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Pathogenic Streptococci: Virulence, Host Response and Therapy

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A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Antimicrobial Agents and Resistance".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 26123

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Special Issue Editors

Dr. Slawomir Lukomski

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Guest Editor

Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine Morgantown, Morgantown, WV, USA
Interests: Streptococcus pyogenes; infectious diseases; virulence; pathogens; virulence factors

Dr. Melody N. Neely

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Guest Editor

Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME, USA
Interests: infectious diseases; virulence factors; virulence; pathogens; Streptococcus agalactiae

Dr. Hasan Yesilkaya

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Guest Editor

Department of Respiratory Sciences, University of Leicester, Leicester, UK
Interests: virulence factors; Streptococcus pneumoniae; virulence; microbial physiology and metabolic adaptation

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to this Special Issue entitled “Pathogenic Streptococci: Virulence, Host Response and Therapy”. Streptococci constitute a heterogeneous group of Gram-positive bacteria that colonize and infect humans, causing diverse diseases. Streptococcal infections remain a major concern for all age groups regardless of their immune status. While the pneumococcal vaccines have been effective to a certain extent, so far, we do not have vaccines against Streptococcus pyogenes and Streptococcus agalactiae. In addition, an increasing trend of drug-resistant and drug-tolerant isolates among the three human streptococcal pathogens is a major concern and requires the development of new therapeutic approaches.

To address the continuing threat of streptococcal infections, this Special Issue will focus on new research that provides advancement in knowledge on virulence mechanisms, host response to infection and new therapeutic strategies that contribute to host survival during infection.

In this Special Issue, original research articles and reviews are welcome. Manuscripts submitted to this Special Issue could fall under the journal’s scope of microbial genetics, medical microbiology, microbial physiology and pharmaceutical microbiology.

We look forward to receiving your contributions.

Dr. Slawomir Lukomski
Dr. Melody N. Neely
Dr. Hasan Yesilkaya
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Microorganisms is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

group A, B, C, G streptococci
pneumococci
streptococcal pathogenesis
host response
immune evasion
streptococcal vaccines

Published Papers (10 papers)

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Research

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15 pages, 2461 KiB

Open AccessArticle

The Cell Wall Deacetylases Spy1094 and Spy1370 Contribute to Streptococcus pyogenes Virulence

by Tiger Aspell, Adrina Hema J. Khemlani, Catherine Jia-Yun Tsai, Jacelyn Mei San Loh and Thomas Proft

Microorganisms 2023, 11(2), 305; https://doi.org/10.3390/microorganisms11020305 - 24 Jan 2023

Cited by 1 | Viewed by 1287

Abstract

Streptococcus pyogenes, or Group A Streptococcus (GAS), is a strictly human pathogen that causes a wide range of diseases, including skin and soft tissue infections, toxic shock syndrome and acute rheumatic fever. We have recently reported that Spy1094 and Spy1370 of S. pyogenes serotype M1 are N-acetylglucosamine (GlcNAc) deacetylases. We have generated spy1094 and spy1370 gene deletion mutants in S. pyogenes and gain-of-function mutants in Lactococcus lactis. Similar to other cell wall deacetylases, our results show that Spy1094 and Spy1370 confer lysozyme-resistance. Furthermore, deletion of the genes decreased S. pyogenes virulence in a human whole blood killing assay and a Galleria mellonella (Greater wax moth) larvae infection model. Expression of the two genes in L. lactis resulted in increased lysozyme resistance and survival in whole human blood, and reduced survival of infected G. mellonella larvae. Deletion of the spy1370, but not the spy1094 gene, decreased resistance to the cationic antimicrobial peptide cecropin B, whereas both enzymes increased biofilm formation, probably resulting from the increase in positive charges due to deacetylation of the cell wall. In conclusion, Spy1094 and Spy1370 are important S. pyogenes virulence factors and might represent attractive targets for the development of antibacterial agents. Full article

(This article belongs to the Special Issue Pathogenic Streptococci: Virulence, Host Response and Therapy)

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18 pages, 2350 KiB

Open AccessArticle

Exploiting Conserved Quorum Sensing Signals in Streptococcus mutans and Streptococcus pneumoniae

by Giulia Bernabè, Anthony Pauletto, Annj Zamuner, Leonardo Cassari, Ignazio Castagliuolo, Paola Brun and Monica Dettin

Microorganisms 2022, 10(12), 2386; https://doi.org/10.3390/microorganisms10122386 - 30 Nov 2022

Cited by 4 | Viewed by 1998

Abstract

Bacterial species of the Streptococcus genera are considered either commensal bacteria or potential pathogens, according to their metabolic evolution and production of quorum sensing (QS)-controlled virulence factors. S. mutans, in particular, has become one of the best-studied examples of bacteria that are able to get along or cheat commensal species, even of the same genera. S. mutans and S. pneumoniae share homolog QS pathways and a competence stimulating peptide (CSP) for regulating bacteriocin production. Intriguingly, the abundance of S. pneumoniae and S. mutans alternates in complex microbial communities, thus opening the role for the fratricide communication of homolog QS systems. Since the inhibition of the QS has been proposed in treating bacterial infections, in this study, we designed and synthesized analogs of S. pneumoniae CSP with precise residual modifications. We reported that S. pneumoniae CSP analogs reduced the expression of genes involved in the QS of S. mutans and biofilm formation without affecting bacterial growth. The CSP analogs inhibited bacteriocin production in S. mutans, as reported by co-cultures with commensal bacteria of the oral cavity. The peptide CSP1AA, bearing substitutions in the residues involved in QS receptor recognition and activation, reported the most significant quorum-quenching activities. Our findings provide new insights into specific chemical drivers in the CSP sequences controlling the interconnection between S. mutans and S. pneumoniae. We think that the results reported in this study open the way for new therapeutic interventions in controlling the virulence factors in complex microbial communities such as the oral microbiota. Full article

(This article belongs to the Special Issue Pathogenic Streptococci: Virulence, Host Response and Therapy)

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15 pages, 2293 KiB

Open AccessArticle

Loss of rpoE Encoding the δ-Factor of RNA Polymerase Impacts Pathophysiology of the Streptococcus pyogenes M1T1 Strain 5448

by Joseph S. Rom, Yoann Le Breton, Emrul Islam, Ashton T. Belew, Najib M. El-Sayed and Kevin S. McIver

Microorganisms 2022, 10(8), 1686; https://doi.org/10.3390/microorganisms10081686 - 22 Aug 2022

Cited by 1 | Viewed by 1778

Abstract

Streptococcus pyogenes, also known as the Group A Streptococcus (GAS), is a Gram-positive bacterial pathogen of major clinical significance. Despite remaining relatively susceptible to conventional antimicrobial therapeutics, GAS still causes millions of infections and hundreds of thousands of deaths each year worldwide. Thus, a need for prophylactic and therapeutic interventions for GAS is in great demand. In this study, we investigated the importance of the gene encoding the delta (δ) subunit of the GAS RNA polymerase, rpoE, for its impact on virulence during skin and soft-tissue infection. A defined 5448 mutant with an insertionally-inactivated rpoE gene was defective for survival in whole human blood and was attenuated for both disseminated lethality and lesion size upon mono-culture infection in mouse soft tissue. Furthermore, the mutant had reduced competitive fitness when co-infected with wild type (WT) 5448 in the mouse model. We were unable to attribute this attenuation to any observable growth defect, although colony size and the ability to grow at higher temperatures were both affected when grown with nutrient-rich THY media. RNA-seq of GAS grown in THY to late log phase found that mutation of rpoE significantly impacted (>2-fold) the expression of 429 total genes (205 upregulated, 224 downregulated), including multiple virulence and “housekeeping” genes. The arc operon encoding the arginine deiminase (ADI) pathway was the most upregulated in the rpoE mutant and this could be confirmed phenotypically. Taken together, these findings demonstrate that the delta (δ) subunit of RNA polymerase is vital in GAS gene expression and virulence. Full article

(This article belongs to the Special Issue Pathogenic Streptococci: Virulence, Host Response and Therapy)

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17 pages, 8869 KiB

Open AccessArticle

The LCP Family Protein, Psr, Is Required for Cell Wall Integrity and Virulence in Streptococcus agalactiae

by Atefeh Rajaei, Hannah M. Rowe and Melody N. Neely

Microorganisms 2022, 10(2), 217; https://doi.org/10.3390/microorganisms10020217 - 20 Jan 2022

Cited by 1 | Viewed by 2050

Abstract

A robust cell envelope is the first line of protection for an infecting pathogen when encountering the immune defense of its host. In Gram-positive organisms, LytR-CpsA-Psr (LCP) family proteins play a major role in the synthesis and assembly of the cell envelope. While these proteins could be considered for potential new drug targets, not enough is known about how they function to support the integrity of the cell wall. Streptococcus agalactiae (group B streptococcus or GBS) is known to encode at least three LCP family proteins, including CpsA, LytR (BrpA) and Psr. Using strains of GBS that have mutations in two of the three LCP proteins, we were able to determine a role for these proteins in GBS cell wall integrity. The results presented here demonstrate that the absence of Psr results in a decreased growth rate, decreased viability over time, inconsistent cocci morphology and diminished cell wall integrity, as well as an increased penicillin susceptibility, decreased capsule levels and attenuation in virulence in a zebrafish model of infectious disease. A strain that is missing two of the LCP family proteins, CpsA and Psr, exhibits an increase in these defective phenotypes, indicating that CpsA and Psr are partially redundant in function. Full article

(This article belongs to the Special Issue Pathogenic Streptococci: Virulence, Host Response and Therapy)

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14 pages, 437 KiB

Open AccessArticle

Invasive Group B Streptococcal Disease in Neonates and Infants, Italy, Years 2015–2019

by Roberta Creti, Monica Imperi, Alberto Berardi, Erika Lindh, Giovanna Alfarone, Marco Pataracchia, Simona Recchia and The Italian Network on Neonatal and Infant GBS Infections

Microorganisms 2021, 9(12), 2579; https://doi.org/10.3390/microorganisms9122579 - 13 Dec 2021

Cited by 7 | Viewed by 2510

Abstract

Invasive infections by group B streptococci (iGBS) are the leading cause of sepsis and meningitis in the first three months of life worldwide. The clinical and microbiological characteristics of neonatal and infant iGBS in Italy during the years 2015–2019 were investigated. Voluntary-based surveillance reported 191 cases (67 early-onset (EOD) and 124 late-onset disease (LOD)) and 89 bacterial isolates were received. The main clinical manifestations were sepsis (59.2%) followed by meningitis (21.5%), bacteremia (12.0%) and septic shock (6.3%). Hospitalized preterm babies accounted for one third of iGBS and constituted the most fragile population in terms of mortality (8.2%) and brain damage (16.4%). GBS serotype III was predominant in EOD (56%) and caused almost all LOD (95%). The rate of resistance to clindamycin reached 28.8%. Most of clindamycin-resistant GBS strains (76%) were serotype III-ST17 and possessed the genetic markers of the emerging multidrug resistant (MDR) CC-17 sub-clone. Our data revealed that iGBS is changing since it is increasingly reported as a healthcare-associated infection (22.6%), mainly caused by MDR-CC17. Continuous monitoring of the clinical and microbiological characteristics of iGBS remains of primary importance and it represents, at present, the most effective tool to support prevention strategies and the research on the developing GBS vaccine. Full article

(This article belongs to the Special Issue Pathogenic Streptococci: Virulence, Host Response and Therapy)

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11 pages, 1401 KiB

Open AccessArticle

Signaling Peptide SpoV Is Essential for Streptococcus pyogenes Virulence, and Prophylaxis with Anti-SpoV Decreases Disease Severity

by Andrea L. Herrera and Michael S. Chaussee

Microorganisms 2021, 9(11), 2321; https://doi.org/10.3390/microorganisms9112321 - 10 Nov 2021

Viewed by 1487

Abstract

Streptococcal peptide of virulence (SpoV) is a Streptococcus pyogenes (group A streptococcus (GAS))-specific peptide that is important for GAS survival in murine blood, and the expression of the virulence factors streptolysin O (slo) and streptolysin S (sagA). We used a spoV mutant in isolate MGAS315 to assess the contribution of the SpoV peptide to virulence by using a murine model of invasive disease and an ex vivo human model (Lancefield assay). We then used antibodies to SpoV in both models to evaluate their ability to decrease morbidity and mortality. Results showed that SpoV is essential for GAS virulence, and targeting the peptide has therapeutic potential. Full article

(This article belongs to the Special Issue Pathogenic Streptococci: Virulence, Host Response and Therapy)

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21 pages, 7088 KiB

Open AccessArticle

The Two-Component System 09 of Streptococcus pneumoniae Is Important for Metabolic Fitness and Resistance during Dissemination in the Host

by Stephanie Hirschmann, Alejandro Gómez-Mejia, Thomas P. Kohler, Franziska Voß, Manfred Rohde, Max Brendel and Sven Hammerschmidt

Microorganisms 2021, 9(7), 1365; https://doi.org/10.3390/microorganisms9071365 - 23 Jun 2021

Cited by 3 | Viewed by 2881

Abstract

The two-component regulatory system 09 of Streptococcus pneumoniae has been shown to modulate resistance against oxidative stress as well as capsule expression. These data and the implication of TCS09 in cell wall integrity have been shown for serotype 2 strain D39. Other data have suggested strain-specific regulatory effects of TCS09. Contradictory data are known on the impact of TCS09 on virulence, but all have been explored using only the rr09-mutant. In this study, we have therefore deleted one or both components of the TCS09 (SP_0661 and SP_0662) in serotype 4 S. pneumoniae TIGR4. In vitro growth assays in chemically defined medium (CDM) using sucrose or lactose as a carbon source indicated a delayed growth of nonencapsulated tcs09-mutants, while encapsulated wild-type TIGR4 and tcs09-mutants have reduced growth in CDM with glucose. Using a set of antigen-specific antibodies, immunoblot analysis showed that only the pilus 1 backbone protein RrgB is significantly reduced in TIGR4ΔcpsΔhk09. Electron microscopy, adherence and phagocytosis assays showed no impact of TCS09 on the TIGR4 cell morphology and interaction with host cells. In contrast, in vivo infections and in particular competitive co-infection experiments demonstrated that TCS09 enhances robustness during dissemination in the host by maintaining bacterial fitness. Full article

(This article belongs to the Special Issue Pathogenic Streptococci: Virulence, Host Response and Therapy)

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Review

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17 pages, 972 KiB

Open AccessReview

Updates on Group B Streptococcus Infection in the Field of Obstetrics and Gynecology

by Yeseul Choi, Hyung-Soo Han, Gun Oh Chong, Tan Minh Le, Hong Duc Thi Nguyen, Olive EM Lee, Donghyeon Lee, Won Joon Seong, Incheol Seo and Hyun-Hwa Cha

Microorganisms 2022, 10(12), 2398; https://doi.org/10.3390/microorganisms10122398 - 2 Dec 2022

Cited by 3 | Viewed by 4218

Abstract

Group B Streptococcus (GBS, Streptococcus agalactiae) is a Gram-positive bacterium that is commonly found in the gastrointestinal and urogenital tracts. However, its colonization during pregnancy is an important cause of maternal and neonatal morbidity and mortality worldwide. Herein, we specifically looked at GBS in relation to the field of Obstetrics (OB) along with the field of Gynecology (GY). In this review, based on the clinical significance of GBS in the field of OBGY, topics of how GBS is being detected, treated, and should be prevented are addressed. Full article

(This article belongs to the Special Issue Pathogenic Streptococci: Virulence, Host Response and Therapy)

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23 pages, 1369 KiB

Open AccessReview

An Overview of Macrolide Resistance in Streptococci: Prevalence, Mobile Elements and Dynamics

by Dàmaris Berbel, Aida González-Díaz, Guillem López de Egea, Jordi Càmara and Carmen Ardanuy

Microorganisms 2022, 10(12), 2316; https://doi.org/10.3390/microorganisms10122316 - 23 Nov 2022

Cited by 14 | Viewed by 4085

Abstract

Streptococcal infections are usually treated with beta-lactam antibiotics, but, in case of allergic patients or reduced antibiotic susceptibility, macrolides and fluoroquinolones are the main alternatives. This work focuses on studying macrolide resistance rates, genetic associated determinants and antibiotic consumption data in Spain, Europe and also on a global scale. Macrolide resistance (MR) determinants, such as ribosomal methylases (erm(B), erm(TR), erm(T)) or active antibiotic efflux pumps and ribosomal protectors (mef(A/E)-mrs(D)), are differently distributed worldwide and associated with different clonal lineages and mobile genetic elements. MR rates vary together depending on clonal dynamics and on antibiotic consumption applying selective pressure. Among Streptococcus, higher MR rates are found in the viridans group, Streptococcus pneumoniae and Streptococcus agalactiae, and lower MR rates are described in Streptococcus pyogenes. When considering different geographic areas, higher resistance rates are usually found in East-Asian countries and milder or lower in the US and Europe. Unfortunately, the availability of data varies also between countries; it is scarce in low- and middle- income countries from Africa and South America. Thus, surveillance studies of macrolide resistance rates and the resistance determinants involved should be promoted to complete global knowledge among macrolide resistance dynamics. Full article

(This article belongs to the Special Issue Pathogenic Streptococci: Virulence, Host Response and Therapy)

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17 pages, 935 KiB

Open AccessReview

Metal Homeostasis in Pathogenic Streptococci

by Madeline S. Akbari, Kelly S. Doran and Lindsey R. Burcham

Microorganisms 2022, 10(8), 1501; https://doi.org/10.3390/microorganisms10081501 - 25 Jul 2022

Cited by 6 | Viewed by 2760

Abstract

Streptococcus spp. are an important genus of Gram-positive bacteria, many of which are opportunistic pathogens that are capable of causing invasive disease in a wide range of populations. Metals, especially transition metal ions, are an essential nutrient for all organisms. Therefore, to survive across dynamic host environments, Streptococci have evolved complex systems to withstand metal stress and maintain metal homeostasis, especially during colonization and infection. There are many different types of transport systems that are used by bacteria to import or export metals that can be highly specific or promiscuous. Focusing on the most well studied transition metals of zinc, manganese, iron, nickel, and copper, this review aims to summarize the current knowledge of metal homeostasis in pathogenic Streptococci, and their role in virulence. Full article

(This article belongs to the Special Issue Pathogenic Streptococci: Virulence, Host Response and Therapy)

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