Low-oxygen tensions found in Salmonella-infected gut tissue boost Salmonella replication in macrophages by impairing antimicrobial activity and augmenting Salmonella virulence
Low-oxygen tensions found in Salmonella-infected gut tissue boost Salmonella replication in macrophages by impairing antimicrobial activity and augmenting Salmonella virulence
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DOI：
10.1111/cmi.12476
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发表时间：
2015-12-01
影响因子：
3.4
通讯作者：
Jantsch, Jonathan
中科院分区：
文献类型：
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作者：
Jennewein, Jonas;Matuszak, Jasmin;Jantsch, Jonathan
在沙门氏菌感染中，沙门氏菌致病岛-2（SPI-2）编码的第三型分泌系统（T3 SS 2）对于系统性疾病和宿主细胞的存活至关重要。例如，在链霉素预处理的小鼠模型中，结肠炎的发生需要固有层中的SPI-2依赖性沙门氏菌复制CD 11 c（-）CXCR 1（-）单核吞噬细胞/巨噬细胞（M phi）。此外，肠道中细胞内沙门氏菌的遏制关键取决于吞噬细胞NADPH氧化酶（PHOX）和可能的2型一氧化氮合酶（NOS 2）的抗菌作用。对于两种抗微生物酶复合物，氧是必需的底物。然而，肠道组织中肠侵袭性沙门氏菌感染后的可用氧量及其对沙门氏菌-M phi相互作用的影响尚不清楚。因此，我们使用发光二维体内氧成像测量沙门氏菌小肠结肠炎模型中的肠道组织氧水平。我们发现，肠道组织氧水平下降，从约78托（约11%O-2）的值约16托（约2%O-2）在感染期间。由于沙门氏菌的体内毒力取决于沙门氏菌在M phi中的存活，因此在如此低氧值下分析沙门氏菌-M phi相互作用。这些实验揭示了野生型和t3 ss 2非表达沙门氏菌的细胞内复制和存活增加。这些发现被钝化的一氧化氮和活性氧（ROS）的生产和减少沙门氏菌ROS感知。此外，低氧还促进了SPI-2的转录和SPI-2编码的毒力蛋白的转运。PHOX和NOS 2的药理学阻断和T3 SS 2毒力功能的单独损害都不能模拟常氧条件下缺氧对沙门氏菌复制的影响。然而，如果使用不表达t3 ss 2的沙门氏菌，则在PHOX和NOS 2缺陷的情况下，缺氧不会进一步增强沙门氏菌的恢复。因此，这些数据表明，缺氧诱导的抗微生物活性和沙门氏菌毒力的损害合作，以允许增强沙门氏菌复制M phi。
In Salmonella infection, the Salmonella pathogenicity island-2 (SPI-2)-encoded type three secretion system (T3SS2) is of key importance for systemic disease and survival in host cells. For instance, in the streptomycin-pretreated mouse model SPI-2-dependent Salmonella replication in lamina propria CD11c(-)CXCR1(-) monocytic phagocytes/macrophages (M phi) is required for the development of colitis. In addition, containment of intracellular Salmonella in the gut critically depends on the antimicrobial effects of the phagocyte NADPH oxidase (PHOX), and possibly type 2 nitric oxide synthase (NOS2). For both antimicrobial enzyme complexes, oxygen is an essential substrate. However, the amount of available oxygen upon enteroinvasive Salmonella infection in the gut tissue and its impact on Salmonella-M phi interactions was unknown. Therefore, we measured the gut tissue oxygen levels in a model of Salmonella enterocolitis using luminescence two-dimensional in vivo oxygen imaging. We found that gut tissue oxygen levels dropped from approximate to 78 Torr (approximate to 11% O-2) to values of approximate to 16 Torr (approximate to 2% O-2) during infection. Because in vivo virulence of Salmonella depends on the Salmonella survival in M phi, Salmonella-M phi interaction was analysed under such low oxygen values. These experiments revealed an increased intracellular replication and survival of wild-type and t3ss2 non-expressing Salmonella. These findings were paralleled by blunted nitric oxide and reactive oxygen species (ROS) production and reduced SalmonellaROS perception. In addition, hypoxia enhanced SPI-2 transcription and translocation of SPI-2-encoded virulence protein. Neither pharmacological blockade of PHOX and NOS2 nor impairment of T3SS2 virulence function alone mimicked the effect of hypoxia on Salmonella replication under normoxic conditions. However, if t3ss2 non-expressing Salmonella were used, hypoxia did not further enhance Salmonella recovery in a PHOX and NOS2-deficient situation. Hence, these data suggest that hypoxia-induced impairment of antimicrobial activity and Salmonella virulence cooperate to allow for enhanced Salmonella replication in M phi.