Mycobacterium avium complex pulmonary infection: immunologic and transcriptomic signatures of disease and treatment response

PROJECT SUMMARY/ABSTRACT We seek to define immunologic and transcriptomic signatures of Mycobacterium avium complex (MAC) pulmonary disease and microbiologic treatment response. Nontuberculous mycobacteria (NTM) are environmental pathogens that is present in the soil and water. MAC is the most common cause of NTM

pulmonary disease, causing chronic, debilitating disease in predominantly older patients with underlying lung disease. Prior work has illustrated that incidence rates of MAC pulmonary disease are increasing substantially, particularly among women. Currently, the role of the host response in the development of disease is not well

described. Treatment, when necessary, consists of 3-4 antibiotics for 18+ months. There is an urgent need to fill the critical gaps in knowledge of factors associated with disease burden and treatment response. Our lack of understanding poses significant diagnostic and therapeutic challenges. First, it is often difficult to discern

colonization vs. disease caused by these organisms, and second it is difficult to predict who will benefit from therapy, or who will remain disease-free after therapy completion. There is a need for non-invasive biomarkers of disease burden and treatment response, to limit exposure to computed tomography scan radiation that is

currently used to monitor disease along with acid-fast sputum culture and patient-reported symptoms. Based on M. tuberculosis literature coupled with observations of NTM disease in the setting of anti-tumor necrosis factor therapy, the Th1 response could explain NTM pulmonary disease pathogenesis in some patients.

This prospective biobank enrolls patients in a sub-study of our ongoing MAC2v3 pragmatic clinical trial, as well as others who meet American Thoracic Society/Infectious Disease Society of America clinical, radiographic, and microbiologic disease criteria and are starting treatment for MAC pulmonary disease. This builds on our existing

NTM Clinical Trials Network infrastructure and extensive experience developing and managing the Northwest NTM Biobank. The Biobank has supported collaborations between MPIs Drs. Winthrop and Lewinsohn to conduct preliminary feasibility studies of immune correlates of disease. MPIs Drs. Lewinsohn and McWeeney

have a longstanding history of collaboration. During Years 1-4, we will collect blood and sputum samples longitudinally from patients initiating treatment for MAC pulmonary disease and conduct Aims 1A and 2A. During Years 3-5 we will complete Aims 1 and 2. In this setting we will conduct high throughput cytometry time-of-flight

(CyTOF) analysis of peripheral blood mononuclear cells to identify an immune signature of disease and microbiologic treatment response. Similarly, we will conduct whole blood next generation RNA sequencing to identify an RNA transcriptome signature of disease and microbiologic treatment response. Ultimately, the

development of a disease signature and biomarkers predictive of treatment response could help better guide therapeutic and diagnostic decision-making with regard to MAC pulmonary disease.