The Diadenylate Cyclase CdaA Is Critical for Borrelia turicatae Virulence and Physiology.
The Diadenylate Cyclase CdaA Is Critical for Borrelia turicatae Virulence and Physiology.
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DOI：
10.1128/iai.00787-20
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发表时间：
2021-05-17
影响因子：
3.1
通讯作者：
Blevins JS
中科院分区：
文献类型：
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作者：
Jackson-Litteken CD;Ratliff CT;Kneubehl AR;Siletti C;Pack L;Lan R;Huynh TN;Lopez JE;Blevins JS
复发性热(RF)是由疏螺旋体属螺旋体引起的一种全球分布的媒介传播疾病，在发展中国家有很高的流行率。到目前为止，RF螺旋体感染和毒力所需的信号通路尚不清楚。环二AMP(c-di-AMP)是由二腺苷酸环化酶(DAC)合成的第二信使，主要存在于革兰氏阳性菌中，与毒力和必要的生理过程有关。虽然疏螺旋体是革兰氏阴性菌，但它编码一个DAC(CDAA)，其重要性仍未确定。为了研究c-di-AMP信号在疏螺旋体中的作用，我们产生了一个CDAA突变体。突变体在小鼠感染过程中显著减弱，遗传互补逆转了这一表型。因为c-di-AMP对许多细菌的生存是必不可少的，所以对CDAA突变体进行了全基因组测序，单核苷酸多态发现了潜在的抑制性突变。此外，CDAA的条件性突变证实了CDAA对正常生长和生理的重要作用。有趣的是，在莱姆病细菌伯氏疏螺旋体中，CDAA突变并没有影响毒力调节蛋白同源基因的表达，其水平受到c-di-AMP信号的影响。最后，CDAA突变体在有盐、渗透压降低和没有丙酮酸的情况下有明显的生长缺陷。虽然盐处理的表型不会被遗传互补逆转，可能是由于抑制突变，但在渗透压降低和缺乏丙酮酸的条件下，生长缺陷可能直接归因于CDAA失活。总体而言，这些结果表明CDAA在滴虫致病中起关键作用，并将c-diAMP与RF螺旋体的渗透调节和中枢代谢联系起来。
Relapsing fever (RF), caused by spirochetes of the genus Borrelia, is a globally distributed, vector-borne disease with high prevalence in developing countries. To date, signaling pathways required for infection and virulence of RF Borrelia spirochetes are unknown. Cyclic di-AMP (c-di-AMP), synthesized by diadenylate cyclases (DACs), is a second messenger predominantly found in Gram-positive organisms that is linked to virulence and essential physiological processes. Although Borrelia is Gram-negative, it encodes one DAC (CdaA), and its importance remains undefined. To investigate the contribution of c-di-AMP signaling in the RF bacterium Borrelia turicatae, a cdaA mutant was generated. The mutant was significantly attenuated during murine infection, and genetic complementation reversed this phenotype. Because c-di-AMP is essential for viability in many bacteria, whole-genome sequencing was performed on cdaA mutants, and single-nucleotide polymorphisms identified potential suppressor mutations. Additionally, conditional mutation of cdaA confirmed that CdaA is important for normal growth and physiology. Interestingly, mutation of cdaA did not affect expression of homologs of virulence regulators whose levels are impacted by c-di-AMP signaling in the Lyme disease bacterium Borrelia burgdorferi. Finally, the cdaA mutant had a significant growth defect when grown with salts, at decreased osmolarity, and without pyruvate. While the salt treatment phenotype was not reversed by genetic complementation, possibly due to suppressor mutations, growth defects at decreased osmolarity and in media lacking pyruvate could be attributed directly to cdaA inactivation. Overall, these results indicate CdaA is critical for B. turicatae pathogenesis and link c-di-AMP to osmoregulation and central metabolism in RF spirochetes.
DOI：
10.1111/j.1469-0691.2009.02785.x
发表时间：
2009-05
期刊：
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
影响因子：
--
作者：
Cadavid D;Londoño D
通讯作者：
Londoño D