Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Mutations in this chloride channel lead to mucus accumulation, subsequent recurrent pulmonary infections, and inflammation, which, in turn, cause chronic lung disease and respiratory failure. Recently, rates of nontuberculous mycobacterial (NTM) infections in CF patients have been increasing. Of particular relevance is infection with , which causes a serious, life-threatening disease and constitutes one of the most antibiotic-resistant NTM species. Interestingly, an increased prevalence of NTM infections is associated with worsening lung function in CF patients who are also coinfected with We established a new mouse model to investigate the relationship between and pulmonary infections. In this model, animals exposed to and coinfected with exhibited increased lung inflammation and decreased mycobacterial burden compared with those of mice infected with alone. This increased control of infection in coinfected mice was mucus independent but dependent on both transcription factors T-box 21 (Tbx21) and retinoic acid receptor (RAR)-related orphan receptor gamma t (RORγ-t), master regulators of type 1 and type 17 immune responses, respectively. These results implicate a role for both type 1 and type 17 responses in control in-coinfected lungs. Our results demonstrate that , an organism found commonly in CF patients with NTM infection, can worsen pulmonary inflammation and impact control in a mouse model.
Members of the Mycobacterium avium complex (MAC), a group of mycobacteria encompassing M. avium and its closest relatives, are omnipresent in natural environments and emerging pathogens of humans and animals. MAC infections are difficult to treat, sometimes fatal, and increasingly common.
Background Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and an increasingly frequent cause of opportunistic infections. Mycobacterium abscessus complex (MAB) is one of the major NTM lung pathogens which disproportionately colonize and infect the lungs of individuals with cystic fibrosis (CF). MAB infection can persist for years, and antimicrobial treatment is frequently ineffective. Methods We sequence the genomes of 175 isolates longitudinally collected from 30 patients with MAB lung infection. We contextualize our cohort amidst the broader MAB phylogeny and investigate genes undergoing parallel adaptation across patients. Finally, we test the phenotypic consequences of parallel mutations by conducting antimicrobial resistance and mercury resistance assays. Results We identify highly related isolate pairs across hospital centers with low likelihood of transmission. We further annotate non-random parallel mutations in 22 genes and demonstrate altered macrolide susceptibility co-occurring with a nonsynonymous whiB1 mutation. Finally, we highlight a 23 kb mercury resistance plasmid whose loss during chronic infection confers phenotypic susceptibility to organic and non-organic mercury compounds. Conclusions We characterize parallel genomic processes through which MAB is adapting to promote survival within the host. The within-lineage polymorphisms we observe have phenotypic effects, potentially benefiting fitness in the host at the putative detriment of environmental survival.
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