## 4 Sensing and Regulatory Processes during Acid Stress  
Although _E. coli_ and _L. monocytogenes_ both possess mechanisms that protect against low environmental pH, most of these mechanisms are deployed only when acidic conditions are encountered. In both bacterial species alternative sigma factors, RpoS (\(\sigma^{8}\)) and SigB (\(\sigma^{8}\)), respectively, contribute to acid resistance by reprogramming the transcriptional landscape during acidic conditions [90; 91]. RpoS is responsible for the regulation of approximately 23% of the genes in the _E. coli_ genome [92] and is regulated by a complex signal transduction pathway, initiated by the low pH sensor EvgS, which is the histidine kinase of the EvgS/EvgA two component system (Figure 1A). The sensing mechanism of EvgS is currently unknown but it has been shown that activation of this protein can be triggered by low pH and alkali metals [93; 94; 95]. A model for EvgS activation that involves structural changes in the EvgS dimer at low pH was proposed [96] and the His226 residue in the periplasmic domain has recently been shown to play a key role in the sensing mechanism [95]. A complex signal transduction cascade that involves SafA, the PhoQ-PhoP system, IraM, and the response regulator RssB leads to the inhibition of RpoS proteolysis [94; 97; 98; 99] (Figure 1A). This pathway results in the upregulation of the expression of GadE, one of the main activators of the glutamate-dependent acid response system, responsible for the upregulation of the _gadA_, _gadBC_, _hdeA_ and _hdeB_ genes [98; 100; 101]. In addition to RpoS, a wide collection of regulators forms an intricate circuit that controls _gadE_ expression under different growth conditions. These include the AraC-like family transcriptional regulators YdeO, GadX,GadW [98; 102; 103] and the global transcriptional regulator H-NS, that directly or indirectly regulates the expression of multiple key components of the acid resistance pathways [104; 105]. In _L. monocytogenes_, \(\sigma^{\text{B}}\) is regulated by a signaling cascade composed by several proteins (RsbR, RsbT, RsbU, RsbV, RsbW, and RsbX) (reviewed recently in [8; 106]), and when activated it results in the upregulation of approximately 300 genes [107; 108; 109] that increase _L. monocytogenes_ resistance towards lethal acid stress [23; 25; 26; 110]. Several acid resistance related genes, including _argA_, _argR_, _gadD1_, and _gadD3_ are regulated by \(\sigma^{\text{B}}\)[16; 28; 111; 112] (Figure 1B). Although this signaling cascade is well studied, the molecular mechanism underpinning the acid sensing remains unknown. It is hypothesized that a supramolecular complex named as the stressosome (composed by RsbR, RsbS and RsbT) is responsible for the detection of environmental low pH, since this bacterium lacks the alternative pathway identified in _Bacillus subtilis_ and _Bacillus cereus_ that converges on RsbV [113; 114; 115]. Additionally, the stressosome has been found to be tethered to the cell membrane by PriI42, a small protein that has been shown to play a role in oxidative stress detection [116]; however, its role in acid sensing remains unstudied. The activation of several acid resistance mechanisms such as the decarboxylation systems discussed above is triggered by a decrease in pH, both in the extracellular milieu and in the cytosol. In _E. coli_, each decarboxylase and their corresponding antiporters have different pH optima, although they are all active in the acidic pH range [100; 117]; (reviewed in [10]). The oligomerization state of the decarboxylases is an important mechanism that contributes to the regulation of their activity. The pH-dependent conformational changes are responsible for the transition between their dimeric form and higher order oligomers (hexamers and decamers) [37; 118; 119]. AdiA activity is regulated by its oligomerization state, with a decamer being the main species at the optimal pH 5.2 and an increased concentration of inactive dimers at pH 7 [37; 119; 120].