Abstract
The nontuberculous mycobacteria (NTM) Mycobacterium avium is a clinically significant pathogen that can cause a wide range of maladies, including tuberculosis-like pulmonary disease. An immunocompromised host status, either genetically or acutely acquired, presents a large risk for progressive NTM infections. Due to this quietly emerging health threat, we evaluated the ability of a recombinant fusion protein ID91 combined with GLA-SE [glucopyranosyl lipid adjuvant, a toll like receptor 4 agonist formulated in an oil-in-water stable nano-emulsion] to confer protection in both C57BL/6 (wild type) and Beige (immunocompromised) mouse models. We optimized an aerosol challenge model using a clinical NTM isolate: M. avium 2-151 smt, observed bacterial growth kinetics, colony morphology, drug sensitivity and histopathology, characterized the influx of pulmonary immune cells, and confirmed the immunogenicity of ID91 in both mouse models. To determine prophylactic vaccine efficacy against this M. avium isolate, mice were immunized with either ID91 + GLA-SE or bacillus Calmette–Guérin (BCG). Immunocompromised Beige mice displayed a delayed influx of innate and adaptive immune cells resulting in a sustained and increased bacterial burden in the lungs and spleen compared to C57BL/6 mice. Importantly, both ID91 + GLA-SE and BCG vaccines significantly reduced pulmonary bacterial burden in both mouse strains. This work is a proof-of-concept study of subunit vaccine-induced protection against NTM.
Highlights
The nontuberculous mycobacteria (NTM) Mycobacterium avium is a clinically significant pathogen that can cause a wide range of maladies, including tuberculosis-like pulmonary disease
Since NTM infection and disease burden are more pronounced in immunocompromised populations, our investigation included the Beige mouse strain as the representative immunocompromised mouse model and the C57BL/6 mouse strain as a wild type (WT) resistant mouse strain
Beige and C57BL/6 mice have been leveraged for comparative assessments of M. avium infections before, utilizing intranasal infections to evaluate the relative contributions of innate immune cells during early infection[29]
Summary
The nontuberculous mycobacteria (NTM) Mycobacterium avium is a clinically significant pathogen that can cause a wide range of maladies, including tuberculosis-like pulmonary disease. Researchers calculated that the age adjusted mortality rate in the United States for Mtb was 3.3 per million person years and 2.3 per million person years for NTM and rising annually in individuals not living with HIV3 These inverse trends between mycobacteria are reflected g lobally[4]. Predominant NTM species that cause significant pulmonary disease include Mycobacterium avium complex (MAC), M. kansasii and M. abscessus[12]. 18% of ‘chronic TB cases’ in Mali were identified as NTM positive upon reevaluation by microscopy, culture and drug sensitivity testing[18] Those patients misdiagnosed as having active Mtb infections are usually given treatments for MDR-TB. Novel drug therapies against MAC are being investigated for safety and efficacy[23,27], but use of these new drugs may eventually lead to the emergence of drug resistance and recurrence of disease
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