mSystems最新文献

Infectious disease treatment success requires symptom resolution (clinical treatment success), which often but not always involves pathogen clearance. Both of these treatment goals face disease-specific and general challenges. In this review, we summarize the current state of knowledge in mechanisms of clinical and parasitological treatment failure in the context of Chagas disease, a neglected tropical disease causing cardiac and gastrointestinal symptoms. Parasite drug resistance and persistence, drug pharmacokinetics and dynamics, as well as persistently altered host immune responses and tissue damage are the most common reasons for Chagas disease treatment failure. We discuss the therapeutics that failed before regulatory approval, limitations of current therapeutic options and new treatment strategies to overcome persistent parasites, inflammatory responses, and metabolic alterations. Large-scale omics analyses were critical in generating these insights and will continue to play a prominent role in addressing the challenges still facing Chagas disease drug treatment.

Glacier-fed streams are permanently cold, ultra-oligotrophic, and physically unstable environments, yet microbial life thrives in benthic biofilm communities. Within biofilms, microorganisms rely on secondary metabolites for communication and competition. However, the diversity and genetic potential of secondary metabolites in glacier-fed stream biofilms remain poorly understood. In this study, we present the first large-scale exploration of biosynthetic gene clusters (BGCs) from benthic glacier-fed stream biofilms sampled by the Vanishing Glaciers project from the world's major mountain ranges. We found a remarkable diversity of BGCs, with more than 8,000 of them identified within 2,868 prokaryotic metagenome-assembled genomes, some of them potentially conferring ecological advantages, such as UV protection and quorum sensing. The BGCs were distinct from those sourced from other aquatic microbiomes, with over 40% of them being novel. The glacier-fed stream BGCs exhibited the highest similarity to BGCs from glacier microbiomes. BGC composition displayed geographic patterns and correlated with prokaryotic alpha diversity. We also found that BGC diversity was positively associated with benthic chlorophyll a and prokaryotic diversity, indicative of more biotic interactions in more extensive biofilms. Our study provides new insights into a hitherto poorly explored microbial ecosystem, which is now changing at a rapid pace as glaciers are shrinking due to climate change.

Importance: Glacier-fed streams are characterized by low temperatures, high turbidity, and high flow. They host a unique microbiome within biofilms, which form the foundation of the food web and contribute significantly to biogeochemical cycles. Our investigation into secondary metabolites, which likely play an important role in these complex ecosystems, found a unique genetic potential distinct from other aquatic environments. We found the potential to synthesize several secondary metabolites, which may confer ecological advantages, such as UV protection and quorum sensing. This biosynthetic diversity was positively associated with the abundance and complexity of the microbial community, as well as concentrations of chlorophyll a. In the face of climate change, our study offers new insights into a vanishing ecosystem.

The gut microbiota plays a crucial role in infant health, with its development during the first 1,000 days influencing health outcomes. Understanding the relationships within the microbiota is essential to linking its maturation process to these outcomes. Several network-based methods have been developed to analyze the developing patterns of infant microbiota, but evaluating the reliability and effectiveness of these approaches remains a challenge. In this study, we created a test data pool using public infant microbiome data sets to assess the performance of four different network-based methods, employing repeated sampling strategies. We found that our proposed Probability-Based Co-Detection Model (PBCDM) demonstrated the best stability and robustness, particularly in network attributes such as node counts, average links per node, and the positive-to-negative link (P/N) ratios. Using the PBCDM, we constructed microbial co-existence networks for infants at various ages, identifying core genera networks through a novel network shearing method. Analysis revealed that core genera were more similar between adjacent age ranges, with increasing competitive relationships among microbiota as the infant microbiome matured. In conclusion, the PBCDM-based networks reflect known features of infant microbiota and offer a promising approach for investigating microbial relationships. This methodology could also be applied to future studies of genomic, metabolic, and proteomic data.

Importance: As a research method and strategy, network analysis holds great potential for mining the relationships of bacteria. However, consistency and solid workflows to construct and evaluate the process of network analysis are lacking. Here, we provide a solid workflow to evaluate the performance of different microbial networks, and a novel probability-based co-existence network construction method used to decipher infant microbiota relationships. Besides, a network shearing strategy based on percolation theory is applied to find the core genera and connections in microbial networks at different age ranges. And the PBCDM method and the network shearing workflow hold potential for mining microbiota relationships, even possibly for the future deciphering of genome, metabolite, and protein data.

Cigarette smoke (CS) promotes the development of chronic pulmonary disease and has been associated with increased risk for influenza-related illness. Here, we directly addressed the impact of CS disordered microbiota on the severity of influenza A virus (IAV) infection. Specific and opportunistic pathogen-free (SOPF) C57BL/6J mice were exposed to CS or room air (RA) for 5.5 months. Each exposed mouse was then cohoused with a group of recipient germ-free (GF) mice for 1 month for microbial transfer. Colonized GF mice were then infected intranasally with IAV and disease development was monitored. Upper and lower airway and fecal microbiota were longitudinally investigated by 16S rRNA gene sequencing and bacterial cultures in donor and recipient mice. The bacterial family Streptococcaceae accounted for the largest difference between CS- and RA-exposed microbiota in the oropharynx. Analysis of the oropharynx and fecal microbiota indicated an efficient transfer to coprophagic recipient mice, which replicated the differences in microbiota composition observed in donor mice. Subsequent IAV infection revealed significantly higher weight loss for CS microbiota recipient mice at 8-10 days post infection (dpi) compared to control recipient mice. In addition, H1N1 infection inflicted substantial changes in the microbiota composition, especially at days 4 and 8 after infection. In conclusion, mice with a CS-associated microbiota suffer from higher disease severity upon IAV infection compared to mice colonized with a normal SOPF microbiota. Our data suggest that independently of CS exposure and concomitant structural lung damage, microbial distortion due to CS exposure may impact the severity of IAV disease course.IMPORTANCEIt has been reported that chronic exposure to CS is associated with a disordered microbiota composition. In this study, we colonized germ-free (GF) mice with the microbiota from SOPF mice which were chronically exposed to CS or RA. This allowed disentangling the effect of the disordered microbiota from the immune-modulating effects of actual CS exposure. We observed a successful transfer of the microbiotas after cohousing including specific microbiota differences induced by CS exposure in formerly GF mice, which were never exposed to CS. We then investigated the effects of IAV infection on the disease course and microbiotas of formerly GF mice. We found that mice with CS-associated microbiota reveal worse disease course compared to the control group. We hypothesize that CS-induced disordering of the microbiota may, indeed, impact the severity of influenza A disease.

Alcohol intake causes many diseases including neuropsychiatric symptoms, nutritional deficiency, progressive pancreatitis, liver cirrhosis, and ischemic heart disease. The gut microbiota changes significantly after alcohol exposure. Alcohol consumption tends to increase in underage and young people, but the feature of the gut microbiota in puberty remains largely unexplored. In this study, we conducted alcohol-exposed pubertal and adult mice model to investigate the intestinal damage and gut microbiota change. Interestingly, the responses of pubertal mice and adult mice after alcohol exposure were different. We found that alcohol dehydrogenase decreased and aldehyde dehydrogenase increased in the liver of pubertal mice, thus reducing the accumulation of toxic acetaldehyde. Furthermore, alcohol exposure caused less intestinal injury in pubertal mice. Through the analysis of metagenome assembly genome, we obtained many unrecognized bacterial genomes. Limosillactobacillus reuteri (cluster_56) and Lactobacillus intestinalis (cluster_57) were assembled from the samples of pubertal mice, which were involved in the production of indole acetic acid and the transformation of bile acids in response to alcohol exposure. This study provided a new insight to investigate the gut microbiota change and explained the difference of the gut microbiota after alcohol exposure between pubertal mice and adult mice.

Importance: This study elucidates the significant impact of alcohol exposure on the gut microbiota and metabolic pathways in mice, highlighting the differential responses between adolescent and adult stages. Alcohol exposure was found to damage the intestinal barrier, alter the microbial composition by decreasing beneficial bacteria like Lactobacillus, and increase harmful bacteria such as Alistipes. The study also discovered unique microbial changes and resilience in pubertal mice. Species-level metagenomic analysis revealed specific microbial taxa and metabolic functions affected by alcohol. Metagenome-assembled genomes (MAGs) found many species that could not be annotated by conventional methods including many members of Lachnospiraceae, greatly expanding our understanding of the gut microbiota composition. These findings underscore the need for further research on alcohol's effects on various organs and the implications of microbial metabolites on disease progression.

Coral reefs are experiencing unprecedented loss in coral cover due to increased incidence of disease and bleaching events. Thus, understanding mechanisms of disease susceptibility and resilience, which vary by species, is important. In this regard, untargeted metabolomics serves as an important hypothesis-building tool enabling the delineation of molecular factors underlying disease susceptibility or resilience. In this study, we characterize metabolomes of four species of visually healthy stony corals, including Meandrina meandrites, Orbicella faveolata, Colpophyllia natans, and Montastraea cavernosa, collected at least a year before stony coral tissue loss disease reached the Dry Tortugas, Florida, and demonstrate that both symbiont and host-derived biochemical pathways vary by species. Metabolomes of Meandrina meandrites displayed minimal intraspecies variability and the highest biological activity against coral pathogens when compared to other species in this study. The application of advanced metabolite annotation methods enabled the delineation of several pathways underlying interspecies variability. Specifically, endosymbiont-derived vitamin E family compounds, betaine lipids, and host-derived acylcarnitines were among the top predictors of interspecies variability. Since several metabolite features that contributed to inter- and intraspecies variation are synthesized by the endosymbiotic Symbiodiniaceae, which could be a major source of these compounds in corals, our data will guide further investigations into these Symbiodiniaceae-derived pathways.

Importance: Previous research profiling gene expression, proteins, and metabolites produced during thermal stress have reported the importance of endosymbiont-derived pathways in coral bleaching resistance. However, our understanding of interspecies variation in these pathways among healthy corals and their role in diseases is limited. We surveyed the metabolomes of four species of healthy corals with differing susceptibilities to the devastating stony coral tissue loss disease and applied advanced annotation approaches in untargeted metabolomics to determine the interspecies variation in host and endosymbiont-derived pathways. Using this approach, we propose the survey of immune markers such as vitamin E family compounds, acylcarnitines, and other metabolites to infer their role in resilience to coral diseases. As time-resolved multi-omics datasets are generated for disease-impacted corals, our approach and findings will be valuable in providing insight into the mechanisms of disease resistance.

Bacteria respond to changes in their external environment, such as temperature, by changing the transcription of their genes. We know little about how these regulatory patterns evolve. We used RNA-seq to study the transcriptional response to a shift from 37°C to 15°C in wild-type Escherichia coli, Salmonella enterica, Citrobacter rodentium, Enterobacter cloacae, Klebsiella pneumoniae, and Serratia marcescens, as well as ∆rpoS strains of E. coli and S. enterica. We found that these species change the transcription of between 626 and 1057 genes in response to the temperature shift, but there were only 16 differentially expressed genes in common among the six species. Species-specific transcriptional patterns of shared genes were a prominent cause of this lack of conservation. Gene ontology enrichment of regulated genes suggested many species-specific phenotypic responses to temperature changes, but enriched terms associated with iron metabolism, central metabolism, and biofilm formation were implicated in at least half of the species. The alternative sigma factor RpoS regulated about 200 genes between 37°C and 15°C in both E. coli and S. enterica, with only 83 genes in common between the two species. Overall, there was limited conservation of the response to low temperature generally, or the RpoS-regulated part of the response specifically. This study suggests that species-specific patterns of transcription of shared genes, rather than horizontal acquisition of unique genes, are the major reason for the lack of conservation of the transcriptomic response to low temperature.

Importance: We studied how different species of bacteria from the same Family (Enterobacteriaceae) change the expression of their genes in response to a decrease in temperature. Using de novo-generated parallel RNA-seq data sets, we found that the six species in this study change the level of expression of many of their genes in response to a shift from human body temperature (37°C) to a temperature that might be found out of doors (15°C). Surprisingly, there were very few genes that change expression in all six species. This was due in part to differences in gene content, and in part due to shared genes with distinct expression profiles between the species. This study is important to the field because it illustrates that closely related species can share many genes but not use those genes in the same way in response to the same environmental change.

Legionella pneumophila uses over 300 translocated effector proteins to rewire host cells during infection and create a replicative niche for intracellular growth. To date, several studies have identified L. pneumophila effectors that indirectly and directly regulate the activity of other effectors, providing an additional layer of regulatory complexity. Among these are "metaeffectors," a special class of effectors that regulate the activity of other effectors once inside the host. A defining feature of metaeffectors is direct, physical interaction with a target effector. Metaeffector identification, to date, has depended on phenotypes in heterologous systems and experimental serendipity. Using a multiplexed, recombinant barcode-based yeast two-hybrid technology we screened for protein-protein interactions among all L. pneumophila effectors and 28 components of the Dot/Icm type IV secretion system (>167,000 protein combinations). Of the 52 protein interactions identified by this approach, 44 are novel protein interactions, including 10 novel effector-effector interactions (doubling the number of known effector-effector interactions).

Importance: Secreted bacterial effector proteins are typically viewed as modulators of host activity, entering the host cytosol to physically interact with and modify the activity of one or more host proteins in support of infection. A growing body of evidence suggests that a subset of effectors primarily function to modify the activities of other effectors inside the host. These "effectors of effectors" or metaeffectors are often identified through experimental serendipity during the study of canonical effector function against the host. We previously performed the first global effector-wide genetic interaction screen for metaeffectors within the arsenal of Legionella pneumophila, an intracellular bacterial pathogen with over 300 effectors. Here, using a high-throughput, scalable methodology, we present the first global interaction network of physical interactions between L. pneumophila effectors. This data set serves as a complementary resource to identify and understand both the scope and nature of non-canonical effector activity within this important human pathogen.

The phylum Gemmatimonadota is widespread but rarely cultured and, in fact, there are only six described species isolated from soil, freshwater, and wastewater treatment. However, no isolates of Gemmatimonadota from marine environment have been described; thus, little is known about the physiology and metabolism of members of the marine lineages. In this study, four novel facultatively anaerobic bacterial strains belonging to Gemmatimonadota were isolated from marine sediments collected from Xiaoshi Island in Weihai, China, using an aerobic enrichment method. The integrated results of phylogenetic and phenotypic characteristics supported that these four strains represent one novel species in a novel genus, for which the name Gaopeijia maritima gen. nov., sp. nov. is proposed, as the first representative of novel taxa, Gaopeijiales ord. nov., Gaopeijiaceae fam. nov. in the class Longimicrobiia. Gaopeijiales was detected in 22,884 out of 95,549 amplicon data sets, mainly from soil. However, the highest mean relative abundances were in sponge (0.7%) and marine sediment (0.35%), showing salt-related character. Most of the Gaopeijiales subgroups potentially belong to the rare bacterial biosphere. The aerobic enrichment in this study could significantly increase the relative abundance of Gaopeijiales (from 0.37% to 2.6%). Furthermore, the metabolic capabilities inferred from high-quality representative Gaopeijiales genomes/MAGs suggest that this group primarily performs chemoorganoheterotrophic metabolism with facultatively anaerobic characteristics and possesses various secondary metabolite biosynthesis gene clusters (BGCs), mirroring those observed in the four novel strains.IMPORTANCEDespite rapid advances in molecular and sequencing technologies, obtaining pure cultures remains a crucial research goal in microbiology, as it is essential for a deeper understanding of microbial metabolism. Gemmatimonadota is a widespread but rarely cultured bacterial phylum. Currently, there are only six cultured strains of this interesting group, all isolated from non-marine environments. Little is known about the physiology and metabolism of members of the marine lineages. Here we isolated and characterized four novel marine strains, and proposed a new order Gaopeijiales within Gemmatimonadota. Furthermore, the global distribution, environmental preference, and metabolic potential of Gaopeijiales are analyzed using public data. Our work enriches the resources available for the under-represented phylum Gemmatimonadota and provides insights into the physiological and metabolic characteristics of the marine lineage (Gaopeijiales) through culturology and omics.