R01AI193097

MOLECULAR MECHANISMS OF ENTEROVIRUS D68 VIRAL ENTRY MEDIATED BY THE MFSD6 RECEPTOR - PROJECT SUMMARY NONPOLIO ENTEROVIRUSES ARE UBIQUITOUS VIRUSES THAT GENERALLY CAUSE MILD RESPIRATORY AND GASTROINTESTINAL SYMPTOMS BUT CAN, IN RARE CASES, CAUSE SEVERE DISEASE. RECENT OUTBREAKS OF ENTEROVIRUS D68 (EV-D68) HAVE BEEN ASSOCIATED WITH SEVERE RESPIRATORY DISEASE REQUIRING HOSPITALIZATION AND NEUROPATHOGENESIS, INCLUDING POLIO-LIKE PARALYSIS SYNDROME. DESPITE THE CLINICAL RELEVANCE OF EV-D68, THERE ARE NO ANTIVIRAL AGENTS OR LICENSED VACCINES AVAILABLE, AND EV-D68’S INTERACTIONS WITH HOST PROTEINS REMAINS LARGELY UNCHARACTERIZED. IN PRELIMINARY DATA, WE HAVE USED GENOME-SCALE CRISPR SCREENS AND IDENTIFIED THE POORLY CHARACTERIZED MULTIPASS MEMBRANE TRANSPORTER MFSD6 AS A HOST ENTRY FACTOR FOR EV-D68. KNOCKOUT OF MFSD6 EXPRESSION ABROGATED EV-D68 INFECTION OF HUMAN CELL LINES DERIVED FROM THE LUNGS AND THE CNS. WE SHOW THAT MFSD6 IS LOCALIZED AT THE PLASMA MEMBRANE, AND IS REQUIRED FOR VIRAL INTERNALIZATION INTO THE HOST CELL. MFSD6 DIRECTLY BINDS TO EV-D68 PARTICLES VIA ITS THIRD EXTRACELLULAR LOOP (L3). A DECOY RECEPTOR, ENGINEERED BY FUSING MFSD6(L3) TO FC, BLOCKED EV-D68 INFECTION OF HUMAN PRIMARY LUNG EPITHELIAL CELLS, AND PROVIDED NEAR COMPLETE PROTECTION AGAINST PATHOGENESIS IN A LETHAL MOUSE MODEL OF EV-D68 CNS INFECTION. THE PRELIMINARY DATA POINT TO AN ESSENTIAL ROLE OF MFSD6 AS ENTRY RECEPTOR, AND ITS BROAD EXPRESSION PATTERN IN MULTIPLE TISSUES, INCLUDING THE SPINAL CORD AND LUNGS, SUGGEST A ROLE IN PATHOGENESIS. WE HYPOTHESIZE THAT THE BINDING OF EV-D68 WITH MFSD6 VIA MOLECULAR INTERACTIONS RESULTS IN THE FUNCTIONAL ENTRY OF EV-D68 RNA INTO THE CELL, AND THAT THIS INTERACTION IS IMPORTANT FOR DISEASE PATHOGENESIS. THE PRIMARY GOALS OF THIS COLLABORATIVE PROPOSAL BETWEEN THE CARETTE, CHIU, AND NAGAMINE LABORATORIES ARE: (1) TO DEFINE THE PRECISE MECHANISM(S) BY WHICH MFSD6 FACILITATES EV-D68 ENTRY INTO CELLS, (2) TO GAIN HIGH-RESOLUTION STRUCTURAL INSIGHT AS TO HOW MFSD6 ENGAGES THE EV-D68 VIRION, AND (3) TO DETERMINE THE DETAILED ROLE OF MFSD6 IN THE PATHOGENESIS OF EV-D68 INFECTION IN VIVO USING MURINE MODELS. OUR RESULTS WILL PROVIDE DETAILED INSIGHTS INTO RECEPTOR-VIRUS INTERACTIONS AND THE FUNDAMENTAL ENTRY MECHANISM OF AN EMERGING NEUROTROPIC PICORNAVIRUS WITH PANDEMIC POTENTIAL. THIS INFORMATION MAY FACILITATE THE DEVELOPMENT OF SMALL MOLECULES OR BIOLOGICALS THAT DISRUPT MFSD6 INTERACTION WITH EV-D68, WHICH COULD FORM THE BASIS OF FUTURE THERAPEUTICS THAT AMELIORATE DISEASE.

The Leland Stanford Junior University

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]

Stanford, California 94305 United States

Single Zip Code

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