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

为了成功复制，噬菌体强烈依赖于其细菌宿主的新陈代谢。细菌通过依赖于第二信使(P)ppGpp的保守的严格反应(SR)严格控制其新陈代谢的各个方面。(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RelA/Spot Homology(RSH)蛋白的成员控制，RSH蛋白合成和/或降解(P)ppGpp。因此，实现高效和资源密集型噬菌体复制的一个策略应该包括对SR进行重新编程，从而对细胞(P)ppGpp水平进行重新编程。具体地说，我们将研究噬菌体phi29和spp1如何干扰其宿主-革兰氏阳性模式生物枯草芽孢杆菌的(P)ppGpp代谢。我们的初步工作表明，RSH型酶Rel与噬菌体感染有关，而另外两个(P)ppGpp合成酶RelP和RelQ则不相关。此外，噬菌体感染触发了Nudex-type水解酶的产生，这可能与噬菌体感染过程中细胞(P)ppGpp池的减少有关。最终，噬菌体还含有它们自己的(P)ppGpp水解酶，这将是这项提议的主题。综上所述，我们将提供一幅噬菌体如何干扰宿主(P)ppGpp反应以使其能够成功繁殖的机械图片。

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.