The asaccharolytic anaerobe Porphyromonas gingivalis is a contextually virulent keystone pathogen in the onset and progression of periodontal diseases. P. gingivalis is equipped with an array of virulence factors that promote oral colonization and adaptation to the prevailing heme and oxygen levels in the periodontal ecosystem. Interactions among the oral polymicrobial community lead to increased nososymbiocity (community pathogenicity), and P. gingivalis is adept at inducing dysbiotic inflammatory responses. In particular, the decoupling of inflammation from bacterial killing mechanisms misdirects innate immunity and provides proteinaceous metabolic substrates. The properties that underlie the success of P. gingivalis also provide the framework for its versatility as a systemic pathogen. P. gingivalis can exert a systemic influence following, for example, hematogenous spread and localization at remote tissues. Additionally, secreted bioactive components and metabolites, as well as locally generated immune effectors, have the potential to disrupt homeostasis on a systemic level. The ability to subvert epithelial cell life-and-death decisions further endows P. gingivalis with oncopathogenic properties. In this review, we first examine polymicrobial synergy, colonization, and metabolic adaptation in the periodontal niche; then analyze mechanisms of immune subversion at epithelial and myeloid interfaces; and finally discuss how these strategies contribute to periodontitis and to systemic inflammatory, autoimmune, neurodegenerative, and neoplastic diseases.
Treponema pallidum subsp. pallidum is the causative agent of syphilis, a chronic and potentially devastating infection that is resurging globally. The bacterium is highly invasive, disseminates rapidly, and establishes decades-long latency that may progress to severe tissue destruction and death. T. pallidum's reduced genome contributes to its dependence on the host. Its impressive TprK antigenic variation, scarce outer membrane proteins, and periplasmic flagella provide for immune evasion, enabling persistence and reinfection. Our understanding of syphilis pathogenesis derives largely from experimental infection in rabbits and from historical studies in humans, though recent advances in continuous cultivation, genetic manipulation, hybrid-capture genome sequencing, and multi-omic approaches have opened new avenues for dissecting host-pathogen interactions and disease pathogenesis. This review highlights mechanisms of syphilis pathogenesis, the central role of the immune response in disease causation and progression, and the role of new technologies in answering long-standing questions and informing vaccine development.
In a process known as phenotypic heterogeneity or phenotypic variation, bacteria can produce distinct phenotypes within an isogenic population in response to shifting environmental conditions. Noise in gene expression, asymmetric cell division, phase variation, and quorum sensing are some of the mechanisms that contribute to this variability, which is maintained by gene regulatory networks (usually involving feedback loops). Bistability in gene regulatory networks generates subpopulations exhibiting specific traits that can contribute to more complex adaptive strategies, promoting the fitness of the bacterial community as a whole. This review explores recent examples of phenotypic heterogeneity and its functional importance in bacterial collective behaviors. We focus on how synthetic biology can be used to better understand bacterial gene regulatory networks and the mechanisms underlying antibiotic resilience and persistence, and we discuss the bistability of integrative and conjugative elements.
Bdellovibrio bacteriovorus represents one of nature's most remarkable examples of obligate bacterial predation. This small, highly motile bacterium exhibits a biphasic life cycle alternating between a free-swimming attack phase and an intraperiplasmic growth phase within gram-negative prey bacteria. Recent advances have elucidated the molecular machinery coordinating prey recognition, invasion, and host manipulation, revealing sophisticated enzymatic arsenals and regulatory networks that orchestrate the predatory program. Transcriptomic studies demonstrate precise temporal control of lytic enzymes, nutrient acquisition systems, and developmental checkpoints throughout the life cycle. Bdellovibrio and related organisms occupy diverse niches, including soil, freshwater, and the mammalian gut, where they influence bacterial community composition through top-down predation. This ecological ubiquity, combined with inherent bactericidal activity, has generated considerable interest in therapeutic applications against multidrug-resistant pathogens, with encouraging results in animal infection models. In this article, we synthesize current understanding of predatory mechanisms, environmental roles, and biotechnological potential of Bdellovibrio while identifying key knowledge gaps: the regulatory logic governing life cycle transitions, molecular determinants of host range, and predator-prey population dynamics. Addressing these questions will advance both fundamental microbiology and antimicrobial innovation.
Malaria, a life-threatening disease caused by eukaryotic intracellular parasites belonging to the genus Plasmodium, is classically characterized by the infection of circulating red blood cells. However, growing evidence reveals that these parasites also accumulate within the bone marrow, the primary site of red cell production. In this review, we detail the evidence for this cryptic reservoir of parasites, the associated implications for host erythropoiesis, and an array of complex host responses elicited by the parasites in this niche. The underlying bone marrow pathology stems from multiple factors, including direct parasite invasion of erythroid precursor cells and inflammatory effects of parasite-derived factors. By consolidating current evidence on this dynamic interaction, this review highlights critical questions for future research into the mechanisms of ineffective erythropoiesis and the development of host-protective therapeutic strategies.
Structural maintenance of chromosomes (SMC) complexes are conserved ATP-driven machines that organize, compact, and segregate genomes in all domains of life. Despite variation in subunit composition and regulation, all SMC complexes share a core structure and mechanism of action. Bacteria possess two major classes of SMC complexes, SMC-ScpAB and MukBEF, which function in chromosome compaction and segregation. In addition, some bacteria contain other SMC complexes or SMC-like systems such as MksBEF, Wadjet, RecN, and SbcC, each with specialized functions. Bacterial SMC complexes coordinate genome maintenance, DNA replication, DNA repair, plasmid defense, and cell physiology. In this review, we discuss the structure and function of these bacterial SMC complexes, highlighting the shared characteristics and unique strategies employed by each.
The mycobacterial cell envelope is a formidable barrier, regarded as one of the most chemically and structurally elaborate architectures in the Bacteria kingdom. Membrane remodeling, defined as changes in membrane lipid composition in response to stressors, has been a subject of broad investigation because of its implications for permeability, antibiotic susceptibility, immunogenicity, and virulence. However, because remodeling is a highly dynamic process governed by multiple, deeply interconnected cellular response pathways, its underlying mechanisms and biophysical consequences remain incompletely understood. In this review, we synthesize the current knowledge of how the composition and organization of membrane lipids shift under physiologically relevant conditions, and we examine how these changes intersect with key stress response pathways. As a unifying thread connecting lipid composition, envelope architecture, and cellular function, we summarize our understanding of mycobacterial membrane biophysical properties, highlighting recent advances as well as conceptual and methodological gaps that remain in the field.
Quorum sensing (QS) enables bacteria to coordinate collective behaviors in response to population density. LuxI/R QS systems, common among gram-negative bacteria, consist of a LuxI-type synthase that produces an N-acyl L-homoserine lactone (AHL) signaling molecule and a LuxR-type receptor that senses the AHL. At threshold AHL concentrations, LuxR-type receptors undergo ligand-induced conformational changes that affect DNA binding and target gene transcription. Because of their role in regulating myriad collective behaviors, LuxI/R systems are targets for many applications, including antivirulence strategies and the engineering of beneficial microbiomes. Recent structural studies have led to substantial progress in understanding molecular mechanisms of LuxI/R systems. However, LuxR-type receptors fall into functionally diverse subfamilies for which structural bases remain incompletely understood. In this article, we summarize recent structural and mechanistic insights into LuxR-type receptor function, including interactions with small molecules, protein partners, and DNA. We identify critical knowledge gaps that highlight the need for additional structural and mechanistic information regarding LuxI/R QS.
The type IX secretion system (T9SS) is a Bacteroidota -specific multiprotein machine that supports a wide range of biological processes, from nutrient acquisition and surface modification to host interaction and gliding motility. T9SS effectors represent a structurally diverse repertoire of enzymes, adhesins, and surface proteins that all possess a C-terminal domain that addresses them to their final destination. Recent structural and mechanistic information has revealed the modular organization of the T9SS and molecular details governing effector selection, transport, processing, and sorting. In motile Bacteroidota , the T9SS has been co-opted, evolved, and specialized for gliding motility. In this review, we summarize current knowledge on T9SS architecture and function, describe the embedded gliding machinery, and highlight conceptual advances and open questions regarding the mechanisms, dynamics, and ecological implications of this unique system.
Extracellular vesicles (EVs) are released by virtually all cells in normal and in pathological conditions. They exhibit diverse sizes, contents, and surface markers. These vesicles transport cellular components such as proteins, mRNAs, miRNAs, DNA, and lipids across distances, influencing numerous physiological and pathological events, and they are involved in cellular communication, making EVs promising candidates as therapeutic agents, drug delivery systems, and disease biomarkers. In the context of eukaryotic pathogens, these EVs can be taken up by the parasite and the interacting mammalian cells, influencing parasite behavior (e.g., differentiation, infectivity) and host responses that affect pathogenesis. In this review, we discuss classical and new discoveries related to EVs produced by different cell types, including those involved in the interaction process of eukaryotic microorganisms with their respective hosts.
Ribosome rescue pathways recycle the subunits from stalled ribosomes and target the aborted nascent peptide for degradation. Building upon seminal studies in eukaryotes, recent work in bacteria shows that rescue pathways are triggered by ribosome collisions. When an upstream ribosome catches up to a stalled one, a unique interface that directly recruits rescue factors forms between them. The nuclease SmrB in Escherichia coli, for example, cleaves mRNA, targeting it for decay and triggering the rescue of upstream ribosomes by transfer-messenger RNA (tmRNA). In contrast, MutS2/RqcU in Bacillus subtilis splits stalled ribosomes into subunits without mRNA cleavage. Finally, the helicase HrpA splits stalled ribosomes in E. coli through a different mechanism. This review focuses on the discovery of these factors; the structural basis of their activities on collided disomes; and how, after splitting, the nascent chains trapped on 50S are targeted for degradation by the ribosome-associated quality control pathway.
The emergence of the endomembrane system marks a pivotal milestone in eukaryogenesis, transforming a primitive prokaryotic cell into a highly intracellular, compartmentalized eukaryotic cell. The molecular machinery underlying the endomembrane system has been considered a defining feature of eukaryotes. Yet its evolutionary origin remains elusive. Over the past decade, the rapid expansion of archaeal diversity, coupled with advancements in metagenomic technologies and cell biological characterization, has revealed that many key protein components of the endomembrane system likely originated from the archaeal ancestors of eukaryotes, a specific archaeal lineage that underwent a symbiotic fusion with the mitochondrial ancestor. This review summarizes and discusses the remarkable progress made in these research fields, offering a refined perspective on the origin of the eukaryotic endomembrane system within an updated tree of life.
Microbial organisms assemble a diverse array of surface structures to facilitate critical functions including motility, adhesion, and biofilm formation. As extracellular organelles, pili and related surface structures must be able to function in harsh environments and withstand various stressors. Microbes have evolved different strategies to assemble structures able to function under these challenging conditions. This review focuses on bacterial and archaeal systems that utilize donor-strand exchange (DSE) interactions between subunit proteins. DSE is a noncovalent assembly mechanism where one subunit contributes a β-strand to complete the structure of its neighboring subunit. This subunit-subunit interaction is one of the strongest noncovalent interactions known, with the resulting fiber being capable of withstanding extreme environmental stresses and shear forces. We summarize the structural biology and biogenesis of these surface structures, highlighting how DSE-mediated polymerization contributes to the assembly of extracellular structures in both the bacterial and archaeal domains.
The focal site of ribosome assembly and maturation in bacteria is the 5' untranslated region (UTR). Leaderless messenger RNAs (mRNAs) lack a 5' UTR and therefore present a conundrum for translation initiation. Leaderless mRNAs in Escherichia coli are rare and poorly translated, consistent with an inefficient by-product of the canonical mechanism. By contrast, transcription profiling approaches have unexpectedly found that leaderless mRNAs are both abundant and well-translated in certain bacterial clades, identifying those bacteria as leaderless adept. Mycobacteria are leaderless adept and offer multiple experimental model species that collectively broaden conclusions derived from leaderless translation studies. We review criteria derived from native mycobacterial mRNAs and from plasmid reporters expressed in mycobacteria that define leaderless mRNA features. We also look ahead at the unresolved conundrum of how leaderless mRNAs are efficiently translated. We anticipate that mycobacteria, along with diverse leaderless-adept Eubacteria and Archaea, will continue to make fundamental contributions in characterizing this major alternative mode of translation initiation.
Cellular weaponry includes a diverse array of ballistic structures, generally referred to as extrusomes, found across the tree of life. Extrusomes have evolved multiple times independently; are morphologically diverse, including structures such as coiled filaments, paracrystalline rods, and telescopic tubules; and facilitate prey capture, defense against predation, and host cell invasion. Their widespread distribution reflects extensive convergent evolution driven by similar ecological pressures. Conversely, homologous extrusomes in closely related taxa can diverge markedly in structure and function following lifestyle shifts, including transitions to parasitism. Alveolates, cryptists, heliozoans, euglenozoans, and numerous other protists possess distinct extrusomes with different discharge mechanisms. Comparable projectiles also occur in multicellular eukaryotes, including cnidarian nematocysts, ctenophore colloblasts, and the infectious spores of parasitic fungi and oomycetes, demonstrating that analogous cellular weaponry has evolved at multiple biological scales. In this article, we synthesize the diversity and phylogenetic distribution of cellular weaponry across eukaryotes, exploring novel examples of convergent evolution at different levels of biological organization.
Life on Earth has evolved under the predictable rotation of the planet, giving rise to intrinsic timing mechanisms that synchronize physiology and behavior with the 24-h day-night cycle. These molecular timing systems organize metabolism, immunity, and cellular renewal into recurring daily programs that optimize energy use and defense. Increasing evidence now reveals that circadian logic extends beyond the host to include its microbial partners. Host feeding rhythms, epithelial renewal, and immune activity impose temporal order on the microbiota, while microbial metabolites and immune signaling feedback to reinforce host circadian oscillations. When this temporal coordination is lost, through genetic disruption of clock genes, high-fat diet, or behavioral desynchrony, microbial and host rhythms collapse, leading to metabolic syndrome, obesity, and impaired xenobiotic detoxification. Thus, temporal order emerges as a coevolved property of host-microbe symbiosis, linking planetary rotation to cellular physiology across kingdoms and defining a chronobiological foundation for health and disease.
Malaria remains a major global health burden despite decades of effort toward its prevention and treatment. Much of this difficulty stems from the complexity of the Plasmodium parasite's life cycle and its interactions with the human host. Here, we review receptor-ligand interactions between the Plasmodium parasite and human host, with a focus on clinically relevant antigens. The parasite uses a variety of proteins at each stage of its life cycle to achieve requisite functions such as motility, cell traversal, and invasion. In turn, the human immune response targets these key parasite antigens, and we review well-characterized antibody-antigen interactions. Finally, we describe several mechanisms the parasite uses to evade the human immune response. Understanding of this evolutionary back-and-forth has inspired several different vaccines and therapeutics, and we describe ongoing efforts to create improved next-generation versions.
My scientific career has followed a meandering path centered on the structures and functions of microbial metabolites. These microbes included bacteria, fungi, and single-celled eukaryotes, and the metabolites included representatives from most metabolite families-peptides, complex carbohydrates, and lipids. The journey began with an interest in the structural complexity of microbial toxins and in microbes as chemists, and it evolved into a fixation on microbial metabolites' ability to reveal totally unexpected structure-function and host-guest relations and microbes' ability to affect human health and disease. The results described in this manuscript illustrate the power of interdisciplinary collaborations, clearly defined and soluble questions, a skilled research team, and serendipity.
Despite the ubiquity of fungi in nature, only a small fraction are pathogenic to humans, and the majority of these fungi are opportunistic and affect immunocompromised individuals. In general, pathogen emergence is restricted by the ability of fungi to sense and withstand human host environmental cues and stresses. These stress responses in fungi involve immediate survival reactions as well as long-term adaptations. Additionally, some opportunistic pathogenic behavior suggests that virulence traits evolved for environmental survival, a concept known as exaptation. This review covers recent advances in examining fungal responses to host environments and focuses on stress pathways including HOG (high osmolarity glycerol) and CWI (cell wall integrity), thermotolerance mechanisms, CO2 and oxygen sensing, nutrient and metal stresses, pH adaptation, and antimicrobial defenses. By focusing on both conserved and specialized responses, we highlight the critical role of stress adaptation in pathogenicity and potential avenues for further research and therapeutic intervention.
Alongside the crisis of antimicrobial-resistant gonorrhea is the threat of bystander selection on commensal Neisseria . As Neisseria species are permissive to gene flow across lineages, their evolutionary fates are irrevocably intertwined. Horizontal gene transfer (HGT) within the genus occurs through transformation and exchange of plasmids through conjugation. Both mechanisms of HGT threaten the long-term efficacy of antimicrobial treatments, with resistance passed between commensals and pathogens multiple times (e.g., mosaic penA and mtr alleles). Here, we underscore the importance of commensal Neisseria as a bubbling cauldron of adaptive solutions for pathogenic Neisseria , review the mechanisms of resistance harbored by commensals and transferred to the gonococcus, and discuss the impact of contemporary selective pressures on the future evolutionary trajectory of the genus. Ultimately, we believe that predicting the future efficacy of antimicrobials for the treatment of gonorrhea will only be successful if the commensal Neisseria are also considered.
