# In Host Evolution of Nontuberculous Mycobacteria in Cystic Fibrosis

> **NIH NIH R21** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $272,623

## Abstract

PROJECT SUMMARY
Nontuberculous mycobacteria (NTM) have emerged as an increasingly common cause of severe lung disease
in patients with cystic fibrosis (CF). Unfortunately, diagnosis, prognosis, and treatment remain exceedingly
difficult. Infection can result in more rapid decline in lung function and even death. During chronic infection,
NTM frequently become resistant to the most effective antibiotic regimens, and infection is typically difficult or
impossible to eradicate. Moreover, little is known about the molecular determinants of pathogenesis,
inflammation, immune evasion, and persistence in NTM-driven disease. Here we propose an approach that
follows the genomic evolution of NTM over time in chronically infected CF patients. We will rigorously apply
whole genome sequencing and a battery of phylogenomic analyses to identify genetic changes in NTM strains
that are likely to increase pathogen fitness. Because the CF lung harbors a complex and dynamic microbial
ecosystem we will also comprehensively assess co-inhabiting microbiota, including well-known CF pathogens
and other members of the respiratory microbiota. While some microbiota may compete with NTM, others may
act to reinforce NTM infections, and some could even serve as reservoirs for genes that are beneficial to the
pathogen (e.g., antibiotic resistance). We hypothesize that NTM undergoes predictable phenotypic and
genotypic changes, which are likely influenced by co-infecting microbiota, to allow for enhanced NTM
fitness, virulence, and persistence in the lung. AIM 1 examines longitudinal isolates from CF patients
infected with NTM, emphasizing a deep sampling approach and population-level estimates of microbial
diversity, mutation, recombination, and natural selection. Evolutionary changes in NTM populations will be
associated with detailed clinical and phenotypic information, to identify genes that may be involved in antibiotic
resistance, virulence, and persistence. AIM 2 uses a novel, whole 16S-rRNA gene sequencing approach to
examine the cross-sectional and longitudinal interaction of NTM with other lung microbiota including co-
infecting CF pathogens. We will compare patients with and without NTM and associate differences in the
microbial population. Completing these aims will identify genes and microbial interactions that can be targeted
for future functional studies aimed at uncovering the basic mechanisms and strategies that allow NTM
adaptation during in-host evolution. We will also test and validate bioinformatic pipelines and sampling
strategies that can be used in future NTM phylogenomic studies, and we will gain a fine-grained understanding
of the NTM population dynamics during chronic infection. Characterizing in-host NTM adaptation will allow us
to more effectively identify strains that may be difficult to eradicate or treat, and design new, targeted
interventions to subvert these adaptations.!

## Key facts

- **NIH application ID:** 9896274
- **Project number:** 1R21AI144561-01A1
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** PAUL J PLANET
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $272,623
- **Award type:** 1
- **Project period:** 2020-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896274

## Citation

> US National Institutes of Health, RePORTER application 9896274, In Host Evolution of Nontuberculous Mycobacteria in Cystic Fibrosis (1R21AI144561-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896274. Licensed CC0.

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