Editorial: Insights in infectious agents and disease: 2022

Streptococcus, and Clostridium; Gram-negative bacteria of the genera Brucella, Escherichia, Francisella, Salmonella, Stenotrophomonas, and Vibrio, with Brucella, Francisella, and Salmonella representing major intracellular pathogens; and finally Mycobacterium tuberculosis, which is also a major intracellular pathogenic species, with a particular cell wall distinct from Gram-positive or Gram-negative bacteria. Of related interest Soni et al. (2024) published a recent review on "understanding bacterial pathogenicity: a closer look at the journey of harmful microbes". The authors classified bacterial pathogens based on Gram staining, as above, and precised that Gram-negative bacteria are more dangerous than their Gram-positive counterparts due to their formidable defenses. They possess an outer membrane that acts as a barrier, and efflux pumps that actively remove antibiotics. These bacteria can form biofilms, making them resistant to treatment, and can change surface structures to evade the immune system. In addition, what's particularly concerning is their propensity for multidrug resistance, rendering many antibiotics ineffective. The authors used also the bacterial classification based on their lifestyle, i.e. intracellular versus extracellular as indicated above for the bacterial pathogens of the present Research Topic.To start with Gram-positive extracellular pathogens, Afshar et al. reported biofilm formation and inflammatory potential of Staphylococcus saccharolyticus as a possible cause of orthopedic implant-associated infections. S. saccharolyticus is a coagulase-negative staphylococcal species and has some unusual characteristics for human-associated staphylococci, such as slow growth and its preference for anoxic culture conditions. This species is relatively abundant in the human skin microbiota, but its microbiological properties, as well as the pathogenic potential, have scarcely been investigated, despite being occasionally isolated from different types of infections including orthopedic implant-associated infections. Using several in vitro and cellular approaches including transcriptome analysis, the authors provided evidence for biofilm formation of this species together with a set of upregulated genes in biofilm-embedded cells, including factors involved in adhesion, colonization, and competition. In a cellular infection model S. saccharolyticus was in addition shown to trigger the secretion of proinflammatory cyto-and chemokines, but was less cytotoxic than Staphylococcus aureus. This study thus demonstrated a substantial pathogenic potential of the species S. saccharolyticus, which can be a potential cause of orthopedic implant-associated infections and other types of deep-seated infections. Deshmukh et al. studied gene expression of S100a8/a9 as a potential biomarker to predict S. aureus-induced septic arthritis. Septic arthritis is an aggressive joint disease associated with high morbidity and mortality. Early antibiotic treatment is crucial for a better prognosis to save the patients from severe bone damage and later joint dysfunction.According to the authors, to date there are no specific predictive biomarkers for septic arthritis.By transcriptome sequencing analysis they identified S100a8/a9 genes to be highly expressed in septic arthritis compared to non-septic arthritis at the early course of infection in an S. aureus septic arthritis mouse model. Regarding pathogenesis, importantly downregulation of S100a8/a9 mRNA expression at the early course of infection was noticed in mice infected with the S. aureus Sortase A/B mutant strain totally lacking arthritogenic capacity compared with the mice infected with parental S. aureus arthritogenic strain. The authors concluded S100a8/a9 gene expression may serve as a potential biomarker to predict septic arthritis, enabling the development of more effective treatment strategies. Lei et al. demonstrated that slipped-strand mispairing within a polycytidine tract in the transcriptional regulatory gene mga leads to M protein phase variation and Mga length polymorphism in Group A Streptococcus. The M surface protein is a major virulence factor of this group, and can be downregulated or lost during culture, due to a general mechanism called phase variation. This variation refers to a reversible on/off switch for control of expression of one or more proteins between individual cells of a clonal population. The authors thus identified slipped-strand mispairing within a polycytidine tract of the transcriptional regulatory gene mga as a reversible switch controlling M protein production phase variation in multiple common M types of Group A Streptococcus. Janzic et al. provided evidence for macrophage polarization during Group B Streptococcus agalactiae infection as being isolate specific, by studying a diverse set of strains belonging to different serotypes and sequence types on the immune response of THP-1 macrophages. Their data suggest that Group B isolates differ in their potential to become invasive or remain colonizing.In addition, colonizing isolates appeared to be more cytotoxic, whereas invasive isolates appeared to exploit macrophages to their advantage, avoiding the immune recognition and antibiotics. Schwanbeck et al. defined Clostridioides difficile minimal nutrient requirements for flagellar motility. As many gastro-intestinal pathogens, the majority of Clostridioides difficile strains express flagella together with a complete chemotaxis system. The resulting swimming motility is likely contributing to the colonization success of this important pathogen. The authors identified, by removal of individual amino acids from the medium, proline and cysteine as the most important amino acids that power swimming motility. A maximal and stable swimming motility was achieved with only four compounds, including the amino acids proline, cysteine and isoleucine together with a single, but interchangeable carbohydrate source. The authors expect that the identified "minimal motility medium" will be useful in future Regarding Gram-negative intracellular pathogens, Altamirano-Silva et al. studied phenotypes controlled by the Brucella abortus two component system BvrR/BvrS that appeared differentially impacted by BvrR phosphorylation. B. abortus is a zoonotic pathogen whose virulence depends on its ability to survive intracellularly at the endoplasmic reticulum derived compartment. The two-component system BvrR/BvrS (BvrRS) is essential for intracellular survival due to the transcriptional control of the type IV secretion system VirB and its transcriptional regulator VjbR. It is in addition a master regulator of several traits including membrane homeostasis by controlling gene expression of membrane components, such as Omp25. BvrR phosphorylation is related to DNA binding at target regions, thereby repressing or activating gene transcription. The BvrRS-contolled phenotypes investigated were resistance to polymyxins and intracellular survival. By using a set of mutants affecting BvrR phosphorylation, the authors provide evidence for a differential transcriptional response of genes depending on the phosphorylation status of BvrR, with resulting different phenotypes.The data suggest that unphosphorylated BvrR binds and impacts the expression of a subset of genes, as for example the dominant negative BvrR did not interact with the omp25 promoter whereas it could interact with the vjbR promoter. BvrR thus appears to possess diverse strategies to exert transcriptional control on the genes it regulates and, consequently, impacting on the phenotypes controlled by this response regulator. Among pathogenic factors, biofilm production is known to enable bacteria to successfully colonize and persist in different environments and in different parts of the human body in the course of infection. Schaudinn et al. studied biofilm production in Francisella tularensis subspecies holarctica and showed that this subspecies is able to colonize natural aquatic ex vivo biofilms. Infections in humans are mostly associated with the highly virulent F. tularensis subspecies tularensis and the less virulent subspecies holarctica. Subspecies holarctica is more frequently associated with aquatic habitats. In the present sudy, the authors showed for the first time that a F. tularensis subspecies holarctica wild-type strain is able to successfully colonize an aquatic multi-species ex vivo biofilm. The authors speculate that subspecies holarctica might become more persistent in the environment when it forms its own biofilm or integrates in an existing one. Multi-species biofilms have been shown to be more resistant against stress compared to single-species biofilms. This may have an important impact on the long-term survival of Francisella in aquatic habitats and infection cycles in nature. Regarding biofilm formation, Zhang et al. studied its regulation in Vibrio parahaemolyticus, another important pathogen occurring in aquatic habitats and which is the primarily causative agent of the seafood-associated gastroenteritis.The authors provided evidence, using respective mutant backgrounds, that the quorum sensing regulatory proteins QsvR and OpaR coordinately repress biofilm formation by V. parahaemolyticus. More precisely, QsvR restored the biofilm-associated phenotypic changes caused by opaR mutation, and vice versa. In addition, QsvR and OpaR worked coordinately to regulate the transcription of bacterial colonization/biofilm formation genes such as exopolysaccharide-associated genes, type IV pili genes, capsular polysaccharide genes and cdi-GMP metabolism-related genes. Regarding virulence regulation, Hirakawa et al. provided evidence that the PapB/FocB family protein TosR acts as a positive regulator of flagellar expression and is required for optimal virulence of uropathogenic Escherichia coli. Uropathogenic E. coli (UPEC) is a major causative agent of urinary tract infections. The bacteria internalize into the uroepithelial cells, where aggregate and form microcolonies. UPEC fimbriae and flagella are important for the formation of microcolonies in uroepithelial cells.PapB/FocB family proteins are small DNA-binding transcriptional regulators consisting of approximately 100 amino acids that have been reported to regulate the expression of various fimbriae, including P, F1C, and type 1 fimbriae, and adhesins. In the present study, the authors showed that TosR, a member of this family, is a transcriptional activator that increases expression of the flagella flhDC operon genes, contributing to flagellar expression and optimal virulence. Ojiakor et al. investigated the evolutionary diversification of the artAB toxin locus of another important enterobacterial pathogen, namely Salmonella enterica. S. enterica is a diverse species of bacterial pathogens comprised of >2,500 serovars with variable host ranges and virulence properties. Accumulating evidence indicates that two AB5-type toxins, typhoid toxin and ArtAB toxin, contribute to the more severe virulence properties of the Salmonella strains that encode them. The authors focused on two genetic loci, artAB and pltC, the latter encoding an alternative delivery subunit for typhoid toxin. By assessing Salmonella genome sequences available in the NCBI genome database, they identified 7 subtypes of ArtAB toxins and 4 different PltC sequence groups that are distributed throughout the Salmonella genus.Interestingly, both artAB and pltC were located within numerous diverse prophages, indicating a central role for phages in their evolutionary diversification. This particular situation combined with genetic variation at both loci can thus be exploited by a continuously adapting pathogen such as Salmonella to yield novel toxins with distinct properties. Regarding pathogen evolution,Stenotrophomonas maltophilia in the airways of adults with cystic fibrosis. Using genomic analyses, the authors investigated the natural history, transmission potential, and evolution of S. maltophilia in a large Canadian cohort of 321 cystic fibrosis patients over a 37-year period.These analyses suggested common, indirect sources as the origins of S. maltophilia infections in the clinic population. Infection within individual cystic fibrosis patients is driven by unique strains that are likely of environmental origins, as observed with other cystic fibrosis pathogens. While some patients may carry genetically related strains, these do not appear to be associated with patient-to-patient transmission but more likely with independent acquisition from environmental sources. The infection process is largely clonal at the SNP level, but significant diversity is present and driven by differences in gene content within strains.To end this section on pathogenesis and pathogen evolution' collection of articles, more in relation to pathogen persistence and host-defense evasion, García-Bengoa et al. provided a review on the role of phagocyte extracellular traps during Mycobacterium tuberculosis infections and tuberculosis disease processes. M. tuberculosis infections remain one of the most significant causes of mortality worldwide. This pathogen is highly successful in evading the host-defense by manipulating host-signaling pathways. It concerns two cell types, macrophages and neutrophils. Both cells are known to act in multiple ways when encountering an invading pathogen, including phagocytosis, release of cytokines and chemokines, and oxidative burst. In addition, the formation of neutrophil extracellular traps (NETs) and macrophage extracellular traps (METs) has been described to contribute to M. tuberculosis infections. NETs/METs are extracellular DNA fibers with associated granule components, which are released upon activation of the cells by the pathogen or by pro-inflammatory mediators. In this review, the authors thus summarize the progress made in understanding the role of NETs/METs in the pathogenesis of tuberculosis.With the increasing rate over the past decades of multiple antibiotic resistance to almost all strain, either with (+) or without (-) the nimA gene. Among differentially expressed proteins in the nimA(+) strain, the flavodiiron protein FprA, an enzyme involved in oxygen scavenging, was identified. Interestingly, a far higher number of proteins were found to be differentially expressed in the nimA(-) strain upon metronidazole induction. They included factors for the import of hemin which were strongly downregulated, indicating impaired iron import in the nimA(-) strain. Together with other physiological data, the authors present a novel hypothetic model of metronidazole resistance and NimA function.To combat or limit the spread of antimicrobial resistance in bacteria several approaches have been proposed or are under evaluation. Among them are new non-antibiotic strategies to limit or eradicate multi-resistant bacteria carriage without globally disrupting the microbiota. Bonnet et al. addressed in a Review article the question of decolonization of asymptomatic carriage of multidrug-resistant bacteria by bacteriophages. Asymptomatic colonization of the digestive tract by multidrug-resistant bacteria such as extended-spectrum beta-lactamase-or carbapenemase-producing Enterobacterales, poses several risks, including increased risk of infection, spread among patients and to the wider community, as well as resistance gene exchange between bacteria. This review discusses strategies for decolonizing the digestive tract of multidrug-resistant bacteria, including probiotics, fecal microbiota transplantation, and lytic bacteriophages. Highlighting that even though successful decolonization using lytic bacteriophages has been studied in vivo and in vitro, and observed clinically, limitations remain due to animal models, phage characteristics, and gut anatomy and further work is needed. In addition to this review, Li et al. reported that host CD3+ T-cells can significantly modulate phage treatment effects on bacterial bioburden in mouse models. Using A. baumannii phage mixtures the authors uncovered that the interplay between bacterial bioburden and host immune system may be bidirectional, and that there is an interaction between host CD3+ T-cells and phage dosage, which significantly impacts bacterial bioburden. Furthermore, the bacterial bioburden and wound size association was significantly modulated by the host CD3+ T-cells.This study provided evidence for strong relationships between host immune competency, therapeutic efficacy, bacterial clearance, and wound healing. Besides the obvious beneficial approaches of using bacteriophages to combat the spread of antimicrobial resistance, paradoxically Andersson et al. reported the enrichment of antibiotic resistance genes within bacteriophage populations in saliva samples from individuals undergoing oral antibiotic treatments. Indeed, horizontal gene transfer mediated through bacteriophages may also play an important role in the spread of antimicrobial resistance genes. In a cohort of Tanzanian patients suffering from bacterial infections, the authors demonstrated significant differences in the oral microbial diversity between infected and non-infected individuals, as well as before and after oral antibiotics treatment. Furthermore, the resistome carried both by bacteria and bacteriophages were shown to vary significantly, with extended cephalosporin blaCTX-M-1 resistance genes being mobilized and enriched within phage populations. Spread of resistance through bacteriophages in a biological context, as well in terms of treatment regimens should thus also be considered. 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