Pivotal Roles for Ribonucleases in Streptococcus pneumoniae Pathogenesis

Sinha, Dhriti; Frick, Jacob P; Clemons, Kristen; Winkler, Malcolm E.; Lay, Nicholas R. De

doi:10.1128/mbio.02385-21

Cited by 9 publications

(9 citation statements)

References 86 publications

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“…RNase Y and PNPase were recently shown to affect S. pneumoniae virulence in a murine model [4]. The transcriptional landscape of the respective mutants indicated a global effect of RNase Y on pneumococcal physiology and an implication of PNPase on S. pneumoniae virulence control, likely through sRNA regulation [4]. In agreement with this, PNPase was shown to interact with several noncoding RNAs in a RNA-protein complexome study [5].…”

Section: Introductionmentioning

confidence: 72%

“…In spite of their great importance, not much is known about pneumococcal ribonucleases. RNase Y and PNPase were recently shown to affect S. pneumoniae virulence in a murine model [4]. The transcriptional landscape of the respective mutants indicated a global effect of RNase Y on pneumococcal physiology and an implication of PNPase on S. pneumoniae virulence control, likely through sRNA regulation [4].…”

Section: Introductionmentioning

confidence: 99%

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RNase R, a New Virulence Determinant of Streptococcus pneumoniae

et al. 2022

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Pneumococcal infections have increasingly high mortality rates despite the availability of vaccines and antibiotics. Therefore, the identification of new virulence determinants and the understanding of the molecular mechanisms behind pathogenesis have become of paramount importance in the search of new targets for drug development. The exoribonuclease RNase R has been involved in virulence in a growing number of pathogens. In this work, we used Galleria mellonella as an infection model to demonstrate that the presence of RNase R increases the pneumococcus virulence. Larvae infected with the RNase R mutant show an increased expression level of antimicrobial peptides. Furthermore, they have a lower bacterial load in the hemolymph in the later stages of infection, leading to a higher survival rate of the larvae. Interestingly, pneumococci expressing RNase R show a sudden drop in bacterial numbers immediately after infection, resembling the eclipse phase observed after intravenous inoculation in mice. Concomitantly, we observed a lower number of mutant bacteria inside larval hemocytes and a higher susceptibility to oxidative stress when compared to the wild type. Together, our results indicate that RNase R is involved in the ability of pneumococci to evade the host immune response, probably by interfering with internalization and/or replication inside the larval hemocytes.

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Section: Introductionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

RNase R, a New Virulence Determinant of Streptococcus pneumoniae

et al. 2022

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“…Metal amounts in samples were normalized relative to total protein amounts in the matched samples. Mouse models of infection: All procedures were approved in advance by UTHealth Animal Welfare Committee and carried out as previously described (41). Male ICR mice (21-24 g; Envigo) were anaesthetized by inhaling 4 to 5 % isoflurane.…”

Section: Methodsmentioning

confidence: 99%

The five homologous CiaR-controlled Ccn sRNAs ofStreptococcus pneumoniaemodulate Zn-resistance

De Lay,

Verma,

Sinha

et al. 2023

Preprint

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Zinc is a vital transition metal forStreptococcus pneumoniae, but is deadly at high concentrations. Zn intoxication ofS. pneumoniaeresults from a deficiency in Mn, which is required for key metabolic enzymes and defense against oxidative stress. Here, we report our identification and characterization of the function of the five homologous, CiaRH-regulated Ccn sRNAs in controllingS. pneumoniaevirulence and metal homeostasis. We show that deletion of all fiveccngenes (ccnA,ccnB,ccnC,ccnD, andccnE) fromS. pneumoniaestrains D39 (serotype 2) and TIGR4 (serotype 4) causes Zn hypersensitivity and an attenuation of virulence in a murine invasive pneumonia model. We provide evidence that addition of Zn disproportionately impairs Mn uptake by the ΔccnABCDEmutants. Consistent with a response to Mn starvation, expression of genes encoding the CzcD Zn exporter and the Mn-independent ribonucleotide reductase, NrdD-NrdG, were increased in the ΔccnABCDEmutant relative to its isogenicccn+parent strain. The growth inhibition by Zn that occurs as the result of loss of theccngenes is rescued by supplementation with Mn or Oxyrase™, a reagent that removes dissolved oxygen. Lastly, we found that the Zn-dependent growth inhibition of the ΔccnABCDEstrain was not altered by deletion ofsodA, whereas theccn+ΔsodAstrain phenocopied the ΔccnABCDEstrain. Overall, our results indicate that the Ccn sRNAs have a crucial role in preventing oxidative stress inS. pneumoniaeduring exposure to excess Zn by modulating Mn uptake.AUTHOR SUMMARYZn and Mn are essential micronutrients for many bacteria, includingStreptococcus pneumoniae. While Zn performs vital structural or catalytic roles in certain proteins, in excess, Zn can inhibit Mn uptake byS. pneumoniaeand displace, but not functionally replace Mn from key enzymes including superoxide dismutase A (SodA). Here, we show that the Ccn small regulatory RNAs promoteS. pneumoniaeMn uptake and resistance to the oxidative stress. Furthermore, we demonstrate that these small regulatory RNAs modulate the ability ofS. pneumoniaeto cause invasive pneumonia. Altogether, these findings reveal a new layer of regulation ofS. pneumoniaeZn and Mn homeostasis and suggest that there are factors in addition to known transporters that modulate intracellular Mn levels.

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“…Despite their important roles, knowledge on pneumococcal RNases is still in its infancy, with only a small number of recent studies. RNase R, PNPase and RNase Y were all shown to affect S. pneumoniae virulence [4, 5]. PNPase seems to act on virulence through its interaction with noncoding RNAs [5, 6].…”

Section: Introductionmentioning

confidence: 99%

“…RNase R, PNPase and RNase Y were all shown to affect S. pneumoniae virulence [4, 5]. PNPase seems to act on virulence through its interaction with noncoding RNAs [5, 6]. In a recent study RNase YhaM was identified as a stabilizer of noncoding RNAs involved in pneumococcal competence [6].…”

Section: Introductionmentioning

confidence: 99%

RNase R Controls Membrane Fatty Acid Composition inStreptococcus pneumoniae

Alipio

Bárria

Pobre

et al. 2023

Preprint

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Previous studies on RNase R have highlighted significant effects of this ribonuclease in several processes ofStreptococcus pneumoniaebiology. In this work we have studied the global impact of RNase R by comparing the transcriptional landscape of a deleted RNase R mutant to that of the wild-type strain, and this led us investigate specific targets affected by RNase R. RNA-Seq showed that RNase R deletion affects transcripts from several different biological processes. Of particular interest, elimination of RNase R results in overexpression of most of the genes encoding the components of type II fatty acid biosynthesis (FAS-II) cluster. We demonstrate that RNase R governs the turnover of most of genes from this pathway, affecting the outcome of the whole FAS-II cluster, and leading to an unbalanced membrane fatty acid composition. Our results show that the membrane of the deleted strain contains a higher proportion of unsaturated and long-chained fatty acids than the wild type strain. This leads to a higher fluidity of the Δrnrmutant membrane, which is probably related with the increased sensitivity to detergent observed in this strain. We demonstrate that RNase R expression is induced in cells challenged with H2O2, which is suggestive of a role for this ribonuclease on the regulation of membrane homeostasis under oxidative stress. Reprogramming of membrane fluidity is an adaptative cell response crucial for bacterial survival in constantly changing environmental conditions. The fact that RNase R controls the expression of several essential genes to the fatty acid synthesis unveils a new important function of this enzyme.

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Pivotal Roles for Ribonucleases in Streptococcus pneumoniae Pathogenesis

Cited by 9 publications

References 86 publications

RNase R, a New Virulence Determinant of Streptococcus pneumoniae

RNase R, a New Virulence Determinant of Streptococcus pneumoniae

The five homologous CiaR-controlled Ccn sRNAs ofStreptococcus pneumoniaemodulate Zn-resistance

RNase R Controls Membrane Fatty Acid Composition inStreptococcus pneumoniae

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