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Streptococcus pyogenes (Group A Streptococcus; GAS) is exquisitely adapted to the human host, resulting in asymptomatic infection, pharyngitis, pyoderma, scarlet fever or invasive diseases, with potential for triggering post-infection immune sequelae. GAS deploys a range of virulence determinants to allow colonization, dissemination within the host and transmission, disrupting both innate and adaptive immune responses to infection. Fluctuating global GAS epidemiology is characterized by the emergence of new GAS clones, often associated with the acquisition of new virulence or antimicrobial determinants that are better adapted to the infection niche or averting host immunity. The recent identification of clinical GAS isolates with reduced penicillin sensitivity and increasing macrolide resistance threatens both frontline and penicillin-adjunctive antibiotic treatment. The World Health Organization (WHO) has developed a GAS research and technology road map and has outlined preferred vaccine characteristics, stimulating renewed interest in the development of safe and effective GAS vaccines.In this Review, Brouwer et al. summarize recent developments in our understanding of Group A Streptococcus (GAS), focusing on the epidemiologic and clinical features of GAS infection and the molecular mechanisms associated with GAS virulence and drug resistance.

A new variant of Streptococcus pyogenes serotype M1 (designated ‘M1 UK ’) has been reported in the United Kingdom, linked with seasonal scarlet fever surges, marked increase in invasive infections, and exhibiting enhanced expression of the superantigen SpeA. The progenitor S. pyogenes ‘M1 global ’ and M1 UK clones can be differentiated by 27 SNPs and 4 indels, yet the mechanism for speA upregulation is unknown. Here we investigate the previously unappreciated expansion of M1 UK in Australia, now isolated from the majority of serious infections caused by serotype M1 S. pyogenes . M1 UK sub-lineages circulating in Australia also contain a novel toxin repertoire associated with epidemic scarlet fever causing S. pyogenes in Asia. A single SNP in the 5’ transcriptional leader sequence of the transfer-messenger RNA gene ssrA drives enhanced SpeA superantigen expression as a result of ssrA terminator read-through in the M1 UK lineage. This represents a previously unappreciated mechanism of toxin expression and urges enhanced international surveillance. A variant of group A Streptococcus serotype M1 (UK) has been increasingly reported and can be differentiated from the global variant by its overexpression of the superantigen SpeA. Here, Davies et al probe the mechanism behind enhanced SpeA expression and demonstrate that a SNP in the 5’ leader sequence of ssrA is responsible for this virulence phenotype.

The re-emergence of scarlet fever poses a new global public health threat. The capacity of North-East Asian serotype M12 ( emm 12) Streptococcus pyogenes (group A Streptococcus , GAS) to cause scarlet fever has been linked epidemiologically to the presence of novel prophages, including prophage ΦHKU.vir encoding the secreted superantigens SSA and SpeC and the DNase Spd1. Here, we report the molecular characterization of ΦHKU.vir-encoded exotoxins. We demonstrate that streptolysin O (SLO)-induced glutathione efflux from host cellular stores is a previously unappreciated GAS virulence mechanism that promotes SSA release and activity, representing the first description of a thiol-activated bacterial superantigen. Spd1 is required for resistance to neutrophil killing. Investigating single, double and triple isogenic knockout mutants of the ΦHKU.vir-encoded exotoxins, we find that SpeC and Spd1 act synergistically to facilitate nasopharyngeal colonization in a mouse model. These results offer insight into the pathogenesis of scarlet fever-causing GAS mediated by prophage ΦHKU.vir exotoxins. The pathogenesis of Streptococcus pyogenes (GAS) causing scarlet fever has been associated with the presence of prophages, such as ΦHKU.vir, and their products. Here, the authors characterize the exotoxins SpeC and Spd1 of ΦHKU.vir and show these to act synergistically to facilitate nasopharyngeal colonization in mice.

Streptococcus dysgalactiae subsp. equisimilis (SDSE) is an emerging cause of human infection with invasive disease incidence and clinical manifestations comparable to the closely related species, Streptococcus pyogenes . Through systematic genomic analyses of 501 disseminated SDSE strains, we demonstrate extensive overlap between the genomes of SDSE and S. pyogenes . More than 75% of core genes are shared between the two species with one third demonstrating evidence of cross-species recombination. Twenty-five percent of mobile genetic element (MGE) clusters and 16 of 55 SDSE MGE insertion regions were shared across species. Assessing potential cross-protection from leading S. pyogenes vaccine candidates on SDSE, 12/34 preclinical vaccine antigen genes were shown to be present in >99% of isolates of both species. Relevant to possible vaccine evasion, six vaccine candidate genes demonstrated evidence of inter-species recombination. These findings demonstrate previously unappreciated levels of genomic overlap between these closely related pathogens with implications for streptococcal pathobiology, disease surveillance and prevention. Streptococcus dysgalactiae subsp. equisimilis (SDSE) is an emerging cause of human infection closely related to Streptococcus pyogenes . Here the authors investigate the degree of genomic similarity between the two species and assess implications for development of vaccines.

The transition from a petroleum‐based manufacturing to biomanufacturing is an important step towards a sustainable bio‐economy. In particular, biotechnological processes which use one carbon (C1) compounds as feedstock represent an interesting avenue. Many bacterial species evolved naturally to thrive on such compounds, among them Cupriavidus necator, which has been studied in the past due to its range of metabolic capabilities in utilisation and production of compounds of interest. Cupriavidus necator strain H16 is the reference laboratory strain for this species and by far the most extensively studied. In contrast, research efforts and genomic characterisation of other strains within this species have been limited and sporadic. Therefore, the genomic diversity and full metabolic potential across the broader species remain poorly understood. In this work, we collected publicly available genomes along with newly sequenced ones. From a collection of 44 genomes, we curated a final collection of 22 genomes deemed to be C. necator. We examined hallmark metabolic functions, including carbon dioxide fixation, formate assimilation and hydrogen utilisation. We identified methylation motifs and restriction modification systems. Finally, strains ATCC 25207, TA06, and 1978 are proposed as candidate strains of interest based on their genomic make‐up and observations from literature. This work provides a comprehensive genomic resource for the C. necator species, facilitating its development as a biomanufacturing platform and advancing our understanding of its metabolic diversity and potential applications. Cupriavidus necator is a promising microbe for one‐carbon biomanufacturing. Newly sequenced strains and a comparative assessment of all available genomes define further this species and its traits of interest.

During infection, microbes must escape host immune responses and survive exposure to reactive oxygen species produced by immune cells. Here, we identify the ABC transporter substrate binding protein GshT as a key component of the glutathione salvage pathway in glutathione-auxotrophic GAS. The nasopharynx and the skin are the major oxygen-rich anatomical sites for colonization by the human pathogen Streptococcus pyogenes (group A Streptococcus [GAS]). To establish infection, GAS must survive oxidative stress generated during aerobic metabolism and the release of reactive oxygen species (ROS) by host innate immune cells. Glutathione is the major host antioxidant molecule, while GAS is glutathione auxotrophic. Here, we report the molecular characterization of the ABC transporter substrate binding protein GshT in the GAS glutathione salvage pathway. We demonstrate that glutathione uptake is critical for aerobic growth of GAS and that impaired import of glutathione induces oxidative stress that triggers enhanced production of the reducing equivalent NADPH. Our results highlight the interrelationship between glutathione assimilation, carbohydrate metabolism, virulence factor production, and innate immune evasion. Together, these findings suggest an adaptive strategy employed by extracellular bacterial pathogens to exploit host glutathione stores for their own benefit. IMPORTANCE During infection, microbes must escape host immune responses and survive exposure to reactive oxygen species produced by immune cells. Here, we identify the ABC transporter substrate binding protein GshT as a key component of the glutathione salvage pathway in glutathione-auxotrophic GAS. Host-acquired glutathione is crucial to the GAS antioxidant defense system, facilitating escape from the host innate immune response. This study demonstrates a direct link between glutathione assimilation, aerobic metabolism, and virulence factor production in an important human pathogen. Our findings provide mechanistic insight into host adaptation that enables extracellular bacterial pathogens such as GAS to exploit the abundance of glutathione in the host cytosol for their own benefit.

Colorectal cancer (CRC) patients exhibit distinct gut microbiota disruption, known as dysbiosis, which is believed to play a causative role in CRC. One of the key bacterial species implicated in CRC dysbiosis is Bacteroides fragilis, which presents a paradox as it is also present in most healthy individuals. This discrepancy underscores the need for analysis beyond species-level associations and to investigate intraspecies variation within B. fragilis. From a highly specific collection of B. fragilis isolates from CRC patients and controls, a pangenome-wide association study was conducted, identifying intraspecies genetic variations associated with CRC. The CRC association of these genetic variations were then validated in a metagenome sequencing cohort of faecal samples from 877 individuals, with and without CRC. To test group differences a mixed effects logistic regression with cohort as a random effect was performed for each genetic variation. Here we show that CRC-associated B. fragilis isolates are infected with specific Caudoviricetes prophages, significantly more often than negative controls. The initial discovery was made in our highly specific isolate collection and then validated in an independent metagenome sequencing cohort, finding that CRC patients were twice as likely to have detectable levels of these phages (OR = 2.05, p = 2.522E-7, SE = 0.139). To our knowledge, these findings mark the first link between one of the most implicated driver bacteria and phages in CRC and suggest a more complex role of phages in CRC dysbiosis than current models suggest and highlights the potential of phages as CRC biomarkers.

A new variant of Streptococcus pyogenes serotype M1 (designated 'M1 ') has been reported in the United Kingdom, linked with seasonal scarlet fever surges, marked increase in invasive infections, and exhibiting enhanced expression of the superantigen SpeA. The progenitor S. pyogenes 'M1 ' and M1 clones can be differentiated by 27 SNPs and 4 indels, yet the mechanism for speA upregulation is unknown. Here we investigate the previously unappreciated expansion of M1 in Australia, now isolated from the majority of serious infections caused by serotype M1 S. pyogenes. M1 sub-lineages circulating in Australia also contain a novel toxin repertoire associated with epidemic scarlet fever causing S. pyogenes in Asia. A single SNP in the 5' transcriptional leader sequence of the transfer-messenger RNA gene ssrA drives enhanced SpeA superantigen expression as a result of ssrA terminator read-through in the M1 lineage. This represents a previously unappreciated mechanism of toxin expression and urges enhanced international surveillance.

The transition from a petroleum-based manufacturing to biomanufacturing is an important step towards a sustainable bio-economy. In particular biotechnological processes which use one carbon (C1) compounds as feedstock represent an interesting avenue. Many bacterial species evolved naturally to thrive on such compounds, among them Cupriavidus necator, which has been studied in the past due to its range of metabolic capabilities in utilization and production of compounds of interest. Cupriavidus necator strain H16 is the reference laboratory strain for this species and by far the most extensively studied. In contrast, research efforts and genomic characterization of other strains within this species have been limited and sporadic. Therefore, the genomic diversity and full metabolic potential across the broader species remain poorly understood. In this work, we collected publicly available genomes along with newly sequenced ones. From a collection of 44 genomes we curated a final collection of 22 genomes deemed to be C. necator. We examined hallmark metabolic functions, including carbon dioxide fixation, formate assimilation, and hydrogen utilization. We identified methylation motifs and restriction modification systems. Finally, strains ATCC 25207, TA06, and 1978 are proposed as candidate strains of interest based on their genomic make-up and observations from literature. This work provides a comprehensive genomic resource for the C. necator species, facilitating its development as a biomanufacturing platform and advancing our understanding of its metabolic diversity and potential applications. The green transition from petroleum-based manufacturing to a biomanufacturing economy requires new solutions. One of these is the development of bacterial platforms for production of valuable chemicals, in particular from CO2 and derived molecules. In this context, Cupriavidus necator is one of the most studied platform strains, although the genomic potential of this species has been seldom explored. This work provides a curated set of C. necator genomes, collected from public repositories and additional newly sequenced genomes. Through multiple analyses, C. necator ATCC 25207, TA06, and 1978 are proposed as strains of interest for further use. These findings lay the groundwork for advancing C. necator as a key organism in sustainable biomanufacturing, highlighting its potential for efficient carbon fixation, formate assimilation, and hydrogen utilization. The identification of methylation motifs and restriction modification systems further supports genetic engineering efforts, making these strains highly valuable for future biotechnological applications.