Although the molecular mechanism underlying the formation of the VBNC state is not fully understood, several genes that exhibit importance in the VBNC state have also been found to play integral roles in the formation of VBNC cells. Here, it is worth discussing the rpoS gene. The major stress regulator, RpoS (σS), which is expressed by the rpoS gene, is a stationary-phase sigma factor that allows bacteria to survive under different environmental stresses (such as acidic conditions, high osmotic pressure, oxidation, and starvation) (Bhagwat et al., 2006). This capability implies that RpoS can improve the ability of cells to adapt to the environment and thus hinder formation of the VBNC state. It has been shown that rpoS mutants lacking ppGpp more rapidly enter the VBNC state than normal strains (Boaretti et al., 2003). Additionally, Kusumoto et al. (2012) showed a reduced RpoS level during VBNC induction of Salmonella, and RpoS indeed delayed the formation of VBNC cells. Although RpoS is an obstacle for the formation of the VBNC state, it has been reported that VBNC cells continue to express the rpoS gene (Smith and Oliver, 2006). It is possible that VBNC cells must regulate RpoS, which is important for the maintenance of resistance and persistence under stresses. Boaretti et al. (2003) confirmed this hypothesis and found that the rpoS mutants lost culturability and died earlier than VBNC cells of their E. coli parental strains, suggesting that the rpoS gene is closely related to persistence in the VBNC state. These findings indicate that although the expression and regulation of the rpoS gene significantly hinder the formation of VBNC cells, long-term survival of VBNC cells is not possible in the absence of RpoS protein. However, a contrasting viewpoint has been proposed. This opposing perspective is that (p)ppGpp modulated by protein RelA may be an inducer of the VBNC state and that cells lacking ppGpp are less likely to enter the VBNC state (Ayrapetyan et al., 2015). It is known that (p)ppGpp is a regulatory signaling molecule that can regulate RpoS, and the elevated level of (p)ppGpp will lead to a several-fold increase in the amount of RpoS, which plays a crucial role in the accumulation of RpoS (Magnusson et al., 2005). Thus, the possibility that (p)ppGpp may be an inducer of the VBNC state suggests that RpoS may be an inducer that can facilitate the more rapid entry of cells into the VBNC state. Although these two views are conflicting, they both illustrate that RpoS significantly affects the formation of VBNC cells and also enhances stress resistance in VBNC cells.