1) Host Pathogenesis. Chronic lung infections associated with nontuberculous mycobacteria (NTM) often occur in the setting of known structural lung disease such as COPD or bronchiectasis associated with cystic fibrosis or primary ciliary dyskinesia. Our observational cohort study serves as the backbone for pathogenesis research focused on patients with idiopathic nodular bronchiectasis associated with NTM infection occurring predominantly in older women. We have previously describe the association of ciliary dysfunction in this population. Infection of air-liquid interface cultures primary epithelial cells from healthy individuals with Mycobacterium avium complex and Mycobacterium abscessus with assessment of gene expression was notable for downregulation of ciliary genes and upregulation of genes associated with cytokines/chemokines such as IL-32 and cholesterol biosynthesis. (Am J Respir Cell Mol Biol. 2018) Some of these pathways may be amenable to therapeutic intervention such as use of nitric oxide enhancement of ciliary function as we have previously shown in vitro with sildenafil. In contrast, development of pulmonary NTM infection does not appear to result from altered T cell function as was demonstrated to occur with M avium associated immune reconstitution inflammatory syndrome in advanced HIV infection (Clin Infect Dis. 2018) Collaborative work focused on the association of ciliary function with development of chronic airway infection led to the first comprehensive description of respiratory manifestations of a rare ciliopathy, Alstrom syndrome (Pediatr Pulmonol. 2017) and development of the first guidelines for the diagnosis of primary ciliary dyskinesia (Am J Respir Crit Care Med. 2018) which capitalized on rapid development of validated diagnostic tools and genetic discovery through the NHLBI funded Genetic Disorders of Mucociliary Consortium. (2) Epidemiology. In 2008 our lab along with extramural academic partners developed a US Bronchiectasis Research Registry that has been administered by the COPD Foundation. This Registry has enrolled over 2000 patients in the US and is being used as a source of participants in clinical trials and for epidemiologic research. Continued analysis of Registry data focused on the association of Staphylococcus aureus infection in nonCF bronchiectasis which does not seem to correlate with disease severity in these patients. (Ann Am Thorac Soc. 2018). We published two studies looking at the geographic distribution and associated characteristics of pulmonary NTM disease. The first analyzed data from the US Veterans Health Administration and identified a NTM pulmonary disease incidence of 12.6/100K person-years. COPD was a comorbidity in 68% of the cases and like other studies have shown, NTM infection predominated in the Southeastern US. (PLoS One. 2018) The second study utilized the CF Foundation Patient Registry to identify a 5 year period prevalence of 20% of CF patients with NTM identified at least once with 12% having M. avium complex, 8% M. abscessus, and 4% with other NTM. Prevalence of NTM showed a significant increase of 5% per year which varied by genographic region (Ann Am Thorac Soc. 2018). (3) Microbial pathogenesis. Work over the past year has focused on developing laboratory based models such as amoeba and zebrafish to assess genomic changes in serial clinical isolates of M. abscessus obtained from patients over the course of their disease to identify host adaptation factors of the mycobacterial that may relate to virulence and serve as targets for therapeutic intervention. We described the use of amoeba, which have been described as potential environmental hosts for M. abscessus, as an effective discriminatory model of relative virulence among several phenotypically and genomically characterized clinical strains of M. abscessus. (Res Microbiol. 2018) Continued work in the lab is focused on use of amoeba and zebra fish to evaluate novel antimicrobial peptides as potential therapeutic agents (4) Drug development. The success of Phase 2 and 3 studies of amikacin liposomal inhalation suspension (early clinical development done as part of a NIAID CRADA) as a novel treatment for refractory pulmonary M. avium complex infections has generated considerable industry interest in drug development for these chronic infections. Success of future trials will be dependent on use of standardized terms for treatment outcomes. A consensus approach was utilized to publish standardized terms and definitions for future trials. (Eur Respir J. 2018)
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