Abstract
Prevalence of Mycobacterium abscessus infections is increasing in patients with respiratory comorbidities. After initial colonisation, M. abscessus smooth colony (S) variants can undergo an irreversible genetic switch into highly inflammatory, rough colony (R) variants, often associated with a decline in pulmonary function. Here, we use an adult zebrafish model of chronic infection with R and S variants to study M. abscessus pathogenesis in the context of fully functioning host immunity. We show that infection with an R variant causes an inflammatory immune response that drives necrotic granuloma formation through host TNF signalling, mediated by the tnfa, tnfr1 and tnfr2 gene products. T cell-dependent immunity is stronger against the R variant early in infection, and regulatory T cells associate with R variant granulomas and limit bacterial growth. In comparison, an S variant proliferates to high burdens but appears to be controlled by TNF-dependent innate immunity early during infection, resulting in delayed granuloma formation. Thus, our work demonstrates the applicability of adult zebrafish to model persistent M. abscessus infection, and illustrates differences in the immunopathogenesis induced by R and S variants during granulomatous infection.
Highlights
Prevalence of Mycobacterium abscessus infections is increasing in patients with respiratory comorbidities
To determine if M. abscessus produces a persistent infection in adult zebrafish, we performed CFU recovery on animals across 28 days of infection (Fig. 1A)
Variation in the initial inoculum ranging from 104 to 106 CFU did not appear to impact the course of infection burden with stable burden of the R variant within a 1-log window either side of the inoculation dose up to 28 days post infection and progressive growth of the S variant to approximately 1-log above the inoculation dose at 28 dpi in each of three experiments
Summary
Prevalence of Mycobacterium abscessus infections is increasing in patients with respiratory comorbidities. Mycobacterium abscessus is an increasingly recognized human pathogen responsible for a wide array of clinical manifestations including muco-cutaneous infections and disseminated or chronic pulmonary diseases[1]. The latter is mostly encountered in patients with underlying lung disorders, such as bronchiectasis or cystic fibrosis (CF). Irrespective of being a rapid-growing mycobacteria (RGM), M. abscessus displays many pathophysiological traits with slowgrowing mycobacteria (SGM), such as Mycobacterium tuberculosis These include the capacity to persist silently within granulomatous structures and to produce pulmonary caseous lesions[2,3]. An improved model of intratracheal agar bead inoculation has been adapted for M. abscessus causing a persistent infection for at least two months post implantation[17,19]
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