PDF(Pubmed)
Abstract：
L-arginine metabolism is strongly linked with immunity to mycobacteria, primarily through the antimicrobial activity of nitric oxide (NO). The potential to modulate tuberculosis (TB) outcomes through interventions that target L-arginine pathways are limited by an incomplete understanding of mechanisms and inadequate in vivo modeling. These gaps in knowledge are compounded for HIV and Mtb co-infections, where activation of arginase-1 due to HIV infection may promote survival and replication of both Mtb and HIV. We utilized in vitro and in vivo systems to determine how arginase inhibition using Nω-hydroxy-nor-L-arginine (nor-NOHA) alters L-arginine pathway metabolism relative to immune responses and disease outcomes following Mtb infection. Treatment with nor-NOHA polarized murine macrophages (RAW 264.7) towards M1 phenotype, increased NO, and reduced Mtb in RAW macrophages. In Balb/c mice, nor-NOHA reduced pulmonary arginase and increased the antimicrobial metabolite spermine in association with a trend towards reduced Mtb CFU in lung. In humanized immune system (HIS) mice, HIV infection increased plasma arginase and heightened the pulmonary arginase response to Mtb. Treatment with nor-NOHA increased cytokine responses to Mtb and Mtb/HIV in lung tissue but did not significantly alter bacterial burden or viral load. Our results suggest that L-arginine pathway modulators may have potential as host-directed therapies to augment antibiotics in TB chemotherapy.
摘要：
L-精氨酸代谢与对分枝杆菌的免疫力密切相关，主要通过一氧化氮（NO）的抗菌活性。通过靶向L-精氨酸途径的干预来调节结核病（TB）结局的潜力受到对机制的不完全理解和体内建模不足的限制。这些知识差距在艾滋病毒和Mtb共感染方面更加复杂，其中由于HIV感染引起的精氨酸酶-1的激活可能促进Mtb和HIV的存活和复制。我们利用体外和体内系统来确定使用Nω-羟基-nor-L-精氨酸(nor-NOHA)的精氨酸酶抑制相对于Mtb感染后的免疫应答和疾病结果如何改变L-精氨酸途径代谢。用nor-NOHA极化鼠巨噬细胞（RAW264.7）治疗M1表型，增加NO,并降低RAW巨噬细胞中的Mtb。在Balb/c小鼠中，nor-NOHA降低了肺精氨酸酶并增加了抗微生物代谢物精胺，与肺中MtbCFU降低的趋势有关。在人源化免疫系统（HIS）小鼠中，HIV感染增加了血浆精氨酸酶，并增强了肺精氨酸酶对Mtb的反应。nor-NOHA治疗增加了肺组织中对Mtb和Mtb/HIV的细胞因子应答,但没有显著改变细菌负荷或病毒载量。我们的结果表明，L-精氨酸途径调节剂可能具有作为宿主导向疗法的潜力，可以增强结核病化疗中的抗生素。
