[R21] Use of scnn1b transgenic mice to develop new vaccines against pulmonary Mycobacterium avium
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2028-05-31
Importo max: 423.500 EUR
Paese: US
Descrizione
Over the past fifteen years, there has been an increase in the prevalence of pulmonary nontuberculous mycobacteria
(NTM) in the US and other developed countries. Patients with underlying lung diseases such as chronic obstructive lung
disease (COPD) and cystic fibrosis (CF) are at increased risk of developing pulmonary NTM infections. Mycobacterium
avium complex (MAC) is the most common cause of pulmonary NTM. Management of pulmonary MAC is challenging.
Despite multiple drugs given for at least 18 months, failure rates are in the range of 30% to 40%. Thus, there is a dire need
to develop vaccine and therapeutics. Development of safe vaccines and therapeutics require the use of animals with
structural lung diseases to imitate the structural lung diseases in humans which increase the risk of pulmonary MAC.
Scnn1b-transgenic mouse lungs are characterized by enlarged alveoli, mucus accumulation in the bronchioles, and
neutrophilic infiltration even in the absence of infection. This mouse model has made studies of pulmonary
infections/colonization common in CF patients (e.g., early Pseudomonas colonization) possible. We have received scnn1b
transgenic mice from the University of North Carolina and we now have an established protocol for breeding scnn1b-
transgenic mice and confirming their background genetically. Therefore, this study is proposed with the following two aims:
1. Evaluate lung pathology, MAC growth and immunity following aerosol MAC infection of scnn1b-trangenic mice.
2. Test the effectiveness of DAR-901 and BCG as a vaccine for pulmonary MAC in scnn1b-trangenic mice.
In aim1, we will compare scnn1b-transgenic mice with BALB/c and C57BL/6 mice for growth of MAC in lungs,
histopathology and changes in mucosal immunity following aerosol MAC infection. Mucosal immunity will be measured
using T cells from lungs for flowcytometry and BAL for cytokine/chemokine array. Changes in mucosal immunity following
pulmonary MAC infection in the three strains of mice will be compared with changes in systemic immunity. Antibody
responses in the blood will be measured by ELISA. In aim-2, using scnn1b-transgenic mice, we will evaluate the safety of
BCG, test MAC-specific mucosal and systemic immunity induced by DAR-901 and BCG, and assess the ability of DAR-
901 and BCG to protect against pulmonary MAC-infection. The results from this study will help develop a mice model with
structural lung disease for studies on pulmonary MAC and help advance two whole cell vaccines, DAR-901 and BCG, for
further studies in animals and humans.
Istituzione: SAINT LOUIS UNIVERSITY
PI: Getahun Abate
Progetto: 1R21AI193591-01A1
Settori: National Institute of Allergy and Infectious Diseases
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