Glycoside metabolization is a crucial function in bacteria and a key feature in fermentation and synthetic biology. To feed on various glycosides with complex structures, bacteria have developed very diverse mechanisms to recognize, transport and degrade them. Despite their crucial role, transporters are hard to identify and study due to challenges in expressing membrane proteins in recombinant form and the fact that most bacteria are uncultivable. In this review, we present the available methods and technologies for identifying and characterizing bacterial glycoside transporters. We consolidate existing knowledge on experimentally validated glycoside transporters from different families, including TonB-dependent transporters (TBDTs), ATP-binding cassette (ABCs) transporters, the phosphotransferase system (PTS) and the major facilitator superfamily (MFS), highlighting their taxonomic, functional, mechanistic and structural diversity. The disparity between the number of functionally characterized glycoside transporters and the vast amount of sequence data available underlines the need for more efficient approaches to determine their specificity and to better understand the molecular mechanisms of glycoside utilization in bacteria.
Enterohemorrhagic Escherichia coli (EHEC) is a major foodborne pathogen that causes hemorrhagic colitis and hemolytic uremic syndrome. Increasing evidence indicates that the gut microbiota plays a central role in modulating EHEC pathogenesis through complex metabolic and signaling networks. Beneficial commensals, including Bifidobacterium, Lactobacillus, and segmented filamentous bacteria, contribute to colonization resistance by competing for nutrients and adhesion sites, producing antimicrobial metabolites, and enhancing epithelial barrier integrity. In contrast, certain species such as Bacteroides thetaiotaomicron and Enterococcus faecalis may promote EHEC virulence by altering intestinal nutrient availability or triggering the expression of virulence genes. Microbiota-derived metabolites, including short-chain fatty acids, succinate, indole, riboflavin, nicotinamide, ethanolamine, and L-malate, act as important regulatory signals that connect microbial metabolism with LEE-mediated virulence pathways. Understanding these host-microbe-pathogen interactions provides a mechanistic basis for developing microbiota-targeted interventions such as probiotics, prebiotics, and fecal microbiota transplantation that enhance colonization resistance and attenuate virulence. Integration of AI-based analytics with multi-omics approaches is expected to facilitate the design of personalized, mechanism-driven therapeutic strategies for the control of EHEC infection.
Autophagy is a highly conserved cellular degradative pathway in eukaryotes that exerts a dual regulatory role in the host antiviral defense. On the one hand, as an essential component of the host antiviral defense network, autophagy participates in the direct degradation of viral components, synergistically modulates innate immune signaling pathways including TLRs, RLRs, and cGAS-STING, and regulates adaptive immune responses such as MHC class I/II-mediated antigen presentation. On the other hand, diverse viruses have evolved sophisticated immune evasion mechanisms during long-term coevolution with the host. These viruses target key steps of autophagy, including initiation, membrane nucleation, elongation, maturation, and lysosomal fusion, to hijack or suppress the autophagic pathway and facilitate their replication. The regulation of autophagy by different viruses exhibits remarkable molecular specificity. In-depth dissection of these molecular mechanisms underlying autophagy-virus interactions will provide novel insights into the pathogenesis of viral diseases. This review systematically summarizes the core process of autophagy and its multiple regulatory mechanisms in antiviral immunity. We further highlight how viruses employ specific molecular strategies to target distinct stages of autophagy during infection, thereby hijacking the autophagic pathway to complete their replication cycles and pathogenic progression.
Bacterial regulatory small RNAs (sRNAs) are integral components of posttranscriptional control, shaping environmental adaptation, metabolic homeostasis, and virulence. Advances in transcriptomics and RNA technologies have greatly expanded the repertoire of bacterial sRNAs and revealed their extensive roles in posttranscriptional regulatory networks. This review provides an updated framework for the biogenesis of bacterial sRNAs and their regulatory roles within posttranscriptional networks. Crucially, we describe the regulatory pathways controlling sRNA expression, including environmental signal sensing and regulation mediated by σ factors and transcription factors, to illustrate how sRNAs respond dynamically to changing conditions. Expanding beyond expression control, we further discuss the diverse roles of sRNA-mediated regulation in metabolic adaptation, stress responses, and bacterial virulence, emphasizing their importance in linking environmental changes to cellular phenotypes. Concurrently, we review current experimental and computational methods used for sRNA discovery and target identification. Overall, this review provides an integrated perspective on how bacterial sRNAs connect environmental sensing with adaptive cellular responses and highlights the broader significance of RNA-mediated regulation in bacterial physiology.
The human gut microbiome exhibits profound interindividual variability, challenging the efficacy of generalized interventions and underscoring the need for precision approaches to microbiome-associated diseases. Such strategies require comprehensive, individualized assessment of microbial ecosystems and their functional responses, an objective that remains difficult to achieve in vivo. In vitro gut models offer a promising alternative, maintaining personalized microbial communities in controlled environments and enabling detailed investigation of microbiome dynamics. Complementary microbe-host co-culture systems incorporating human cells further permit mechanistic interrogation of host responses to microbial stimuli. Together, these integrated platforms offer a translational framework for developing tailored therapeutics. In this Perspective, we examine how in vitro gut models can advance microbiome-based personalized medicine, discuss key determinants of therapeutic variability, and outline the relevance, limitations, and future directions of these systems in designing targeted, more effective interventions.
The high osmolarity glycerol (HOG) pathway enables adaptation to hyperosmotic and other environmental stresses. This review highlights key differences between the pathway in Saccharomyces cerevisiae and in filamentous fungi, focusing on the major pathogen Aspergillus fumigatus. In the multistep phosphorelay of the HOG pathway, stress signals are detected by hybrid histidine kinases (HHKs). According to the current model, HHKs function as kinases under nonstress conditions to maintain phosphorylation of downstream relay components. Upon stress exposure, their activity decreases or may switch to phosphatase activity, resulting in dephosphorylation of the relay. This change ultimately activates the downstream MAP kinase cascade, creating an inverse relationship between phosphorylation and signaling output in the two sections of the pathway. Fungi differ markedly in their HHK repertoire, ranging from a single HHK in S. cerevisiae to multiple functionally distinct HHKs in filamentous fungi. This review examines how this diversity has shaped the organization of the multistep phosphorelay and its integration into the HOG pathway. We summarize current knowledge of HHK function across fungal species, discuss why the multistep phosphorelay represents an Achilles' heel for fungi, and consider how the spatial organization of HOG pathway components influences signaling and how HHK repertoires may have diversified across the fungal kingdom.
Sulfoquinovosyldiacylglycerol (SQDG) is a ubiquitous sulfolipid of phototroph membranes, including those of oxygenic phototrophs and some anoxygenic phototrophic bacteria, and its headgroup sulfoquinovose (SQ) represents one of the most abundant organosulfur compounds in the biosphere. Global SQ production is estimated at ∼10 Pg yr-1, with marine systems alone contributing ∼1.5 Pg C yr-1 in SQ-containing compounds. In marine systems, heterotrophic processing of SQ is increasingly well characterized, whereas the pathways governing SQ transformation in freshwater environments remain poorly resolved. SQ enters both marine and freshwater systems primarily through turnover of phototrophic biomass, with freshwater systems also receiving terrestrial plant-derived sulfolipids. Although phototrophs synthesize SQDG for membrane function, cyanobacteria appear to have limited capacity for SQ catabolism, and SQ turnover is largely mediated by heterotrophic microorganisms. This functional partitioning establishes a metabolic relay in which distinct microbial guilds mediate successive steps of SQ processing, from extracellular sulfolipid hydrolysis to intracellular sulfoglycolysis and terminal sulfur mineralization. Here, we integrate current knowledge of the enzymatic pathways and microbial interactions underpinning SQ transformation within their ecological context. We propose that SQ metabolism constitutes an important, yet underappreciated, axis of aquatic sulfur biogeochemistry, particularly in freshwater systems where cyanobacterial production of dimethylsulfoniopropionate is minimal.
The filamentous cyanobacterium Microcoleus vaginatus is a pioneer soil colonizer and the most important microorganism for the formation of cyanobacterial biological soil crusts (or biocrusts), biofilm-like communities developing on soil surfaces exposed to light that become prominent in arid and polar lands. Among the most abundant cyanobacteria by global biomass, it contributes significantly through its biocrust-building to the global terrestrial carbon and nitrogen cycles. Locally, it contributes to the fertility and stability against erosion of the soils it inhabits and has become an indispensable tool in arid soil restoration efforts. Despite its importance, it remains relatively understudied. Because most work has been descriptive and ecological in nature, the knowledge amassed could be called a natural history. We provide an integrative review of what is known about its biology, what is not, and what is hindering advancement. We touch on its evolutionary history and population genetics, its physiological, genetic (genomic), behavioral, and ecological capacities, including some that present apparent paradoxes. We also explore the consequential relationships it keeps with other microbes, both mutualistic and antagonistic. The different aspects are guided by a dual leitmotiv to facilitate the understanding of its ecological success and environmental impact, and to predict its fate in a changing world.
Quorum sensing (QS) is a cell-density-dependent communication system that coordinates bacterial virulence, biofilm formation, motility, and stress adaptation, making it a compelling target for antivirulence intervention. Due to the possibility of sulfonyl (-SO₂-) and sulfinyl (-S = O-) functional groups to impart specific electronic and steric properties that can modulate bacterial signaling and receptor interactions, organosulfur compounds are increasingly gaining attention. This review highlights recent advances in the development of sulfonyl- and sulfinyl-containing organosulfur compounds as modulators of QS and biofilm formation in clinically relevant Gram-negative pathogens. Both natural and synthetic quorum-sensing inhibitors are considered, with activity directed toward LuxR-type regulators, diffusible signal factor (DSF)-mediated systems, and the Las/Rhl networks of Gram-negative bacteria, including Pseudomonas aeruginosa, Vibrio spp., Chromobacterium violaceum, and Xylella fastidiosa. Emphasis is placed on emerging structure-activity relationships and mechanistic insights derived from biochemical and computational studies. Key challenges, including resistance potential, pharmacological constraints, and delivery considerations, are also discussed. Together, we provide an integrated microbiological and medicinal chemistry perspective for the rational development of organosulfur-based strategies to attenuate QS-regulated pathogenicity.
In cyanobacteria, the free-living ancestors of chloroplasts, photosynthesis simultaneously sustains growth and generates reactive oxygen species (ROS) that damage proteins, lipids, and DNA when light capture outpaces carbon fixation. Maintaining redox balance, therefore, requires cells to read photosynthetic electron flow as a signal that continuously tunes gene expression and protein activity. This review traces how these redox signals are transduced to transcription machinery through three routes: membrane-localized sensors, cytoplasmic redox sensors downstream of photosystem I, and ROS generated when electron sinks are saturated. Membrane-bound histidine kinases (two-component systems) relay the redox state of the plastoquinone pool to control photosystem remodeling, pigment biosynthesis, and circadian timing. Cytoplasmic one-component regulators, by contrast, sense redox directly through thiol-disulfide switches, glutathionylation, iron-sulfur clusters, and metal-catalyzed oxidation to control photosystem-cofactor, electron-carrier, and transition-metal homeostasis. Because many of these regulators persist in algal and plant chloroplasts, cyanobacteria illuminate principles of redox control across photosynthetic eukaryotes. Post-transcriptional and translational control further shapes redox-dependent gene expression programs through transcript stability, ribosome assembly, and translation initiation, extending redox regulation beyond transcription to every step of protein synthesis and even activity modulation. Finally, we connect redox regulation to photosynthetic physiology, stress resilience, and the rational engineering of cyanobacteria for sustainable bioproduction.
Infectious and metabolic disorders have risen sharply and pose a significant threat to human populations worldwide. Despite being deemed unrelated, mounting evidence indicates that metabolic disorders markedly heightened both the likelihood and severity of infectious disease. The mechanism underlying this association is only beginning to be appreciated and involves a complex interaction between altered metabolic state, pathogen virulence mechanisms, and immune effector pathways. Here, we highlight that a dysregulated metabolic environment disrupts homeostasis, creating a nutrient-rich, immunocompromised milieu that promotes bacterial survival and replication in the host. Metabolic dysfunction is also discussed as a factor that promotes bacterial persistence by altering reactive oxygen species production and inducing tissue hypoxia, conditions that favor biofilm growth. We also examine how bacteria directly exploit nutrient surplus in metabolic diseases to boost their virulence programs and biofilm formation. Moreover, given the ever-increasing problem of antibiotic resistance, we discuss how metabolic diseases contribute to this challenge. Collectively, uncovering how metabolic disorders increase chronic or recurrent infections can guide the development of effective treatment strategies.
Extracellular vesicles (EVs) are membranous nanoparticles released by cells that help shape the extracellular environment, remove cellular waste, and mediate cell-to-cell communication. Their release is ubiquitous across kingdoms, species, and cell types, highlighting their functional importance. Nearly as evolutionarily widespread and heterogeneous is the release of viruses, which have evolved to co-opt the host's cellular machinery to facilitate their replication and spread within all branches of life. Nearly all viruses, enveloped or not, repurpose EVs to modulate infection dynamics, while EVs also play a crucial role in the host's response to infection. This review explores the interplay between EVs and viruses across the phylogenetic diversity of virus species. We urge virologists and EV biologists to look beyond a single infection model and learn from the unique concepts and shared commonalities observed between close, as well as distantly related viruses, whether they infect mammals, vertebrates, insects, plants, bacteria, or more. To facilitate these efforts, we provide a comprehensive, taxonomical overview of the current knowledge regarding DNA and RNA virus families, and discuss recurring motifs in EV release and function during infection.
Mitogen-activated protein kinase (MAPK) signaling cascades are conserved modules that orchestrate multiple processes, including immunity, stress adaptation, and tissue homeostasis. In insects, MAPK pathways function as central regulatory circuits, coordinating defense responses and resistance mechanisms against diverse pathogens. MAPK cascades couple damage sensing in the gut epithelium to intestinal regeneration, pathogen/microbiota stability, cellular and humoral immune responses, and immune homeostasis. Consequently, a wide range of pathogens (parasites, viruses, and bacteria) target, suppress, or hijack key regulatory bottlenecks in MAPK networks to promote pathogen invasion, replication, or transmission. Understanding this molecular arms race provides insight into fundamental principles governing insect-microbe coevolution and reveals critical regulatory nodes that could be exploited to develop innovative strategies for controlling insect pests and vector-borne diseases.
Fungi occupy a wide range of ecological niches in which they compete or associate with other organisms through the perception of external signals and appropriate cellular responses. Fungal G protein-coupled receptors (GPCRs) are seven-transmembrane domain proteins that mediate the perception of extracellular cues. Despite their critical importance, the majority of fungal GPCRs are currently orphan receptors with unknown ligands and functions. In this review, we summarize the current knowledge on the role of fungal GPCRs in the perception of non-self signals and address persistent inconsistencies in the literature regarding fungal GPCR classification. We propose a refined system that differentiates between characterized, proposed, and uncharacterized GPCRs. Finally, we discuss how synthetic biology tools and experimental work in the native fungal organisms can elucidate the physiological role of fungal GPCRs during interspecies cell-cell communication.
Corals and lichens represent some of the most diverse mutualistic symbioses in the marine and terrestrial ecosystems. Their evolutionary success is partly attributed to their association with internal, photosynthetic symbionts, which provide carbon and enable colonization of a wide-range of habitats. Although corals and lichens occupy fundamentally different ecosystems and are phylogenetically unrelated-corals are animals associated with dinoflagellates, while lichens are fungi associated with green algae/cyanobacteria-they share surprisingly many morphological, ecological, and life history traits. Here, we juxtapose morphology, reproduction, dispersal, symbiont acquisition strategies, and symbiont diversity in coral and lichen mutualisms, focusing mainly on the host and associated photobiont partner. We highlight how shared traits lead to convergent mechanisms of niche specialization, including adaptation to abiotic conditions through the formation of environment-specific host-symbiont combinations. The comparison enhances our understanding of evolutionary forces shaping these symbioses and provides a framework for evaluating their adaptive potential in a changing world.
Phytopathogenic bacteria rely on type III effectors to suppress host immunity and facilitate colonization. While necessary for virulence, effectors can also trigger effector-triggered immunity (ETI) if hosts have appropriate NLR immune receptors, resulting in a coevolutionary arms races driving high diversity in both the pathogen "effectorome" and the host "NLRome." Here, we synthesize current knowledge of effectoromes into an "interconnected module model", that emphasizes how functional redundancy among effectors organizes them into modules targeting shared host processes; how low target specificity creates interconnections between these modules; how effector-effector interactions can modify infection outcomes; and how the cumulative presence of multiple ETI-eliciting effectors within a repertoire generates an overall ETI load that constrains pathogen fitness. This systems-level perspective reframes the classical gene-for-gene model into a dynamic NLRome-effectorome model characterized by quantitative ETI responses whose magnitude and ultimate outcome is a dynamic balance between ETI load and suppression. Advancing disease resistance requires strategies that exploit this equilibrium, including rational stacking of NLRs targeting core, conserved effectors. Such approaches highlight the potential of network-based frameworks for designing durable, broad-spectrum crop immunity.
The fitness and virulence of Pseudomonas aeruginosa rely on its ability to maintain a functional pool of ribosomes, which are essential for protein synthesis. This review explores the intricate ways of ribosome protection, rescue, and hibernation, by which P. aeruginosa preserves ribosome functionality under stress. These processes enhance the adaptability and resistance of this pathogen to ribosome-targeting antibiotics and present significant challenges to current therapeutic strategies. By highlighting recent discoveries and identifying promising directions for future research, this review aims to explore potential targets for innovative drug discovery.
The global rise of antimicrobial resistance (AMR) demands urgent attention. While genetic drivers are well studied, epigenetic mechanisms, particularly DNA methylation, are emerging as key contributors to bacterial adaptation under antibiotic pressure. This review examines the roles of N6-methyladenine (m6A), N4-methylcytosine (m4C), and 5-methylcytosine (m5C), each catalysed by distinct DNA methyltransferases (MTases), in regulating resistance-related processes, such as efflux pump expression, β-lactamase activity, and stress responses. Advances in long-read sequencing technologies, including SMRT and ONT, now enable single-base resolution detection of methylation and support strain-specific methylome mapping. These efforts reveal methylation patterns that are dynamic, strain-dependent, and environmentally responsive, complicating resistance profiling. Emerging applications for tackling methylation-linked AMR include methylation-aware diagnostics and CRISPR-based epigenetic editing. Tools like CRISPR-dCas9 fused to DNA methyltransferases enable targeted, reversible suppression of resistance genes regulated by methylation. Current findings position DNA methylation as both a regulator of AMR and a promising target for next-generation diagnostics and therapeutics. However, challenges remain, including the lack of validated biomarkers, inconsistent protocols, and difficulty interpreting mixed-species data. Integrating methylation profiles with transcriptomic and phenotypic data will be essential to fully understand and target resistance mechanisms.
Small intestinal microbial overgrowth (SIMO) results from a breakdown in the delicate equilibrium between luminal environment, gut motility, and microbial ecology. Despite extensive research, these factors have largely been investigated as separate entities, with limited integrative insights into their interplay. This review is the first comprehensive synthesis of physicochemical, mechanical, and microbial parameters shaping SIMO pathogenesis. By reviewing both clinical and experimental data, we reveal how alterations in pH, transit time, digestive secretion dynamics, bile acid composition and impaired intestinal absorption collectively reshape microbial load, diversity, and metabolic output, establishing a self-perpetuating loop of dysfunction. We further discuss the limitations of current diagnostic tools and the transformative potential of emerging approaches, from sampling capsules enabling molecular analyses, to in vitro models simulating human small intestinal ecosystem. This integrative perspective shifts the paradigm from a microbe-centered to an ecosystem-based understanding of SIMO, outlining key challenges and opportunities for personalized diagnostics, mechanistic research, and microbiota-targeted next-generation therapeutics including pre-, pro-, postbiotics and faecal transplantation.
Chemotaxis receptor complexes sense chemical gradient in the cellular environment to direct swimming towards favorable environments. The core signaling units of these complexes are made up of two trimers-of-dimers of chemoreceptors, two CheW and a CheA dimer, which further assemble into large hexagonal signaling arrays. Structural and biochemical studies have provided important information on the architecture and interfaces of these complexes. However, the signaling pathway of these complexes that controls the kinase is not fully understood. In this review, we highlight the highest resolution models of this system and examine the current consensus on the protein-protein interfaces based on models and interface experiments. We also highlight differences observed between signaling states for the individual proteins and the protein interfaces that are proposed to be part of the signaling mechanism. Overall, we conclude that there is strong structural consensus for the protein interfaces but, despite some intriguing results, more information is needed to understand how the interfaces change between signaling states and the role they play in signaling. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at https://proteopedia.org/w/Journal:FEMS_Microbiology_Reviews:1.
