# Global Transcriptomic Response of _Staphylococcus aureus_ to Viulent Bacteriophage Infection
## 4 Discussion
In turn, the studied vB_SauM-515A1 bacteriophage is able to reduce the level of (p)ppGpp alarmone by expressing the _l\(mzG\)_ gene. The _l\(mzG\)_ gene is a homolog of the _mazG_ gene of the MazFG toxin-antitoxin system, which mediates programmed cell death. MazF protein degrades mRNA, whereas MazG protein inhibits MazF and (p)ppGpp synthesis [47; 48]. In addition to the described mechanism, the found changes in the expression of LytSR regulatory system genes ([_lytR_\(\uparrow\) at 5 min], IrgAB [_lrgB_\(\downarrow\) at 30 min], and SarV [_sarV_\(\downarrow\) at 5 min]) might also be involved in preventing cell death. The two-component LytSR system is a negative regulator of autolysis and biofilm formation in _S. aureus_[49] and directly affects _lrgAB_ operon transcription, which, in turn, encodes an anti-holin-like protein, preventing autolysis [50]. In a recently published study, analysis of the _sarV_ mutant indicated that this gene regulates extracellular and intracellular murein hydrolase activity and constitutes an important \"hub\" for the control of autolysis by _mgrA_ and _sarA_. _S. aureus_ strains were highly susceptible to lysis when _sarV_ was overexpressed [51]. In addition to the affected nucleic acid metabolism, GO enrichment analysis revealed notable changes in the expression level of amino acid metabolism genes, which is also consistent with previously published data [18; 20; 21]. Differences in amino acid gene expression profile caused by phage infection are generally associated with the fact that bacteriophages can have different amino acid requirements than uninfected bacterial cells [21]. Furthermore, since _S. aureus_ has been shown to use amino acids as a carbon source, degrading them to the metabolic intermediates, namely pyruvate (from alanine, serine, glycine, threonine, and cysteine), 2-oxoglutarate (from glutamate, glutamine, histidine, arginine, and proline), and oxaloacetate (from aspartate and asparagine) [52], the depletion of the free amino acid pool can lead to a slowdown in the metabolism and growth of the bacterial cell. Analysis of subsequent time points revealed a rather different expression profile compared to the onset of infection: the bulk of the DEGs at the 15 th and 30 th minutes were upregulated and mostly overlapped between the two time points. It is worth noting that a significant part of the upregulated DEGs comprised one of the three found in the genome prophages and virulence factors. The discovered features raise the issue of the use of clinical strains as propagation hosts, as they are likely to contain prophages and can produce toxin genes and determinants of antibiotic resistance, e.g., in _S. aureus_ prophages encode such toxins as Panton-Valentine leukocidin, exfoliative toxins Eta and Etb, etc. [53]. In connection with the induction of the prophage, the probability of horizontal toxin gene transfer in the population of the pathogenic bacterium increases; therefore, a more detailed study of the possibility of prophage induction when using virulent bacteriophages for therapeutic purposes is necessary. At the same time, overexpression of certain virulence factors genes, which are not associated with prophage regions, was discovered for the first time for virulent bacteriophage-bacteria pairs; this finding imposes additional requirements for phage purification methods.