# Using Collaborative Cross mice to develop a novel model of Mycobacterium abscesses lung infection

> **NIH NIH R21** · HACKENSACK UNIVERSITY MEDICAL CENTER · 2020 · $221,375

## Abstract

Abstract
Lung disease caused by Non-Tuberculous Mycobacteria (NTM) poses an increasing threat to individuals with
preexisting lung conditions including cystic fibrosis, chronic obstructive pulmonary disease or bronchiectasis, as
well as immunocompromised patients. Infections caused by the intrinsically drug resistant NTM Mycobacterium
abscessus (Mab) are considered non-curable with current chemotherapy. Thus, novel therapies against Mab
infection are urgently needed, and their discovery and development require predictive animal models and a
detailed understanding of involved immunopathology. However, guinea pigs and wild type mouse strains typically
used in antimicrobial development are resistant to Mab infection. Thus, current drug testing approaches use
mice with severe immunodeficiencies, which do not develop the pathologies observed in human patients.
Furthermore, the mice were infected via systemic high dose inoculation, while natural infection in humans occurs
by inhalation of a low pathogen dose. Based on M. tuberculosis and NTM literature indicating that the outcome
of infection depends on the genotypes of the host and the pathogen, we hypothesized that it is possible to identify
a wild type (immunocompetent) mouse strain-Mab isolate pair that would recapitulate the human mode of
infection, robust persistent Mab burden, and relevant pulmonary pathology. To test our hypothesis, we inoculated
immunocompetent BALB/c mice intranasally with 10 different clinical Mab isolates. After 40 days, some mouse
groups had cleared the infection while others had a bacterial burden of up to 3 logs in lungs, indicating a
considerable variability in persistence among clinical Mab isolates. Bacilli of the most highly persistent isolate
were then implanted into the lungs of 7 genetically distinct mouse strains, including collaborative cross (CC)
founder strains. The kinetics of bacterial burden in lungs and spleen over 28 days and pulmonary histopathology
analyses showed that Mab lung infection in wild type mice progresses through an early stage productive infection
followed by a mouse genotype-dependent, broad spectrum of disease outcomes ranging from mild to severe
pathology and low to high pulmonary bacterial burden. In this application we propose to build on these promising
results by infecting 20 CC mouse strains covering a large array of complex genetic traits with the most virulent
Mab clinical isolate identified in our preliminary experiments and study bacterial persistence and pulmonary
pathology. The mouse strain most closely mimicking human Mab infection pathologically and regarding
robustness of infection will be sex-specific profiled in depth including bacterial kinetics, lung pathology, cytokine
analysis, specific T cell responses and the efficacy of clinically relevant antibiotics. These studies will generate
a robust immunocompetent mouse model for Mab lung disease, which will provide a more predictive platform for
Mab drug discovery and enable...

## Key facts

- **NIH application ID:** 9934109
- **Project number:** 5R21AI145396-02
- **Recipient organization:** HACKENSACK UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Martin Alfons Gengenbacher
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $221,375
- **Award type:** 5
- **Project period:** 2019-05-23 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934109

## Citation

> US National Institutes of Health, RePORTER application 9934109, Using Collaborative Cross mice to develop a novel model of Mycobacterium abscesses lung infection (5R21AI145396-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9934109. Licensed CC0.

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