Innate immunity to NIAID Category B protozoa.

This initiative will support basic research to define the mechanisms of action by which the innate immune system recognizes and responds to the food and waterborne eukaryotes classified as NIAID Category B priority protozoan pathogens ( Cryptosporidium parvum, Cyclospora cayetanensis, Giardia lamblia, Entamoeba histolytica, Toxoplasma, and Microsporidia) (http://www2. niaid.nih.gov/Biodefense/bandc_priority.htm).

The NIH and other agencies in the Department of Health and Human Services (DHHS) are currently supporting extramural research to develop new products to protect the public from the health consequences of biological agents that might be used in acts of terrorism or war. The research supported by this RFA will contribute to meeting the goals for host defense described in the NIAID Strategic Plan for Biodefense, which is located at: http://www2.niaid. nih.gov/Biodefense/Research/strat_plan.htm, by increasing our understanding of the mechanisms by which the innate immune system recognizes, responds to, and neutralizes the complex defense systems of protozoan pathogens. The complexity of the interactions between the host innate immune system and protozoan pathogens requires in-depth knowledge of innate immunity, mucosal immunity, and protozoan microbiology/biochemistry.

There is evidence that the innate immune system recognizes and responds to protozoan parasites. Recent studies have shown that Toxoplasma gondii stimulates host cells through TLR2 and TLR4, activates B lymphocytes, NK and NKT cells, and stimulates Interferongamma and NO production. In other studies, Cryptosporidium parvum infection activated both CD4+ and CD8+ gamma/delta T cells, and Giardia species stimulated the release of several effector molecules, including defensins, cryptdins, and indolicidin. Utilizing the NIAID Category B protozoa to better understand the innate immune response to eukatyotic pathogens may lead to new broad spectrum immunotherapeutics and adjuvants for protozoan vaccines.

Eukaryotic pathogens are a serious public health problem in developing countries. Exposure to pathogens such as Giardia, Cryptosporidium, and Entamoeba has been greatly diminished in the U.S. due to effective regulation of public water supplies and commercial food processing. Thus, interest in protozoan vaccine development has lagged behind that for prokatyotic pathogens. With the recently increased threat of biowarfare, the potential for adulteration of U.S. food and water supplies has increased. In-depth understanding of innate immune responses to protozoa is important because their genomic complexity affords them a greater variety of immune evasion mechanisms than those displayed by prokatyotes.

The major goal of this PEA is to support research focused on the mechanisms of action by which the mammalian innate immune system responds to the food and waterborne protozoa from the NIAID Category B Priority Pathogens list. Studies utilizing human cells or clinical samples are not required, but are strongly encouraged. Appropriate areas of research include, but are not limited to: 1) Characterization of host cells involved in the innate immune response to protozoa; 2) Identification of novel pathogen-associated molecular pattern recognition receptors on host cells; 3) Characterization of mediators of innate immunity that are produced by host cells stimulated by protozoa; 4) Elucidation of the intracellular signaling pathways in the mammalian innate immune cells that are stimulated by protozoa; 5) Comparison of human versus animal model molecular responses to protozoan pathogens or their components; 6) Human or animal model gene mutations or polymorphisms associated with distinctive innate immune responses to protozoa.

This initiative will unite interdisciplinary teams of researchers with expertise in innate immunity, mucosal immunity, and protozoan microbiology to stimulate scientifically sound, original research that will advance the field and encourage productive interactions among Principal Investigators. In the long term, these efforts will form a basis for the rational design of pathogen- or class-specific immunotherapeutics, as well as adjuvants that will enhance the future development of vaccines against potential bioweapons.

In some cases, immunological mechanisms relevant to biodefense are broadly applicable for many pathogens and may be most efficiently studied using model systems. Immunological research that is directed at protozoa other than those listed as NIAID Category B Priority Pathogens is responsive to this announcement if the research specifically addresses a practical approach to inducing, controlling, or improving the effectiveness of the innate immune response to NIAID Category B protozoan infection. Applicants must justify how the proposed research is applicable to immune responses against the listed agents.

Note: This RFA will NOT support clinical trials; applications requesting support for clinical trials will be considered nonresponsive and will be returned to the applicant without review. However, utilization of human-derived material in studies is considered responsive.

This funding opportunity will use the individual Research Project Grant (R01) and Exploratory/ Developmental Research Grant (R21) award mechanisms.

This funding opportunity uses just-in-time concepts. It also uses the modular as well as the nonmodular budget formats (see http://grants.nih.gov/grants/ funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format described in the PHS 398 application instructions, available at http://grants.nih.gov/grants/funding/ phs398/phs398/398.html in an interactive format. Otherwise, follow the instructions for nonmodular research grant applications. For further assistance contact GrantsInfo, 301-435-0714, (telecommunications for the hearing impaired: TTY 301-451-0088) or by e-mail: [e-mail].

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling 866-705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The deadline for receipt of letters of intent is October 24, 2005, with November 22, 2005 the deadline for receipt of applications. The complete version of this RFA is available at http://www.niaid. nih.gov/ncn/budget/QA/fra-05-042.htm.

Contact: David B. Winter, Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, Room 3014, MSC-6601, 6610 Rockledge Drive, Bethesda, MD 20892-6601 USA, (for express mail use 20817), 301-496-7551, fax: [phone], e-mail: dwinter@ niaid.nih.gov. Reference RFA-AI-05-042