequate Copper Status on Cytokine Expression in Immune Cells" 
Dr. Mark Failla, Univ. N. Carolina, Greensboro, NC
11:10 "Antioxidant Cytokines and Influenza Infection in the Aged"
Dr. Simin Meydani, Tufts Univ., Boston, MA
 
11:35 - 11:45
General Discussion/Critical Questions
List of "Suggested" Critical Questions
  1. Since compartmentalization is an important component of the way the immune response is regulated in vivo, how does the reliance on tissue immune cells (e.g., peritoneal macrophages, splenocytes) in most rodent studies versus peripheral blood immune cells for human studies effect the comparability of these data?
  2. Are cell lines particularly useful in assessing the impact of nutrient status on specific aspects (B cells, Macrophages or interactions among) of innate vs acquired immunity?
  3. How should one select the most appropriate cell or animal model that would relate these studies to humans?
  4. Does vitamin A deficiency represent a condition of chronic (mild) inflammation that biases the immune system towards Th1 type of response?
 
11:45 - 12:45
Lunch
 
Implications for Treatment and Disease
Moderators, Drs. Richard Guerrant, Univ. Virginia and Frances Davidson, USAID, Washington DC 
 
12:45 "The Immunological Evaluation of the Nutritionally At Risk Host"
Dr. Carl Keen (Univ. California, Davis, CA)
1:10 "Transfusional Iron Overload: An Analytical Model of Nutrient Immune Interactions"
Dr. Susanna Cunningham Rundles, Cornell Univ., New York, NY
1:35 "Nutritional Modulation of Immune Responses: Implications for Disease"
Dr. Wafaie Fawzi, Harvard University, Cambridge, MA
1:50 "Implications for International Research and Child Health"
Dr. Gerald Keusch, Forgarty International Center, Bethesda, MD
 
2:15 - 2:45
General Discussion/Critical Questions
List of "Suggested" Critical Questions
  1. What are the practical issues pertaining to the inclusion of state-of-the-art immunological parameters in field studies?
  2. What are the public health implications of nutritional immunology? Can we design specific micronutrient interventions for specific infectious diseases? Is it time to form a professional society of nutritional immunology? What has had more of an impact on infectious disease case fatality rates in developing countries--better nutrition or technologically advanced medicine?
  3. What are the consequences of marginal vs frank deficiencies and are there markers of marginal deficiencies applicable to field situations? Are micronutrient effects linked to macronutrient status?
  4. Considering the importance of the ultimate move from "bench to bedside", in the field of nutrition and infectious diseases, what factors/issues should be considered in establishing guidelines/standards. For example, is a Board of nutrition and ID experts needed? 
2:45 - 3:00
Break
 
3:00 - 3:30
Discussion of Objectives
 
3:30 - 3:45
Workshop Summary and Recommendations for Future Research
 
3:45 - 4:00
Funding Opportunities