Interplay of the phages phi29 and SPP1 with the B. subtilis (p)ppGpp response

为了成功地复制，细菌高度依赖于其细菌宿主的代谢。细菌通过依赖于第二信使（p）ppGpp的保守的严格反应（SR）来严格控制其代谢的各个方面。（p）ppGpp核苷酸基本上控制细菌代谢的所有水平，包括核苷酸和氨基酸代谢、DNA复制、转录和翻译。细胞（p）ppGpp水平通常由合成和/或降解（p）ppGpp的RelA/SpoT同源（RSH）蛋白的成员控制。因此，一种能够实现生产性和资源密集型噬菌体复制的策略应该包括SR的重编程，从而包括细胞（p）ppGpp水平。具体来说，我们将研究如何在Ephi 29和SPP 1干扰（p）ppGpp代谢的宿主，革兰氏阳性模式生物枯草芽孢杆菌。我们的初步工作表明，在噬菌体感染期间，RH型酶Rel是相关的，而另外两个（p）ppGpp合成酶RelP和RelQ不是。此外，噬菌体感染触发Nudix型水解酶的产生，其可能参与噬菌体感染期间细胞（p）ppGpp池的减少。最终，它们也有自己的（p）ppGpp水解酶，这将是本提案的主题。 两者合计，我们将提供一个机械的图片如何干扰主机（p）ppGpp的反应，以使他们的成功繁殖。

In order to successfully replicate, phages strongly rely on the metabolism of their bacterial hosts. Bacteria tightly control all aspects of their metabolism via the conserved stringent response (SR) that relies on the second messengers (p)ppGpp. The (p)ppGpp nucleotides essentially control all levels of the bacterial metabolism, including nucleotide and amino acid metabolism, DNA replication, transcription and translation. Cellular (p)ppGpp levels are typically controlled by members of the RelA/SpoT homology (RSH) proteins, which synthesize and/or degrade (p)ppGpp. Therefore, one strategy enabling the productive and resource-intense phage replication should include a reprogramming of the SR, and thus the cellular (p)ppGpp levels. Specifically, we will study how the phages phi29 and SPP1 interfere with the (p)ppGpp metabolism of their host, the Gram-positive model organism Bacillus subtilis. Our preliminary work shows that the RSH-type enzyme Rel is relevant during phage infection, while the two other (p)ppGpp synthetases RelP and RelQ are not. Also, phage infection triggers the production of Nudix-type hydrolases, which might be involved in the reduction of the cellular (p)ppGpp pools during phage infection. Eventually, phages also harbor their own (p)ppGpp hydrolases, which will be subject of this proposal. Taken together, we will provide a mechanistic picture of how phages interfere with the host (p)ppGpp response in order to enable their successful reproduction.