R01AI181904

MICROBIAL DETERMINANTS OF EXCESSIVE INFLAMMATION AND SEVERE LYME DISEASE - PROJECT SUMMARY/ABSTRACT LYME DISEASE HAS REACHED EPIDEMIC PROPORTIONS IN SEVERAL REGIONS IN UNITED STATES AND EUROPE AND POSES A SUBSTANTIAL BURDEN ON AFFECTED COMMUNITIES. THE ILLNESS ENCOMPASSES A SPECTRUM OF CLINICAL MANIFESTATIONS WHICH VARY IN SEVERITY AND DURATION, INCLUDING COMPLICATIONS THAT PERSIST AFTER ANTIBIOTIC-THERAPY, TERMED POST- LYME SYNDROMES. HOWEVER, THE REASONS FOR THIS RANGE IN DISEASE SEVERITY ARE NOT CLEAR AND BIOMARKERS TO IDENTIFY PATIENTS AT GREATER RISK FOR ADVERSE OUTCOMES ARE LACKING. OUR FINDINGS SUGGEST THAT INAPPROPRIATE IMMUNE RESPONSES, WHICH ARE SHAPED BY MICROBIAL AND HOST GENETICS, ARE AN IMPORTANT FACTOR IN DISEASE SEVERITY. WE PREVIOUSLY IDENTIFIED A PARTICULARLY VIRULENT BORRELIA BURGDORFERI (BB) RST1 STRAIN WHICH LEADS TO EXCESSIVE INFLAMMATION AND SEVERE DISEASE, INCLUDING HIGHLY SYMPTOMATIC EARLY INFECTION AND A GREATER RISK FOR ANTIBIOTIC-REFRACTORY LYME ARTHRITIS, A POST-LYME COMPLICATION OF THIS DISEASE. THESE FINDINGS PROVIDED A NEW PARADIGM FOR STUDYING MICROBIAL UNDERPININGS OF MALADAPTIVE IMMUNITY AND UNTOWARD CLINICAL OUTCOMES IN LYME DISEASE. HOWEVER, BB COMPONENTS RESPONSIBLE FOR EXCESSIVE INFLAMMATION AND SEVERE DISEASE ARE NOT KNOWN. SEVERAL LINES OF EVIDENCE POINT TO DIFFERENCES IN EXPRESSION OR SEQUENCE VARIATION IN BORRELIA LIPOPROTEINS AS A MAJOR DETERMINANT OF THESE OUTCOMES. IN THIS PROPOSAL, WE ARE LEVERAGING OUR UNIQUE COLLECTION OF CLINICAL SAMPLES FROM WELL-DEFINED PATIENTS, AND FUNCTIONAL STUDIES USING GENETICALLY-ENGINEERED ISOGENIC BB STRAINS TO SYSTEMATICALLY DELINEATE THE IMMUNOGENIC LIPOPROTEINS AND ASCERTAIN THEIR FUNCTION IN DYSREGULATED IMMUNE RESPONSES AND ADVERSE CLINICAL OUTCOMES IN LYME DISEASE. WE PROPOSE TO: AIM 1. DETERMINE THE INFLAMMATORY CAPACITY OF CANDIDATE LIPOPROTEINS ARP OR OSPC IN VITRO BY GENERATING STRAINS CONTAINING ARP OR OSPC VARIANTS AND TESTING THEIR INFLAMMATORY CAPACITY IN HUMAN PBMC CULTURES. AIM 2. DELINEATE THE IMPACT OF ARP AND OSPC-A EXPRESSING STRAINS ON ARTHRITIS SEVERITY IN MICE BY TESTING EARLY AND LATE IMMUNE RESPONSES AND ARTHRITIS SEVERITY IN C3H MICE INFECTED WITH ISOGENIC STRAINS EXPRESSING ARP OR OSPC VARIANTS, AND ASCERTAIN THE IMPACT OF ARP AND OSPC ON IMMUNE RESPONSE AND DISEASE SEVERITY IN PATIENTS BY CHARACTERIZING EARLY AND LATE IMMUNE RESPONSES IN PATIENTS WITH PTLDS, DEFINING THE IMPACT OF ARP & OSPC ON THESE IMMUNE RESPONSES AND, IDENTIFYING NEW BB DETERMINANTS OF IMMUNOGENICITY AND VIRULENCE USING GWAS WITH IMMUNE AND CLINICAL PHENOTYPE IN PATIENTS. THESE STUDIES WILL GENERATE NEW INSIGHTS INTO PATHOGENESIS OF LYME DISEASE AND MAY HELP LAY THE GROUNDWORK FOR NOVEL DIAGNOSTIC APPROACHES TO IDENTIFY PATIENTS AT GREATER RISK FOR SEVERE DISEASE. THE ABILITY TO IDENTIFY SUCH PATIENTS COULD HELP GUIDE MORE EFFECTIVE TREATMENT STRATEGIES WHICH INCORPORATE IMMUNOMODULATORY THERAPIES TO QUIET THE IMMUNE RESPONSE; AN APPROACH THAT IS ALREADY EMPLOYED FOR TREATMENT OF PATIENTS WITH REFRACTORY LYME ARTHRITIS.

Trustees Of Tufts College

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Massachusetts United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)