Abstract
Infection by rapidly growing Mycobacterium abscessus is increasingly prevalent in cystic fibrosis (CF), a genetic disease caused by a defective CF transmembrane conductance regulator (CFTR). However, the potential link between a dysfunctional CFTR and vulnerability to M.abscessus infection remains unknown. Herein, we exploit a CFTR-depleted zebrafish model, recapitulating CF immuno-pathogenesis, to study the contribution of CFTR in innate immunity against M.abscessus infection. Loss of CFTR increases susceptibility to infection through impaired NADPH oxidase-dependent restriction of intracellular growth and reduced neutrophil chemotaxis, which together compromise granuloma formation and integrity. As a consequence, extracellular multiplication of M.abscessus expands rapidly, inducing abscess formation and causing lethal infections. Because these phenotypes are not observed with other mycobacteria, our findings highlight the crucial and specific role of CFTR in the immune control of M.abscessus by mounting effective oxidative responses.
Highlights
Cystic fibrosis (CF) is a lethal genetic disorder caused by deleterious mutations in the CF transmembrane conductance regulator (CFTR) protein (Gadsby et al, 2006), resulting in compromised mucociliary clearance, chronic bacterial infections, and subsequent progressive inflammatory lung damage (Donaldson and Boucher, 2003)
Loss of CFTR Function Increases the Severity of M. abscessus Infection To address the role of CFTR in M. abscessus subspecies (subsp.) abscessus (Mabs) infection, cftr loss-of-function experiments were carried out in ZF using a specific morpholino-modified oligonucleotide (MO) (Figures S1A and S1B)
Electron microscopy (EM) analysis revealed that Mabs S abscesses in cftr morphant show enhanced replication of extracellular bacilli, promoting rapid bacterial expansion and tissue destruction (Figure 1F), similar to those reported in Mabs R abscesses found in WT fish (Bernut et al, 2014)
Summary
Cystic fibrosis (CF) is a lethal genetic disorder caused by deleterious mutations in the CF transmembrane conductance regulator (CFTR) protein (Gadsby et al, 2006), resulting in compromised mucociliary clearance, chronic bacterial infections, and subsequent progressive inflammatory lung damage (Donaldson and Boucher, 2003). Among the rapidly growing NTM, the Mycobacterium abscessus complex (MABSC) represents the most common species found in CF airways (Floto et al, 2016) and is emerging as a major CF pathogen, in part because of indirect person-to-person transmission (Bryant et al, 2013), and progressing into severe pneumonia and accelerated inflammatory lung damage (Esther et al, 2010). Their presence is a relative contraindication to lung transplantation (Orens et al, 2006). Mabs is widely considered to be the most significant rapidly growing NTM in CF, with a worldwide prevalence rate of 5%–20% (Floto et al, 2016)
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