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

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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.