Trends in Microbiology
ReviewStreptococcus pneumoniae and reactive oxygen species: an unusual approach to living with radicals
Highlights
► Repertoire of oxidative detoxification and repair mechanisms is unique for S. pneumoniae. ► Endogenous production of H2O2 shapes pneumococcal oxidative stress response. ► Regulation of oxidative stress resistance is largely unknown. ► Manganese and zinc are the main cations involved in oxidative stress.
Section snippets
Pneumococcal defence against oxygen
S. pneumoniae is a Gram-positive, catalase-negative, aerotolerant anaerobic bacterium. It is a member of the human nasopharyngeal microbiota but it can also cause serious diseases, such as pneumonia, otitis media, meningitis, and bacteraemia, especially among children, the elderly, and immunocompromised individuals. Due to the limitations of existing vaccines, the rising incidence of antibiotic-resistant clones, and an aging population, it is very likely that pneumococcal diseases will continue
What is unique about the pneumococcal oxidative stress response?
The oxidative stress resistance in S. pneumoniae manifests some important differences when compared to other Gram-positive and Gram-negative bacteria. For example, despite routine exposure to H2O2, the bacterium lacks catalase, which plays a major role in elimination of H2O2 in Gram-positive and Gram-negative bacteria, and unlike other microbes 1, 2, S. pneumoniae has been reported to lack an inducible response to H2O2 [3]. Soluble iron (Fe2+) has been shown to escalate the rate of H2O2 killing
The multifaceted role of SpxB in S. pneumoniae oxidative survival
The endogenous production of H2O2 in S. pneumoniae is largely mediated through the catalytic activity of pyruvate oxidase (SpxB), which converts pyruvate to acetyl phosphate, CO2, and H2O2 using oxygen [12]. Expression of spxB is regulated by SpxR, which senses the energy and metabolic state of the microbe [13]. The production of high concentrations of H2O2 under aerobic conditions has several implications on pneumococcal biology. First, the H2O2 in pneumococcal culture supernatants has been
Enzymatic detoxification mechanisms
One way of managing exposure to ROS, either endogenously or exogenously generated, is by detoxification. The pneumococcal enzymes implicated in enzymatic removal of ROS include NADH oxidase, superoxide dismutase, thiol peroxidase, and alkyl hydroperoxidase. In addition, a tripeptide (γ-L-glutamyl-L-cysteinyl-glycine) known as glutathione is also involved in scavenging free radicals and peroxides by alternating between an oxidised and reduced state [19]. S. pneumoniae can utilise extracellular
Enzymatic repair mechanisms against oxidative stress
Although it is important to remove ROS by enzymatic means, this may not be sufficient or fast enough to prevent damage. This is probably why efficient repair mechanisms are also important for pneumococcal resistance against oxidising agents. So far, several pneumococcal proteins were implicated in the repair inflicted by ROS. These include HtrA, Clp ATP-dependent proteases, and a protein complex consisting of CcdA, TlpA, and MsrAB. The widely conserved heat shock-induced serine proteases (HtrA)
The role of cations in pneumococcal response to oxidative stress
Cations have an important role in the virulence and physiology of pathogenic streptococci, and are interconnected with oxidative stress. Cations are involved in oxidative stress resistance in at least three ways: (i) directly by detoxifying ROS; (ii) indirectly as cofactor for enzymes; and (iii) as critical signals for regulation of genes involved in protection against ROS.
One cation that exemplifies all three possibilities is manganese (Mn2+). Mn2+ can act as a cofactor of ROS detoxifying
Regulation of oxidative stress response in S. pneumoniae
In recent years several pneumococcal regulators have been linked to gene regulation in response to oxidative stress. These include TCS04, PsaR, CiaRH, Rgg, MerR/NlmR, RitR, and SpxR. As described earlier, TCS04 and PsaR exert their effects through regulation of the psaBCA locus and SpxR through regulation of spxB, and RitR controls both genes for iron uptake and other regulatory genes. CiaRH is a two-component system involved in stress response, sugar metabolism, chromosome segregation,
Concluding remarks and future perspectives
S. pneumoniae contains a multitude of proteins involved in resistance to oxidative stress (Figure 1, Table 2), however, it is highly unlikely that these are the only ones. Thus, further work is required to understand effector and regulatory mechanisms governing the oxidative stress response of this inherently oxygen-tolerant microbe. Given that S. pneumoniae oscillates between commensal and parasitic life styles, particular emphasis should be placed upon the role of the oxidative stress
Acknowledgements
J.J.E.B. was funded by a Rosalind Franklin Fellowship of the University Medical Centre Groningen (UMCG).
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