R01AI162802

Transcriptional Networks Governing A. fumigatus Virulence - Abstract

Invasive infections due to Aspergillus fumigatus are increasing and are still associated with unacceptably high mortality, even with new therapies. Our understanding of A. fumigatus infection biology is limited. Among 10,180 predicted genes in the A. fumigatus genome, over 95% are uncharacterized, and fewer than 100 genes have demonstrated roles in virulence. It is critical to identify genes that govern virulence and the pathways in which they act because they can point to high priority targets for therapeutic and diagnostic development.

We have identified a transcriptional regulator in A. fumigatus, WRPA, that shares limited homology with Candida albicans WOR1 and Histoplasma capsulatum RYP1. Our preliminary data indicate that WRPA governs the capacity of A. fumigatus to withstand macrophage killing, grow under hypoxic conditions, and invade and damage pulmonary cells in vitro. WRPA deletion mutants have highly attenuated virulence in the mouse model of invasive aspergillosis. Using RNA-Seq, we found that WRPA governs the expression of ~15% of genes in the A. fumigatus genome, including multiple transcription factor genes. Our premise is that WRPA is a master regulator that governs host cell interactions and virulence. In support of this premise, our initial investigations of the WRPA regulon have already revealed novel pathogenicity-related functions of three WRPA-dependent transcription factors, SRBB, FCR1, and NDT80.

Our goal is to characterize the WRPA regulon in A. fumigatus and to identify downstream effector genes whose products mediate pathogenicity by:

1) Identifying the transcription factors that are directly regulated by WRPA and determining their roles in pathogenicity;
2) Analyzing selected WRPA-dependent transcription factors and identifying their downstream target genes; and
3) Determining the function of effector genes controlled by the WRPA regulon and investigating their roles in virulence.

The results of the experiments described in this proposal will enable us to characterize a key transcriptional regulator that governs A. fumigatus pathogenicity and then use this information to identify downstream effector genes, the products of which mediate host cell interactions and virulence. The results of this work will not only provide foundational understanding of A. fumigatus virulence mechanisms, but also hold promise to identify new diagnostic, therapeutic, and vaccine targets.

Lundquist Institute For Biomedical Innovation At Harbor-Ucla Medical Center

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]

Torrance, California 905022006 United States

Single Zip Code

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

Amendment Since initial award the total obligations have increased 392% from $671,071 to $3,301,255.