Abstract
Mycobacterium abscessus (MAB) is one of the rapidly growing, multidrug-resistant non-tuberculous mycobacteria (NTM) causing various diseases including pulmonary disorder. Although it has been known that type I interferons (IFNs) contribute to host defense against bacterial infections, the role of type I IFNs against MAB infection is still unclear. In the present study, we show that rIFN-β treatment reduced the intracellular growth of MAB in macrophages. Deficiency of IFN-α/β receptor (IFNAR) led to the reduction of nitric oxide (NO) production in MAB-infected macrophages. Consistently, rIFN-β treatment enhanced the expression of iNOS gene and protein, and NO production in response to MAB. We also found that NO is essential for the intracellular growth control of MAB within macrophages in an inhibitor assay using iNOS-deficient cells. In addition, pretreatment of rIFN-β before MAB infection in mice increased production of NO in the lungs at day 1 after infection and promoted the bacterial clearance at day 5. However, when alveolar macrophages were depleted by treatment of clodronate liposome, rIFN-β did not promote the bacterial clearance in the lungs. Moreover, we found that a cytosolic receptor nucleotide-binding oligomerization domain 2 (NOD2) is required for MAB-induced TANK binding kinase 1 (TBK1) phosphorylation and IFN-β gene expression in macrophages. Finally, increase in the bacterial loads caused by reduction of NO levels was reversed by rIFN-β treatment in the lungs of NOD2-deficient mice. Collectively, our findings suggest that type I IFNs act as an intermediator of NOD2-induced NO production in macrophages and thus contribute to host defense against MAB infection.
Highlights
Mycobacterium abscessus (MAB) is one of the rapidly growing non-tuberculous mycobacteria (NTM) causing chronic pulmonary infection and skin and soft tissue infection (SSTI) in immunosuppressed patients [1]
We previously identified that Nucleotide-binding oligomerization domain 2 (NOD2) enhances the antimicrobial effect of macrophage against MAB infection by amplifying nitric oxide (NO) production, through in vitro and in vivo experiments [16]
Intranasal administration of recombinant IFN-b (rIFN-b) reduced the bacterial colony-forming unit (CFU) in the lungs of NOD2-deficient mice, exhibiting comparable levels of CFUs as in WT mice (Figure 6E). These results suggest that NOD2 signaling contributes to the clearance of MAB by promoting type I IFN-mediated NO production in macrophages
Summary
Mycobacterium abscessus (MAB) is one of the rapidly growing non-tuberculous mycobacteria (NTM) causing chronic pulmonary infection and skin and soft tissue infection (SSTI) in immunosuppressed patients [1]. MAB can survive within innate immune cells such as macrophages and escape host immune response. Type I interferons (IFNs) are well-known cytokines that play an important role in host antiviral responses, and there are 13 different type I IFN subfamilies [5]. Upon detecting muramyl dipeptide (MDP) or bacterial peptidoglycan component, NOD2 initiates innate immune response against various microbial pathogens [9]. N-glycolyl MDP exerts higher NOD2 activity than N-acetyl MDP and induces more potent immune response [11]. For this reason, the essential role of NOD2 in host innate and adaptive immune responses against infections with Mycobacterium spp. has been extensively studied [12,13,14,15]. We previously identified that NOD2 enhances the antimicrobial effect of macrophage against MAB infection by amplifying NO production, through in vitro and in vivo experiments [16]
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