![]() ![]() aureus as a pathogen relies on its capacity to sense, respond, and adapt the expression of a large array of virulence factors in response to the environmental cues that bacteria encounter in each tissue 11, 12, 13. aureus easily leads to infections ranging from relatively mild cutaneous infections to life-threatening infections such as pneumonia, sepsis, septic arthritis, endocarditis, and osteomyelitis in people predisposed with risk factors 10. Staphylococcus aureus is an important human pathogen routinely isolated as a commensal organism living in different niches, including skin, nares, and mucosal surfaces of more than a third of the human population 9. This assumption has never been tested because it is presumed that the accumulation of deleterious effects caused by successive mutation of TCSs would convert free-living bacteria into uncultivable species. In principle, if the function of a TCS remains exclusively devoted to sensing and responding to a specific environmental signal, the process of acquiring TCSs should be reversible and the successive removal of TCSs should simply reduce the number of environmental conditions under which bacteria are able to grow. The final consequence of this evolutionary process is that bacteria gain the capacity to colonize a new niche or improve the efficiency to grow under the conditions of the existing niche. The number of TCSs seems to expand primarily through a mechanism of gene duplication and subsequent accumulation of mutations that insulate the new pathways from the existing two-component pathways 7, 8. Thus, bacteria inhabiting relatively stable host environments, such as obligate intracellular parasites, possess few or even none of these signaling systems, while bacteria able to live in a variety of environments and bacteria with complex lifestyles have dozens of unique TCSs, each one potentially responding to different stimuli and thus activating a different cellular response. ![]() The genome of most clinically relevant bacterial species usually encodes multiple two-component HK-RR pairs, this number being proportional to the genome size, the diversity of environments in which organisms live, and the complexity in cellular differentiation 5, 6. The molecular mechanisms underlying TCS signal transduction processes have been exhaustively studied since the capacity of bacterial cells to sense and respond to changes in environmental conditions is critical to understanding bacterial biology and pathogenesis, and also because TCSs are considered suitable drug targets to treat bacterial infections 4. The phosphorylation of the RR activates an output domain, which can then effect changes in cellular physiology often by regulating gene expression, protein interactions, or enzymatic activities. The phosphorylated HK then binds and transfers the phosphoryl group to a conserved aspartate residue on the response regulator (RR). A canonical two-component signaling pathway contains a histidine kinase (HK), which in response to extracellular stimuli, autophosphorylates on a conserved histidine residue. In the case of bacteria, two-component systems (TCSs) are the primary means of the sensorial machinery 1, 2, 3. ![]() Thus, all organisms have evolved signal transduction mechanisms to establish “functional connectiveness” between environmental cues and cellular physiology. This organization, if confirmed in other bacterial species, may provide a general evolutionarily mechanism for flexible bacterial adaptation to life in new niches.Ī key factor that determines the evolutionary success of a living organism is the capacity to sense environmental factors and to respond accordingly. aureus derivatives containing individual TCSs reveals that each TCS appears to be autonomous and self-sufficient to sense and respond to specific environmental cues, although some level of cross-regulation between non-cognate sensor-response regulator pairs occurs in vivo. Under replicating conditions, however, the WalRK system is necessary and sufficient to maintain bacterial growth, indicating that sensing through TCSs is mostly dispensable for living under constant environmental conditions. aureus can be deprived of its complete sensorial TCS network and still survive under growth arrest conditions similarly to wild-type bacteria. The core genome of the major human pathogen Staphylococcus aureus encodes 16 TCSs, one of which (WalRK) is essential. Bacteria use two-component systems (TCSs) to sense and respond to environmental changes. ![]()
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