R01AI198328

ALTERING THE INFECTION ENVIRONMENT FOR THE ERADICATION OF S. AUREUS INFECTION - ABSTRACT SKIN AND SOFT TISSUE INFECTIONS (SSTIS) ARE A LEADING CAUSE OF EMERGENCY DEPARTMENT VISITS, WITH COMMUNITY- ACQUIRED METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS (CA-MRSA) AS THE PREDOMINANT PATHOGEN. SSTIS OFTEN PRESENT AS ABSCESSES AND CAN PROGRESS TO LIFE-THREATENING INFECTIONS SUCH AS OSTEOMYELITIS, SEPSIS, AND ENDOCARDITIS. RISING ANTIBIOTIC RESISTANCE HAS COMPLICATED TREATMENT, WITH FREQUENT RECURRENCE DESPITE THERAPY. THIS HIGHLIGHTS THE NEED FOR ADJUNCTIVE STRATEGIES TO ENHANCE ANTIBIOTIC EFFICACY, PARTICULARLY THROUGH TARGETED IMMUNE MODULATION. WHILE THE IMMUNE RESPONSE CAN BOTH SUPPORT AND HINDER ANTIBIOTIC ACTIVITY, THE MECHANISMS UNDERLYING THESE EFFECTS IN SSTIS REMAIN POORLY DEFINED. OUR CENTRAL HYPOTHESIS IS THAT DISTINCT PHASES OF THE HOST IMMUNE RESPONSE DIFFERENTIALLY INFLUENCE MRSA SUSCEPTIBILITY TO ANTIBIOTICS. IN AIM 1, WE WILL INVESTIGATE HOW NEUTROPHILS ENRICHED IN THE INFLAMMATORY PHASE OF SSTIS, PROMOTE ANTIBIOTIC TOLERANCE. WE SHOW THAT HUMAN NEUTROPHILS INDUCE ROBUST TOLERANCE IN S. AUREUS IN VITRO, AND THAT NEUTROPENIA IMPROVES VANCOMYCIN EFFICACY IN VIVO. IN AIM 2, WE WILL TEST WHETHER ENHANCING THE TRANSITION TO THE RESOLUTION PHASE USING PPARΓ AGONISTS PROMOTES ANTIBIOTIC SUSCEPTIBILITY. WE WILL EXPLORE HOW RESOLUTION-PHASE EFFECTORS—POLYAMINES AND MONOUNSATURATED FATTY ACIDS (MUFAS)—SYNERGIZE WITH ANTIBIOTICS TO CLEAR INFECTION. OUR PRELIMINARY DATA SHOW THAT USA300 ISOLATES ARE UNIQUELY RESISTANT TO SPERMINE BUT REMAIN SENSITIVE TO OTHER POLYAMINES AND MUFAS, WHICH ENHANCE VANCOMYCIN ACTIVITY. IN AIM 3, WE WILL DETERMINE HOW IMMUNE DYSFUNCTION IN DIABETIC INFECTIONS CONTRIBUTES TO ANTIBIOTIC FAILURE AND EMERGENCE OF RESISTANCE. WE FIND THAT DIABETIC SSTIS ARE MARKED BY IMPAIRED OXIDATIVE BURST DUE TO DEFECTIVE MTOR- DEPENDENT GLUT-1 EXPRESSION IN PHAGOCYTES. THIS DYSFUNCTION BLOCKS PROGRESSION TO THE RESOLUTION PHASE, IMPAIRING PRODUCTION OF BACTERICIDAL POLYAMINES AND MUFAS. COMPLETION OF THIS PROPOSAL WILL IDENTIFY HOST IMMUNE PROCESSES THAT INDUCE ANTIBIOTIC TOLERANCE OR AUGMENT ANTIMICROBIAL EFFICACY. BY TARGETING THESE PATHWAYS WITH IMMUNE MODULATORS SUCH AS PPARΓ AND MTOR AGONISTS, WE AIM TO DEVELOP NOVEL ADJUNCTIVE THERAPIES TO IMPROVE OUTCOMES IN MRSA SSTIS, INCLUDING THOSE COMPLICATED BY DIABETES OR ANTIMICROBIAL RESISTANCE.

University Of North Carolina At Chapel Hill

<P>THE GOALS ARE:</P><UL><LI>TO FOSTER FUNDAMENTAL CREATIVE DISCOVERIES, INNOVATIVE RESEARCH STRATEGIES, AND THEIR APPLICATIONS AS A BASIS FOR ULTIMATELY PROTECTING AND IMPROVING HEALTH;</LI><LI>TO DEVELOP, MAINTAIN, AND RENEW SCIENTIFIC HUMAN AND PHYSICAL RESOURCES THAT WILL ENSURE THE NATION'S CAPABILITY TO PREVENT DISEASE;</LI><LI>TO EXPAND THE KNOWLEDGE BASE IN MEDICAL AND ASSOCIATED SCIENCES IN ORDER TO ENHANCE THE NATION'S ECONOMIC WELL-BEING AND ENSURE A CONTINUED HIGH RETURN ON THE PUBLIC INVESTMENT IN RESEARCH; AND</LI><LI>TO EXEMPLIFY AND PROMOTE THE HIGHEST LEVEL OF SCIENTIFIC INTEGRITY, PUBLIC ACCOUNTABILITY, AND SOCIAL RESPONSIBILITY IN THE CONDUCT OF SCIENCE.</LI></UL><P>IN REALIZING THESE GOALS, THE NIH PROVIDES LEADERSHIP AND DIRECTION TO PROGRAMS DESIGNED TO IMPROVE THE HEALTH OF THE NATION BY CONDUCTING AND SUPPORTING RESEARCH:</P><UL><LI>IN THE CAUSES, DIAGNOSIS, PREVENTION, AND CURE OF HUMAN DISEASES;</LI><LI>IN THE PROCESSES OF HUMAN GROWTH AND DEVELOPMENT;</LI><LI>IN THE BIOLOGICAL EFFECTS OF ENVIRONMENTAL CONTAMINANTS;</LI><LI>IN THE UNDERSTANDING OF MENTAL, ADDICTIVE AND PHYSICAL DISORDERS; AND</LI><LI>IN DIRECTING PROGRAMS FOR THE COLLECTION, DISSEMINATION, AND EXCHANGE OF INFORMATION IN MEDICINE AND HEALTH, INCLUDING THE DEVELOPMENT AND SUPPORT OF MEDICAL LIBRARIES AND THE TRAINING OF MEDICAL LIBRARIANS AND OTHER HEALTH INFORMATION SPECIALISTS.</LI></UL>

93.855 - Allergy and Infectious Diseases Research

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

Chapel Hill, North Carolina 27599 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-25-301)