PLoS Biology最新文献

The vaginal microbiota is associated with the health of women and newborns alike. Despite its comparatively simple composition relative to other human microbiota systems, the mechanisms underpinning the dynamics and stability of vaginal microbial communities remain elusive. A crucial, yet so far underexplored, aspect of vaginal microbiota ecology is the role played by nutritional resources. Glycogen and its derivatives, produced by vaginal epithelia, are accessible to all bacterial constituents of the microbiota. Concurrently, free sialic acid and fucose offer supplementary nutritional resources to bacterial strains capable of cleaving them from glycans, which are structurally integral to mucus. Notably, bacteria adept at sialic acid exploitation are often correlated with adverse clinical outcomes and are frequently implicated in bacterial vaginosis (BV). In this study, we introduce a novel mathematical model tailored to human vaginal microbiota dynamics to explore the interactions between bacteria and their respective nutritional landscape. Our resource-based model examines the impact of the relative availability of glycogen derivatives (accessible to all bacterial species) and sialic acid (exclusive to some BV-associated bacteria) on the composition of the vaginal microbiota. Our findings elucidate that the success of BV-associated bacteria is intricately linked to their exclusive access to specific nutritional resources. This private access fortifies communities dominated by BV-associated bacteria, rendering them resilient to compositional transitions. We empirically corroborate our model prediction with longitudinal clinical data on microbiota composition and previously unpublished metabolomic profiles obtained from a North American cohort. The insights gleaned from this study shed light on potential pathways for BV prevention and treatment.

Drug resistance is a critical challenge in treating life-threatening fungal infections. Here, we uncover a mechanism of acquired azole resistance in Candida albicans through mutations in CAP1, encoding a conserved fungal transcription factor that mediates the oxidative stress response. We analyzed 300 clinical isolates and identified 25 distinct CAP1 missense or nonsense mutations, with many occurring within the DNA-binding domain. We identified two nearly identical CAP1 heterozygous nonsense mutations, one in an isolate obtained from a bloodstream infection and one in a population of cells undergoing adaptation to fluconazole in vitro. Both CAP1 nonsense mutations resulted in loss of the C-terminal nuclear export signal, leading to nuclear retention of Cap1 and subsequent activation of genes associated with the oxidative stress response and drug transport. The CAP1 C-terminal truncations conferred significant fitness advantages in the presence of fluconazole, both in vitro and in a murine model of candidiasis. Strikingly, we discovered a therapeutic vulnerability: azole concentrations above the minimal inhibitory concentration were fungicidal to mutants with the CAP1 C-terminal truncation. The fungicidal effect was attributed to both elevated azole-induced reactive oxygen species and a compromised oxidative stress response in Cap1-truncated cells. Our results provide novel characterization of de novo CAP1 point mutations emerging in both laboratory and clinical contexts, elucidate the mechanisms underlying Cap1-regulated stress responses, and reveal a potential therapeutic target for overcoming drug resistance in C. albicans infections.

Oviposition holds crucial significance for insect reproduction. Nevertheless, the research on the neural conduction mechanism of oviposition is still rather limited in most agricultural pests. Here, we demonstrate that the conserved Kainate receptors (KARs) expressed in the glutamatergic neurons (GNs) and the ovipositor neuromuscular junctions (NMJs) regulate the oviposition behavior in Bactrocera dorsalis. We identified two KARs (Grik2b and Grik2c), which control the oviposition behavior by influencing both oviposition preference and egg-laying quantity. Protein-ligand interaction indicated that glutamate serves as the neurotransmitter of Grik2b and Grik2c. Knockdown glutamate-coding genes adversely impacted oviposition preference and egg-laying quantity. Specific knockdown Grik2b (or Grik2c) in the GNs and NMJs could respectively influence oviposition preference and egg-laying quantity. Finally, inhibitors of KARs were screened for their ability to inhibit oviposition. Our study provides strong supporting evidence that a novel neural conduction mechanism for oviposition by uncovering the diverse roles of KARs and provides potential molecular target controlling insect oviposition.

Hijacking of host DNA damage repair (DDR) pathways to facilitate virus replication is broadly conserved amongst diverse viral families. It has been well established that the HIV-1 accessory protein Vpr induces constitutive DDR signaling and G2/M cell cycle arrest, but the virologic function of this activity remains unclear. Here, we use a combination of functional, pharmacologic, biochemical, and genetic approaches to establish that virion-associated and de novo Vpr proteins induce DDR responses that trigger global epigenetic remodeling and activation of transcription programs to enhance HIV-1 promoter activity during acute infection and reactivation from latency. Functional, genetic, and bimolecular fluorescence complementation experiments reveal that Vpr segregates into two functionally discrete pools-a multimeric pool in the nucleus associated with chromatin and a monomeric pool in the cytoplasm associated with a host E3-ubiquitin ligase. Vpr-induced DDR and epigenetic remodeling activities are present in common HIV-1 subtypes circulating globally and in patient-derived isolates.

Differences in immunity in males and females throughout the life span manifest as differences in susceptibility to chronic diseases, infections, cancer, and responses to therapeutic interventions such as immunomodulatory drugs and vaccines. Sex steroids and sex chromosome-linked immune response genes have major roles in driving these differences, but the cells and signaling pathways governing these are disease-specific and often not known. Such knowledge is required to better understand sex differences in disease incidence and clinical course, and to provide treatments tailored to sex-divergent pathways underlying specific diseases. This Essay explores the major areas where further research is required to determine sex-differential mechanisms.

The clinically significant pathogen Clostridioides difficile lacks the transmembrane nutrient germinant receptors conserved in almost all spore-forming bacteria. Instead, C. difficile initiates spore germination using a unique mechanism that requires two signals: a bile acid germinant and a co-germinant, which can be either an amino acid or a divalent cation. While two soluble pseudoproteases, CspC and CspA, were initially identified as the germinant and co-germinant receptors, respectively, in C. difficile, we previously identified residues in an unstructured region of CspC that regulate the sensitivity of C. difficile spores to both signals. However, the mechanism by which CspC transduces these signals remained unclear. Here, we demonstrate that CspC forms a stable complex with CspA and determine the crystal structure of the CspC:CspA heterodimer. The structure reveals extensive interactions along the binding interface, including direct interactions between the unstructured region of CspC and CspA. Using structure-function analyses, we identify CspC:CspA interactions that regulate the sensitivity of C. difficile spores to germinant signals and show that CspA regulates the response of C. difficile to not only co-germinant but also germinant signals. While we show that CspA can form a homodimer and determine its crystal structure, CspA homodimerization appears unimportant for C. difficile spore germination. Collectively, our analyses establish the CspC:CspA heterodimer, rather than its individual constituents, as a critical signaling node for sensing both germinant and co-germinant signals. They also suggest a new mechanistic model for how C. difficile transduces germinant signals, which could guide the development of therapeutics against this important pathogen.

Antimicrobial resistance (AMR) is a global health threat emerging through microbe adaptation, driven by genetic variation, genome plasticity or epigenetic processes. In this study, we investigated how the Mucor circinelloides species complex adapts to the antifungal natural product FK506, which binds to FKBP12 and inhibits calcineurin-dependent hyphal growth. In Mucor bainieri, most FK506-resistant isolates (90%) were found to be unstable and transient, readily reverting to being drug sensitive when passaged without drug, and with no associated DNA mutations. In half of the isolates (50%), FK506-resistance was conferred by RNAi-dependent epimutation in which small interfering RNAs (siRNAs) silenced the fkbA encoding FKBP12 post-transcriptionally. In contrast, most of the remaining FK506-resistant isolates (40%) were found to have undergone heterochromatin-mediated silencing via H3K9 dimethylation, transcriptionally repressing fkbA and neighboring genes. In these heterochromatic epimutants, only minimal enrichment of siRNA to the fkbA locus was observed, but in three of the four examples, siRNA was significantly enriched at a locus distant from fkbA. A similar mechanism operates in Mucor atramentarius, where FK506 resistance was mediated by ectopic heterochromatin silencing of fkbA and associated genes with siRNA spreading across the region. Heterochromatin-mediated fkbA epimutants exhibited stability during in vivo infection, suggesting epimutation could impact pathogenesis. These findings reveal that antifungal resistance arising through distinct, transient epimutation pathways involving RNAi or heterochromatin, highlighting adaptive AMR strategies employed by ubiquitous eukaryotic microbes.

[This corrects the article DOI: 10.1371/journal.pbio.3002814.].

The superficial white matter (SWM), immediately beneath the cortical mantle, is thought to play a major role in cortico-cortical connectivity as well as large-scale brain function. Yet, this compartment remains rarely studied due to its complex organization. Our objectives were to develop and disseminate a robust computational framework to study SWM organization based on 3D histology and high-field 7T MRI. Using data from the BigBrain and Ahead 3D histology initiatives, we first interrogated variations in cell staining intensities across different cortical regions and different SWM depths. These findings were then translated to in vivo 7T quantitative myelin-sensitive MRI, including T1 relaxometry (T1 map) and magnetization transfer saturation (MTsat). As indicated by the statistical moments of the SWM intensity profiles, the first 2 mm below the cortico-subcortical boundary were characterized by high structural complexity. We quantified SWM microstructural variation using a nonlinear dimensionality reduction method and examined the relationship of the resulting microstructural gradients with indices of cortical geometry, as well as structural and functional connectivity. Our results showed correlations between SWM microstructural gradients, as well as curvature and cortico-cortical functional connectivity. Our study provides novel insights into the organization of SWM in the human brain and underscores the potential of SWM mapping to advance fundamental and applied neuroscience research.

Neurodegenerative diseases are often associated with oxidative stress, and while probiotics may influence neuronal health, the underlying mechanisms remain poorly understood. Using the sod-1 A4VM amyotrophic lateral sclerosis (ALS) model in Caenorhabditis elegans, we investigated the protective effects of the probiotic Enterococcus faecium against oxidative stress-induced neurodegeneration. Animals fed E. faecium showed reduced motor neuron degeneration under oxidative stress compared to those maintained on a standard Escherichia coli diet. Transcriptome analysis revealed a significant enrichment of oxidoreductase genes, including cytochrome P450 (cyp) genes. RNAi-mediated knockdown of cyp genes impaired E. faecium-mediated neuroprotection, and this loss correlated with increased reactive oxygen species (ROS) levels. We identified the conserved nuclear hormone receptor NHR-86 as a key regulator of cyp gene expression and neuroprotection. Loss of nhr-86 abolished the probiotic's protective benefits, while transgenic expression of nhr-86 restored cyp induction and neuronal resilience. Importantly, intestinal expression of NHR-86 was sufficient to restore CYP induction and neuronal resilience, whereas neuronal knockdown had no effect, indicating that gut NHR-86 activity is essential for this protective pathway. These findings reveal a previously uncharacterized NHR-CYP regulatory axis activated by an intestinal probiotic, highlighting a mechanistic link between microbial signals and host neuroprotection.