PLoS Biology最新文献

A through-gut is one of the major features of bilaterians. Comparative work among bilaterians has identified common molecular mechanisms during early gut patterning, but the primordial gut later often undergoes different degrees of reorganization in each lineage to form a fully differentiated adult gut with specializations along its anteroposterior (AP) axis. Yet, how the conserved embryonic gut AP pattern relates to the adult guts in diverse bilaterians after metamorphosis is still poorly understood. To unravel the molecular subdivisions of adult guts, we investigated the gut through transcriptomic analyses of five phylogenetically informative species: an annelid, a sea urchin, a hemichordate, a cephalochordate, and a vertebrate. We identified bipartite transcriptional programs defining the AP functional subdivisions. Patterning systems composed of Hox, ParaHox, and, surprisingly, other transcription factors (TFs) known to be involved in gut formation in sea urchin larvae are maintained in these adult tissues. Using unbiased analyses, we identified five conserved TF modules corresponding to the AP compartments of the guts that are elaborated or shifted in different species. Our study inferred conserved and modified adult AP patterning modules along bilaterian guts enabling the reconstruction of ancestral bilaterian features with profound implications for the evolution of the bilaterian body plan.

RNA interference (RNAi) is a sequence-specific mRNA degradation mechanism, in which short interfering RNAs (siRNAs) guide Argonaute proteins to complementary targets, resulting in their degradation. In many organisms, RNAi also serves antiviral roles by processing viral double-stranded RNA (dsRNA) into siRNAs that prevent viral replication. Antiviral RNAi is considered an ancestral mechanism which invertebrates rely on for defense against viruses, whereas vertebrates have evolved instead the interferon pathway. Recent studies suggest that sea anemones, members of the basally-branching phylum Cnidaria, might possess an innate immune response with more vertebrate characteristics than previously thought; however, it is unknown whether cnidarians also employ RNAi as an antiviral response similarly to nematodes and insects. Here, we characterize the response of the model cnidarian Nematostella vectensis to simulated viral infection. We injected dsRNA with eGFP sequence into eGFP-expressing transgenic zygotes and show that siRNAs mapping to the eGFP sequence are generated and induce a moderate but significant knockdown of eGFP expression. Interestingly, we detected no evidence for secondary siRNA production, despite their crucial role in the amplification of antiviral response in other organisms. Notably, siRNA pathway components are specifically upregulated upon dsRNA injection, while microRNA pathway components are downregulated. Furthermore, injection of mRNA coding for self-replicating viral gene fused to eGFP, also induced upregulation of siRNA-related genes and a mild decrease in transgene expression. Overall, we propose that N. vectensis possesses an siRNA-mediated response that lacks secondary amplification and likely functions as a short-term antiviral mechanism.

Temperate phage can transmit both horizontally (lytic cycle) and vertically (lysogenic cycle). Many temperate phage have the ability to modify their lysis/lysogeny decisions based on various environmental cues. For instance, many prophage are known to reactivate when SOS stress responses of their host are triggered. Temperate phage infecting Bacilli can also use peptide signals ("arbitrium") to control their lysis/lysogeny decisions. However, information from the arbitrium and SOS systems can be potentially conflicting, and it is unclear how phage integrate information carried by these two different signals when making lysis-lysogeny decisions. Here, we use evolutionary epidemiology theory to explore how phage could evolve to use both systems to modulate lysis/lysogeny decisions in a fluctuating environment. Our model predicts that it can be adaptive for phage to respond to both host SOS systems and arbitrium signaling, as they provide complementary information on the quality of the infected host and the availability of alternative hosts. Using the phage phi3T and its host Bacillus subtilis, we show that during lytic infection and as prophage, lysis-lysogeny decisions rely on the integration of information on host condition and arbitrium signal concentrations. For example, free-phage are more likely to lysogenise a stressed host, and prophage are less likely to abandon a stressed host, when high arbitrium concentrations suggest susceptible hosts are unavailable. These experimental results are consistent with our theoretical predictions and demonstrate that phage can evolve plastic life-history strategies to adjust their infection dynamics to account for both the within-host environment (host quality) and the external environment that exists outside of their host (availability of susceptible hosts in the population). More generally, our work yields a new theoretical framework to study the evolution of viral plasticity under the influence of multiple environmental cues.

Metabolites generated by host and pathogen have a major impact on the severity and outcomes of infection. The metabolic response to infection shapes the nature and intensity of the immune response, both in bloodstream infections and, especially, in the pathogenesis of pneumonia. Some metabolites are closely linked to pro-inflammatory responses, whereas others act as immunomodulators in mitigating damage to the host, a common consequence of inflammation. Immunometabolites are also major factors in driving bacterial adaptation to the host, enabling pathogens acquired from environmental sources to modify their gene expression to optimize for persistent infection. In this era of diminishing antimicrobial efficacy, an appreciation of the immunometabolic responses to bacterial infection may provide novel targets for therapy.

Foxi1 is a master regulator of ionocytes (ISCs/INCs) across species and organs. Two subtypes of ISCs exist, and both α- and β-ISCs regulate pH- and ion-homeostasis in epithelia. Gain and loss of FOXI1 function are associated with human diseases, including Pendred syndrome, male infertility, renal acidosis, and cancers. Foxi1 was predominantly studied in the context of ISC specification, however, reports indicate additional functions in early and ectodermal development. Here, we re-investigated the functions of Foxi1 in Xenopus laevis embryonic mucociliary epidermis developpment and found a novel function for Foxi1 in the generation of Notch-ligand expressing mucociliary multipotent progenitors (MPPs). We demonstrate that MPPs are a distinct sub-population of epidermal cells in which Foxi1 has two concentration-dependent functions: At low levels, Foxi1 maintains ectodermal competence in MPPs through transcriptional and epigenetic mechanisms, while at high levels, Foxi1 induces a multi-step process of ISC specification and differentiation in cooperation with Ubp1 and Dmrt2. We further describe how foxi1 expression is affected through auto- and Notch-regulation, and how this developmental program affects mucociliary patterning. Together, we reveal novel functions for MPPs and Foxi1 in Xenopus mucociliary epidermis formation, relevant to our understanding of vertebrate development and human disease.

Since early-2024 unprecedented outbreaks of highly pathogenic avian influenza H5N1 clade 2.3.4.4b have been ongoing in dairy cattle in the United States with significant consequences for the dairy industry and public health. Estimation of key epidemiological parameters is required to support outbreak response, including predicting the likely effectiveness of interventions and testing strategies. Here, we pool limited publicly available data from four studies of naturally and experimentally infected dairy cattle. We quantify Ct value trajectories of infected dairy cattle and the relationship between Ct value and the log-titer of infectious virus, a proxy for infectiousness. We estimate that following infection minimum Ct values are rapidly reached within 1-2 days with a population mean Ct value of 15.7 (12.9, 18.4). We identify a threshold Ct value of 21.8 (19.9, 24.6), with values of Ct value above this threshold representing little-to-no infectious viral load. Finally, assuming a direct relationship between Ct value and infectiousness, we estimate the distribution of the duration of infectiousness for dairy cattle (i.e., the duration their Ct value remains below the critical threshold) with a population median of 7.8 (4.1, 13.9) days. Our estimates will be critical inputs to the development of outbreak management guidelines and modeling analyses informing response strategies.

Spatial transcriptome (ST) technologies have transformed the study of tissue structure by retaining the spatial distribution of gene expression. One major challenge in accurately identifying spatial domains is to extract domain-related information from spatial locations and gene expression. Here, we propose MMSpa, a masked graph attention autoencoder framework specifically designed to improve spatial domain identification. MMSpa incorporates an edge-removal strategy to construct an enhanced spatial graph to fundamentally address cross-domain interference and characterize clearer domain boundaries. By focusing on masked gene expression reconstruction, MMSpa learns stable latent representations that capture core biological features, facilitating the identification of similar spatial subdomains and detecting domain differences across biological samples at the same developmental stage. Comparative analyses using ST datasets from multiple ST technologies and platforms demonstrated that MMSpa outperforms existing methods across various accuracy assessments. Notably, MMSpa excels in challenging scenarios involving highly heterogeneous and complex tissues, and can reveal finer-grained functional tissue domains obscured by other methods. This superior capability positions MMSpa as a powerful tool for uncovering new biological insights and compensating for the lack of spatial annotation in histopathology.

Heritable phenotypic switches are fundamental to the ability of cells to respond to specific conditions. Such switches are key to the success of environmental pathogens, which encounter disparate conditions as they transition between the environment and host. We determine that the copy number of chromosome seven in the thermally dimorphic fungus Histoplasma dramatically affects the rate of transition. Though Histoplasma is haploid, a second copy of this chromosome is present in natural isolates of multiple Histoplasma species and is gained and lost at a high rate. Cells carrying two copies of this chromosome exhibit aspects of the environmental transcriptome even under host-like conditions and have a competitive advantage in the transition to the environmental form. Conversely, these cells are considerably less virulent than euploid cells and have a competitive disadvantage in the mouse model of infection. Chromosome seven contains a previously unstudied transcription factor that, when expressed at higher copy number in euploid Histoplasma, is sufficient to promote some of the key phenotypes of aneuploidy. We hypothesize that rapid gain and loss of this chromosome benefits Histoplasma by increasing phenotypic variation, thus helping populations of cells survive abrupt transitions between environment and host.

In the gonad, sex is not an irrevocable commitment and requires active maintenance. A new study in PLOS Biology elucidates the molecular mechanisms that preserve sexual identity in the adult Drosophila testis.

Aging disrupts intestinal stem cell (ISC) lineage fidelity, impairing epithelial barrier function and then promoting systemic health decline. In this study, we identify peroxisomal dysfunction as a critical driver of age-associated ISC mis-differentiation. Using Drosophila and mouse colonic organoids, we demonstrate that reduced PEX5 expression in aged ISCs impairs peroxisomal matrix protein import, leading to very long-chain fatty acids (VLCFAs) accumulation. In addition, we found that RAB7-dependent late endosome maturation and SOX21A were downstream of the peroxisome in controlling aged ISC differentiation. Aspirin, a classic anti-inflammatory drug, restores ISC lineage fidelity by enhancing PEX5-mediated peroxisomal β-oxidation of VLCFAs. Taken together, these findings highlight peroxisomal dysfunction and VLCFA metabolism as pivotal regulators of ISC aging and suggest new therapeutic strategies for combating age-related intestinal decline.