Mycobacterium abscessus (MAB) is an emerging, rapidly growing non-tuberculous Mycobacterium causing therapy-resistant pulmonary disease especially in patients with cystic fibrosis (CF). Smooth and rough colony type MAB can be isolated from infected patients whereby rough colony type MAB are more often associated with severe disease. Disease severity is also associated with an alternated type I interferon (IFN-I) response of the MAB-infected patients. However the relevance of this response for the outcome of MAB infection is still unknown. In this study, we analyzed the IFNβ expression of murine macrophages infected with a MAB rough colony strain (MAB-R) isolated from a patient with progressive CF and compared it to macrophages infected with the MAB smooth colony type reference strain (MAB-S). We found that MAB-R infected macrophages expressed significantly more IFNβ mRNA and protein than MAB-S infected macrophages. Higher IFNβ induction by MAB-R was associated with higher TNF expression and intracellular killing while low IFNβ induction was associated with lower TNF expression and persistence of MAB-S. IFNβ induction was independent of the intracellular cGAS-STING recognition pathway. MAB appeared to be recognized extracellularly and induced IFNβ expression via TLR2-TLR4-MyD88-TRIF-IRF3 dependent pathways. By using macrophages lacking the IFN-I receptor we demonstrate that MAB induced IFN-I response essentially contributed to restricting MAB-R and MAB-S infections by activating macrophage Nos2 expression and nitric oxide production. Thus IFN-I seem to influence the intrinsic ability of macrophages to control MAB infections. As MAB persists over long time periods in susceptible patients, our findings suggest that virulence of MAB strains is promoted by an insufficient IFN-I response of the host.

脓肿分枝杆菌（MAB）是一种新兴的，快速增长的非结核性分枝杆菌导致对治疗有抵抗力的肺部疾病，尤其是在囊性纤维化（CF）患者中。可以从感染的患者中分离出光滑和粗糙的菌落型MAB，从而粗糙的菌落型MAB更常与严重的疾病相关。疾病严重程度还与MAB感染患者的交替I型干扰素（IFN-I）反应有关。但是，这种反应与MAB感染结果的相关性仍然未知。在这项研究中，我们分析了从患有进行性CF的患者中分离出的MAB粗糙集落菌株（MAB-R）感染的鼠巨噬细胞的IFNβ表达，并将其与MAB光滑集落型参考菌株（MAB-S）感染的巨噬细胞进行了比较。 。我们发现，MAB-R感染的巨噬细胞比MAB-S感染的巨噬细胞表达更多的IFNβmRNA和蛋白。MAB-R较高的IFNβ诱导与较高的TNF表达和细胞内杀伤有关，而较低的IFNβ诱导与较低的TNF表达和MAB-S持续存在有关。IFNβ的诱导与细胞内cGAS-STING识别途径无关。MAB似乎在细胞外被识别并通过TLR2-TLR4-MyD88-TRIF-IRF3依赖性途径诱导IFNβ表达。通过使用缺乏IFN-I受体的巨噬细胞，我们证明了MAB诱导的IFN-I反应本质上是通过激活巨噬细胞来限制MAB-R和MAB-S感染的。MAB似乎在细胞外被识别并通过TLR2-TLR4-MyD88-TRIF-IRF3依赖性途径诱导IFNβ表达。通过使用缺乏IFN-I受体的巨噬细胞，我们证明了MAB诱导的IFN-I反应本质上是通过激活巨噬细胞来限制MAB-R和MAB-S感染的。MAB似乎在细胞外被识别并通过TLR2-TLR4-MyD88-TRIF-IRF3依赖性途径诱导IFNβ表达。通过使用缺乏IFN-I受体的巨噬细胞，我们证明了MAB诱导的IFN-I反应本质上是通过激活巨噬细胞来限制MAB-R和MAB-S感染的。Nos2表达和一氧化氮的产生。因此，IFN-1似乎影响巨噬细胞控制MAB感染的内在能力。由于MAB在易感患者中长期持续存在，因此我们的发现表明，宿主的IFN-I反应不足可促进MAB菌株的毒性。