Department of Cell Biology and Molecular Genetics, University of Maryland, Campus Drive, College Park, MD 20742, USA.
BMC Microbiol. 2010 Sep 10;10:237. doi: 10.1186/1471-2180-10-237.
The HIV pandemic raised the potential for facultative-pathogenic mycobacterial species like, Mycobacterium kansasii, to cause disseminating disease in humans with immune deficiencies. In contrast, non-pathogenic mycobacterial species, like M. smegmatis, are not known to cause disseminating disease even in immunocompromised individuals. We hypothesized that this difference in phenotype could be explained by the strong induction of an innate immune response by the non-pathogenic mycobacterial species.
A comparison of two rapid-growing, non-pathogenic species (M. smegmatis and M. fortuitum) with two facultative-pathogenic species (M. kansasii and M. bovis BCG) demonstrated that only the non-pathogenic bacteria induced strong apoptosis in human THP-1 cells and murine bone marrow-derived macrophages (BMDM) and dendritic cells (BMDD). The phospho-myo-inositol modification of lipoarabinomannan (PI-LAM) isolated from non-pathogenic species may be one of the cell wall components responsible for the pro-inflammatory activity of the whole bacteria. Indeed, PI-LAM induces high levels of apoptosis and IL-12 expression compared to the mannosyl modification of LAM isolated from facultative-pathogenic mycobacteria. The apoptosis induced by non-pathogenic M. smegmatis was dependent upon caspase-3 activation and TNF secretion. Consistently, BALB/c BMDM responded by secreting large amounts of TNF upon infection with non-pathogenic but not facultative-pathogenic mycobacteria. Interestingly, C57Bl/6 BMDM do not undergo apoptosis upon infection with non-pathogenic mycobacteria despite the fact that they still induce an increase in TNF secretion. This suggests that the host cell signaling pathways are different between these two mouse genotypes and that TNF is necessary but not sufficient to induce host cell apoptosis.
These results demonstrate a much stronger induction of the innate immune response by non-pathogenic versus facultative-pathogenic mycobacteria as measured by host cell apoptosis, IL-12 and TNF cytokine induction. These observations lend support to the hypothesis that the strong induction of the innate immune response is a major reason for the lack of pathogenicity in fast-growing mycobacteria.
艾滋病大流行使得堪萨斯分枝杆菌等兼性致病分枝杆菌物种有可能在免疫缺陷的人类中引起播散性疾病。相比之下，非致病性分枝杆菌物种，如耻垢分枝杆菌，即使在免疫功能低下的个体中也不会引起播散性疾病。我们假设这种表型上的差异可以通过非致病性分枝杆菌物种强烈诱导先天免疫反应来解释。
对两种快速生长的非致病性（耻垢分枝杆菌和偶发分枝杆菌）与两种兼性致病性（堪萨斯分枝杆菌和卡介苗）进行比较，结果表明，只有非致病性细菌才能诱导人 THP-1 细胞和鼠骨髓来源的巨噬细胞（BMDM）和树突状细胞（BMDD）强烈凋亡。从非致病性细菌中分离出的磷酸肌醇修饰的阿拉伯甘露聚糖（PI-LAM）可能是导致整个细菌具有促炎活性的细胞壁成分之一。事实上，与从兼性致病性分枝杆菌中分离出的甘露糖修饰的 LAM 相比，PI-LAM 诱导高水平的凋亡和 IL-12 表达。非致病性耻垢分枝杆菌诱导的凋亡依赖于半胱天冬酶-3 的激活和 TNF 的分泌。一致地，BALB/c BMDM 在感染非致病性但不是兼性致病性分枝杆菌时会大量分泌 TNF。有趣的是，尽管 C57Bl/6 BMDM 不会在感染非致病性分枝杆菌时发生凋亡，但它们仍然诱导 TNF 分泌增加。这表明这两种小鼠基因型之间的宿主细胞信号通路不同，并且 TNF 是必需的但不足以诱导宿主细胞凋亡。
这些结果表明，非致病性分枝杆菌与兼性致病性分枝杆菌相比，先天免疫反应的诱导要强得多，表现在宿主细胞凋亡、IL-12 和 TNF 细胞因子的诱导上。这些观察结果支持这样一种假设，即先天免疫反应的强烈诱导是快速生长分枝杆菌缺乏致病性的主要原因。
