The Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (PNWRCE) brings together a consortium of investigators with extensive expertise, and basic and translational research capacity directed at a broad range of NIAID Category A-C Pathogens. Our research activities are aimed at providing a deeper understanding of pathogen-host interactions; how these interactions impact innate and adaptive immune responses; and the age-related defects in immunity that lead to immunosenescence and an increased vulnerability to infectious disease. The information generated from these activities will facilitate the development of next-generation therapeutics, diagnostics, and vaccines against Category A-C Pathogens. The PNWRCE will also train young investigators for biodefense and emerging infectious disease research, foster the development of new research programs, and provide facilities and scientific support to first-line responders in the event of a national biodefense or emerging infectious disease emergency.

RESEARCH THEMES
The research activities of the PNWRCE are unified by two distinct but interrelated themes:

The identification of age-related defects in the immune system to facilitate the development of vaccines and supplemental therapies

and

The use of systems biology and systems genetics approaches to define pathogen-host interactions and mechanisms of innate and adaptive immunity

These themes reflect the strengths of PNWRCE investigators and are geared toward addressing significant public health needs in the United States.  In particular, our use of systems-level approaches and focus on innate and adaptive immunity and immunosenescence provide new opportunities to identify targets for therapeutic intervention and enhancements to current vaccine strategies. Moreover, our research activities are designed to extend these benefits to vulnerable populations, including the aged, which represents the fastest growing segment of American society. Our focus on the host side of pathogen-host interactions will allow us to discover new cellular targets for antiviral products that are less likely to be sensitive to escape through pathogen mutation and more likely to have a broad spectrum of action. As outlined in the NIAID Strategic Plan for Biodefense Research (2007 Update), the development of broad-spectrum drugs, particularly antivirals, is an NIAID priority. The development of broad-spectrum platforms is also encouraged, and we will generate and make available an innovative mouse systems genetics platform that can be used to identify host susceptibility alleles to a variety of pathogens. The broad-spectrum strategy recognizes the expanding range of biological threats and the need for a more responsive biodefense capability. In this regard, there is a pressing need for vaccines against many Category A–C Pathogens, and our research will enhance vaccine development strategies as well as provide new methods for the early evaluation of vaccine efficacy through the identification of genomic correlates of immunity.

GOALS AND OBJECTIVES
The overarching goal of the PNWRCE reflects the goal of NIAID in developing the RCE program, namely:

To establish and maintain a strong infrastructure and multifaceted research and development program that will provide scientific information and translational research capacity to facilitate the development of next-generation therapeutics, diagnostics, and vaccines against Category A–C Pathogens.
On the basis of our research themes, we have identified a series of goals specific to the PNWRCE:

• To provide a detailed view of pathogen-host interactions

We will use traditional and systems-level approaches to determine how specific pathogens are recognized by the innate immune system and the intracellular signaling pathways that are put into play upon recognition. Our studies will evaluate how pathogens regulate, modulate, or evade this response; the pathogen factors required for this process; and how this process impacts adaptive immunity.

• To identify common and unique features of pathogen-host interactions that can be exploited as targets for therapeutic intervention or as diagnostic or prognostic markers

We will generate and use systems-level views and computational models of pathogen-host interactions to reveal common features that can serve as targets for broad-spectrum drugs. Conversely, features of the host response that are unique to a given pathogen may serve as diagnostic or prognostic markers.

• To identify manipulations of the host adaptive immune response that broadly improve protective immunity

We will perform a variety of manipulations of the adaptive immune system, including increasing the T-cell receptor repertoire, diversity and enhancing antigen presentation through the modulation of the inflammatory milieu, ablation or reduction of regulatory T-cell numbers or activity, and improvement of effector T-cell differentiation. Our goal is to define specific manipulations that can be used to broadly improve vaccine efficacy or to overcome age-related defects in the immune response.

• To develop broad-spectrum platforms for research and development

We will determine whether inactivation of viruses through hydrogen peroxide exposure will serve as a platform for the development of safe and effective vaccines against diverse Category A-C Pathogens. We will also develop Collaborative-Cross mice as a platform for the identification of host susceptibility alleles to a broad spectrum of pathogens.

• To develop therapeutics, diagnostics, and vaccines against Category A-C Pathogens

Our vaccine approach is aimed at generating vaccines that are safe and effective in immunologically vulnerable populations. We will also identify genomic and immunologic correlates of protective immunity. Our approach to therapeutic development includes the high-throughput screening of compounds for inhibitors of cellular kinases that are required for flavivirus replication and the use of systems-level views to identify cellular targets for the generation of broad-spectrum drugs. Diagnostic development is aimed at the identification of host gene expression or protein abundance profiles (biomarkers) that are indicative of a response to a specific pathogen or predictive of disease or treatment outcome.