Examination of Mycobacterium tuberculosis sigma factor mutants using low-dose aerosol infection of guinea pigs suggests a role for SigC in pathogenesis
Examination of Mycobacterium tuberculosis sigma factor mutants using low-dose aerosol infection of guinea pigs suggests a role for SigC in pathogenesis
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DOI：
10.1099/mic.0.28591-0
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发表时间：
2006-06-01
期刊：
影响因子：
2.8
通讯作者：
Quinn, Frederick D.
中科院分区：
文献类型：
--
作者：
Karls, Russell K.;Guarner, Jeannette;Quinn, Frederick D.
细菌中的次要西格玛因子直接转录防御调节蛋白，以响应特定的压力。为了确定人类呼吸道病原体结核分枝杆菌中的哪些西格玛因子对于体内适应性生存是重要的，在单个西格玛因子基因中创建了明确的零突变。在这项研究中，比较了缺乏功能性sigma因子的结核分枝杆菌突变株(SigC、Sigf或Sigm)与亲本株H37Rv的体外生长毒力和豚鼠病理。突变菌株在米德尔布鲁克7H9发酵液中没有表现出生长缺陷，也没有对人单核巨噬细胞系THP-1的细胞内复制造成任何损害。然而，在小剂量气雾剂感染豚鼠后，可以检测到差异。虽然SIGM突变导致的肺和脾肉芽肿的成分与H37Rv感染动物中发现的相似，但SIGF突变导致部分减弱，表现为坏死性脾肉芽肿和界限不清的肺肉芽肿。SigC突变体在肺和脾中表现出衰减；值得注意的是，没有坏死性肉芽肿。这些数据表明，虽然SigF可能对肺中的生存很重要，但SigC可能是肺和脾中致病和适应性生存的关键调节因子。了解SigC如何在宿主体内调节生存应该被证明对抗结核疗法的发展有用。
Secondary sigma factors in bacteria direct transcription of defence regulons in response to specific stresses. To identify which sigma factors in the human respiratory pathogen Mycobacterium tuberculosis are important for adaptive survival in vivo, defined null mutations were created in individual sigma factor genes. In this study, in vitro growth virulence and guinea pig pathology of M. tuberculosis mutants lacking functional sigma factors (SigC, SigF, or SigM) were compared to the parent strain, H37Rv. None of the mutant strains exhibited a growth deficiency in Middlebrook 7H9 broth, nor were any impaired for intracellular replication in the human monocytic macrophage cell-line THP-1. Following low-dose aerosol infection of guinea pigs, however, differences could be detected. While a SigM mutant resulted in lung and spleen granulomas of comparable composition to those found in H37Rv-infected animals, a SigF mutant was partially attenuated, exhibiting necrotic spleen granulomas and ill-defined lung granulomas. SigC mutants exhibited attenuation in the lung and spleen; notably, necrotic granulomas were absent. These data suggest that while SigF may be important for survival in the lung, SigC is likely a key regulator of pathogenesis and adaptive survival in the lung and spleen. Understanding how SigC mediates survival in the host should prove useful in the development of anti-tuberculosis therapies.