R01AI188584

Airway innate immune responses to Coccidioides infection - Coccidioidomycosis, also known as Valley Fever, is a serious fungal infection caused by the Coccidioides species.

These dimorphic fungi thrive in the arid regions of the Americas, including the southwestern United States, Mexico, and certain parts of Central and South America.

Recently, there has been a substantial rise in Coccidioidomycosis cases, extending into areas previously unaffected and creating a significant health risk.

Predictions suggest that by 2035, more than half of the US could be at risk.

Unlike most fungal infections that typically target those with weakened immune systems, Coccidioides can also infect individuals with healthy immune systems.

While many people may not show symptoms or only suffer mild, flu-like ones, serious cases can lead to ongoing lung and other organ issues, occasionally resulting in death.

The reasons why the disease affects some people more severely than others remain unclear.

There is an urgent need to better understand how our bodies fight off Coccidioides, especially through the initial innate immune defense.

The primary route of infection involves inhaling fungal spores, leading to lung infection.

Our research has discovered that a set of airway epithelial antimicrobial proteins (AMPs), including SCGB1A1 and BPIFA1, were significantly elevated in the lung without apparent inflammation or a spike in inflammatory/immune related genes.

These proteins were not triggered by non-virulent fungi, hinting at a unique response to pathogenic Coccidioides.

In mouse models, the absence of SCGB1A1 markedly increased susceptibility to lung fungal infection.

In vitro studies have confirmed that BPIFA1, but not SCGB1A1, exhibited anti-Coccidioides activity.

Furthermore, SCGB1A1 deficiency impaired airway epithelial BPIFA1 secretion by reducing extracellular vesicle production.

Thus, the epithelial SCGB1A1-BPIFA1 axis plays a critical role in the early pulmonary defense against Coccidioides.

Our goal is to uncover the mechanisms of early innate responses to Coccidioides infection, to understand the mechanisms of antifungal effects of BPIFA1, and to determine the mechanisms of BPIFA1 secretion regulated by SCGB1A1.

This proposal represents the first effort to comprehensively investigate the molecular mechanisms and functional impact of epithelial AMPs during Coccidioides infection.

Notably, all experiments involving Coccidioides spp. must be conducted within a BSL3 containment facility.

Leveraging this critical resource, along with a multidisciplinary team skilled in lung epithelial biology, mycology, EV biology, and AMP engineering, we are uniquely positioned to push the boundaries of mechanistic studies and lay the foundation for the future development of innovative antifungal therapies aimed at advancing the diagnosis and treatment of Coccidioidomycosis.

University Of Arizona

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]

Arizona United States

State-Wide

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