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The human microbiota is an intricate micro-ecosystem comprising a diverse range of dynamic microbial populations mainly consisting of bacteria, whose interactions with hosts strongly affect several physiological and pathological processes. The gut microbiota is being increasingly recognized as a critical player in maintaining homeostasis, contributing to the main functions of the intestine and distal organs such as the brain. However, gut dysbiosis, characterized by composition and function alterations of microbiota with intestinal barrier dysfunction has been linked to the development and progression of several pathologies, including intestinal inflammatory diseases, systemic autoimmune diseases, such as rheumatic arthritis, and neurodegenerative diseases, such as Alzheimer's disease. Moreover, oral microbiota research has gained significant interest in recent years due to its potential impact on overall health. Emerging evidence on the role of microbiota-host interactions in health and disease has triggered a marked interest on the functional role of bacterial extracellular vesicles (BEVs) as mediators of inter-kingdom communication. Accumulating evidence reveals that BEVs mediate host interactions by transporting and delivering into host cells effector molecules that modulate host signaling pathways and cell processes, influencing health and disease. This review discusses the critical role of BEVs from the gut, lung, skin and oral cavity in the epithelium, immune system, and CNS interactions.

Honeybees are important pollinators worldwide, with their gut microbiota playing a crucial role in maintaining their health. The gut bacteria of honeybees consist of primarily five core lineages that are spread through social interactions. Previous studies have provided a basic understanding of the composition and function of the honeybee gut microbiota, with recent advancements focusing on analyzing diversity at the strain level and changes in bacterial functional genes. Research on honeybee gut microbiota across different regions globally has provided insights into microbial ecology. Additionally, recent findings have shed light on the mechanisms of host specificity of honeybee gut bacteria. This review explores the temporospatial dynamics in honeybee gut microbiota, discussing the reasons and mechanisms behind these fluctuations. This synopsis provides insights into host-microbe interactions and is invaluable for honeybee health., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The human microbiome functions as a separate organ in a symbiotic relationship with the host. Disruption of this host-microbe symbiosis can lead to serious health problems. Modifications to the composition and function of the microbiome have been linked to changes in host metabolic outcomes. Industrial lifestyles with high consumption of processed foods, alcoholic beverages and antibiotic use have significantly altered the gut microbiome in unfavorable ways. Therefore, understanding the causal relationship between the human microbiome and host metabolism will provide important insights into how we can better intervene in metabolic health. In this review, I will discuss the potential use of the human microbiome as a therapeutic target to improve host metabolism.

Purpose of Review: Understanding the spectrum of drivers that influence the gut microbiome (GM) remains a crucial field of investigation. Among these factors, diet has received particular attention, as it could explain up to 20% of the variability in GM composition between individuals. This review focuses on the complex relationships between different dietary patterns and GM in humans, based on recent findings., Recent Findings: Current evidence underscores the multifaceted impact of diet on GM richness, diversity, and overall composition. Key contributing factors encompass dietary habits, nutritional interventions, food quality and variety, macronutrient distribution, timing of feeding, and selective exclusion of certain foods., Summary: The intricate interplay between diet and GM is of fundamental importance in shaping the interaction between the host and the environment. Further understanding the causal impact of diet on GM has promising potential for the advancement of strategies to promote health and mitigate cardio-metabolic disease risks through dietary interventions., Graphical Abstract: http://links.lww.com/COCN/A21., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Bacterial extracellular vesicles (bEVs) represent spherical particles with diameters ranging from 20 to 400 nm filled with multiple parental bacteria-derived components, including proteins, nucleic acids, lipids, and other biomolecules. The production of bEVs facilitates bacteria interacting with their environment and exerting biological functions. It is increasingly evident that the bEVs play integral roles in both bacterial and host physiology, contributing to environmental adaptations to functioning as health promoters for their hosts. This review highlights the current state of knowledge on the composition, biogenesis, and diversity of bEVs and the mechanisms by which different bEVs elicit effects on bacterial physiology and host health. We posit that an in-depth exploration of the mechanistic aspects of bEVs activity is essential to elucidate their health-promoting effects on the host and may facilitate the translation of bEVs into applications as novel natural biological nanomaterials., Competing Interests: Competing interests Not applicable., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Comparative physiologists often compare physiological traits across organisms to understand the selective pressures influencing their evolution in different environments. Traditionally focused on the organisms themselves, comparative physiology has more recently incorporated studies of the microbiome-the communities of microbes living in and on animals that influence host physiology. In this commentary, we describe the utility of applying a comparative framework to study the microbiome, particularly in understanding how hosts vary in their dependence on microbial communities for physiological function, a concept we term the "microbial dependence continuum". This hypothesis suggests that hosts exist on a spectrum ranging from high to low reliance on their microbiota. Certain physiological traits may be highly dependent on microbes for proper function in some species but microbially independent in others. Comparative physiology can elucidate the selective pressures driving species along this continuum. Here, we discuss the microbial dependence continuum in detail and how comparative physiology can be useful to study it. Then, we discuss two example traits, herbivory and flight, where comparative physiology has helped reveal the selective pressures influencing host dependence on microbial communities. Lastly, we discuss useful experimental approaches for studying the microbial dependence continuum in a comparative physiology context., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Interactions between eukaryotic hosts and their bacterial symbionts drive key ecological and evolutionary processes, from regulating ecosystems to the evolution of complex molecular machines and processes. Over time, endosymbionts generally evolve reduced genomes, and their relationship with their host tends to stabilize. However, host-bacteria relationships may be heavily influenced by environmental changes. Here, we review these effects on one of the most ancient and diverse endosymbiotic groups, formed by-among others-Legionellales, Francisellaceae, and Piscirickettsiaceae. This group is referred to as Deep-branching Intracellular Gammaproteobacteria (DIG), whose last common ancestor presumably emerged about 2 Ga ago. We show that DIGs are globally distributed, but generally at very low abundance, and are mainly identified in aquatic biomes. Most DIGs harbour a type IVB secretion system, critical for host-adaptation, but its structure and composition vary. Finally, we review the different types of microbial interactions that can occur in diverse environments, with direct or indirect effects on DIG populations. The increased use of omics technologies on environmental samples will allow a better understanding of host-bacterial interactions and help unravel the definition of DIGs as a group from an ecological, molecular, and evolutionary perspective., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a human pathogen that is now endemic to several East Asian countries. The viral large (L) protein catalyzes viral transcription by stealing host mRNA caps via a process known as cap-snatching. Here, we establish an in vitro cap-snatching assay and present three high-quality electron cryo-microscopy (cryo-EM) structures of the SFTSV L protein in biologically relevant, transcription-specific states. In a priming-state structure, we show capped RNA bound to the L protein cap-binding domain (CBD). The L protein conformation in this priming structure is significantly different from published replication-state structures, in particular the N- and C-terminal domains. The capped-RNA is positioned in a way that it can feed directly into the RNA-dependent RNA polymerase (RdRp) ready for elongation. We also captured the L protein in an early-elongation state following primer-incorporation demonstrating that this priming conformation is retained at least in the very early stages of primer extension. This structural data is complemented by in vitro biochemical and cell-based assays. Together, these insights further our mechanistic understanding of how SFTSV and other bunyaviruses incorporate stolen host mRNA fragments into their viral transcripts thereby allowing the virus to hijack host cell translation machinery., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

We present Transkingdom Network Analysis (TkNA), a unique causal-inference analytical framework that offers a holistic view of biological systems by integrating data from multiple cohorts and diverse omics types. TkNA helps to decipher key players and mechanisms governing host-microbiota (or any multi-omic data) interactions in specific conditions or diseases. TkNA reconstructs a network that represents a statistical model capturing the complex relationships between different omics in the biological system. It identifies robust and reproducible patterns of fold change direction and correlation sign across several cohorts to select differential features and their per-group correlations. The framework then uses causality-sensitive metrics, statistical thresholds and topological criteria to determine the final edges forming the transkingdom network. With the subsequent network's topological features, TkNA identifies nodes controlling a given subnetwork or governing communication between kingdoms and/or subnetworks. The computational time for the millions of correlations necessary for network reconstruction in TkNA typically takes only a few minutes, varying with the study design. Unlike most other multi-omics approaches that find only associations, TkNA focuses on establishing causality while accounting for the complex structure of multi-omic data. It achieves this without requiring huge sample sizes. Moreover, the TkNA protocol is user friendly, requiring minimal installation and basic familiarity with Unix. Researchers can access the TkNA software at https://github.com/CAnBioNet/TkNA/ ., (© 2024. Springer Nature Limited.)

The health and well-being of a host are deeply influenced by the interactions with its gut microbiota. Contrasted environmental conditions, such as diseases or dietary habits, play a pivotal role in modulating these interactions, impacting microbiota composition and functionality. Such conditions can also lead to transitions from beneficial to detrimental symbiosis, viewed as alternative stable states of the host-microbiota dialogue. This article introduces a novel mathematical model exploring host-microbiota interactions, integrating dynamics of the colonic epithelial crypt, microbial metabolic functions, inflammation sensitivity and colon flows in a transverse section. The model considers metabolic shifts in epithelial cells based on butyrate and hydrogen sulfide concentrations, innate immune pattern recognition receptor activation, microbial oxygen tolerance and the impact of antimicrobial peptides on the microbiota. Using the model, we demonstrated that a high-protein, low-fibre diet exacerbates detrimental interactions and compromises beneficial symbiotic resilience, underscoring a destabilizing effect towards an unhealthy state. Moreover, the proposed model provides essential insights into oxygen levels, fibre and protein breakdown, and basic mechanisms of innate immunity in the colon and offers a crucial understanding of factors influencing the colon environment.

This review scrutinizes the intricate interplay between the microbiome and the human body, exploring its multifaceted dimensions and far-reaching implications. The human microbiome, comprising diverse microbial communities inhabiting various anatomical niches, is increasingly recognized as a critical determinant of human health and disease. Through an extensive examination of current research, this review elucidates the dynamic interactions between the microbiome and host physiology across multiple organ systems. Key topics include the establishment and maintenance of microbiota diversity, the influence of host factors on microbial composition, and the bidirectional communication pathways between microbiota and host cells. Furthermore, we delve into the functional implications of microbiome dysbiosis in disease states, emphasizing its role in shaping immune responses, metabolic processes, and neurological functions. Additionally, this review discusses emerging therapeutic strategies aimed at modulating the microbiome to restore host-microbe homeostasis and promote health. Microbiota fecal transplantation represents a groundbreaking therapeutic approach in the management of dysbiosis-related diseases, offering a promising avenue for restoring microbial balance within the gut ecosystem. This innovative therapy involves the transfer of fecal microbiota from a healthy donor to an individual suffering from dysbiosis, aiming to replenish beneficial microbial populations and mitigate pathological imbalances. By synthesizing findings from diverse fields, this review offers valuable insights into the complex relationship between the microbiome and the human body, highlighting avenues for future research and clinical interventions.

Plant-microbe interactions (PMIs) are regulated through a wide range of mechanisms in which sterols from plants and microbes are involved in numerous ways, including recognition, transduction, communication, and/or exchanges between partners. Phytosterol equilibrium is regulated by PMIs through expression of genes involved in phytosterol biosynthesis, together with their accumulation. As such, PMI outcomes also include plasma membrane (PM) functionalization events, in which phytosterols have a central role, and activation of sterol-interacting proteins involved in cell signaling. In spite (or perhaps because) of such multifaceted abilities, an overall mechanism of sterol contribution is difficult to determine. However, promising approaches exploring sterol diversity, their contribution to PMI outcomes, and their localization would help us to decipher their crucial role in PMIs., Competing Interests: Declaration of interests None declared by authors., (Copyright © 2024. Published by Elsevier Ltd.)

Specialized host-microbe symbioses canonically show greater diversity than expected from simple models, both at the population level and within individual hosts. To understand how this heterogeneity arises, we utilize the squash bug, Anasa tristis, and its bacterial symbionts in the genus Caballeronia. We modulate symbiont bottleneck size and inoculum composition during colonization to demonstrate the significance of ecological drift, the noisy fluctuations in community composition due to demographic stochasticity. Consistent with predictions from the neutral theory of biodiversity, we found that ecological drift alone can account for heterogeneity in symbiont community composition between hosts, even when 2 strains are nearly genetically identical. When acting on competing strains, ecological drift can maintain symbiont genetic diversity among different hosts by stochastically determining the dominant strain within each host. Finally, ecological drift mediates heterogeneity in isogenic symbiont populations even within a single host, along a consistent gradient running the anterior-posterior axis of the symbiotic organ. Our results demonstrate that symbiont population structure across scales does not necessarily require host-mediated selection, as it can emerge as a result of ecological drift acting on both isogenic and unrelated competitors. Our findings illuminate the processes that might affect symbiont transmission, coinfection, and population structure in nature, which can drive the evolution of host-microbe symbioses and microbe-microbe interactions within host-associated microbiomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The myriad microorganisms that live in close association with humans have diverse effects on physiology, yet the molecular bases for these impacts remain mostly unknown 1-3 . Classical pathogens often invade host tissues and modulate immune responses through interactions with human extracellular and secreted proteins (the 'exoproteome'). Commensal microorganisms may also facilitate niche colonization and shape host biology by engaging host exoproteins; however, direct exoproteome-microbiota interactions remain largely unexplored. Here we developed and validated a novel technology, BASEHIT, that enables proteome-scale assessment of human exoproteome-microbiome interactions. Using BASEHIT, we interrogated more than 1.7 million potential interactions between 519 human-associated bacterial strains from diverse phylogenies and tissues of origin and 3,324 human exoproteins. The resulting interactome revealed an extensive network of transkingdom connectivity consisting of thousands of previously undescribed host-microorganism interactions involving 383 strains and 651 host proteins. Specific binding patterns within this network implied underlying biological logic; for example, conspecific strains exhibited shared exoprotein-binding patterns, and individual tissue isolates uniquely bound tissue-specific exoproteins. Furthermore, we observed dozens of unique and often strain-specific interactions with potential roles in niche colonization, tissue remodelling and immunomodulation, and found that strains with differing host interaction profiles had divergent interactions with host cells in vitro and effects on the host immune system in vivo. Overall, these studies expose a previously unexplored landscape of molecular-level host-microbiota interactions that may underlie causal effects of indigenous microorganisms on human health and disease., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Given that the host-microbe interaction is shaped by the immune system response, it is important to understand the key immune system-microbiota relationship during the period from conception to the first years of life. The present work summarizes the available evidence concerning human reproductive microbiota, and also, the microbial colonization during early life, focusing on the potential impact on infant development and health outcomes. Furthermore, we conclude that some dietary strategies including specific probiotics and other-biotics could become potentially valuable tools to modulate the maternal-neonatal microbiota during this early critical window of opportunity for targeted health outcomes throughout the entire lifespan., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: The gut microbiome is integral to host health, hosting complex interactions between the host and numerous microbial species in the gastrointestinal tract. Key among the molecular mechanisms employed by gut bacteria are transportomes, consisting of diverse transport proteins crucial for bacterial adaptation to the dynamic, nutrient-rich environment of the mammalian gut. These transportomes facilitate the movement of a wide array of molecules, impacting both the host and the microbial community., Summary: This communication explores the significance of transportomes in gut bacteria, focusing on their role in nutrient acquisition, competitive interactions among microbes, and potential pathogenicity. It delves into the transportomes of key gut bacterial species like E. coli, Salmonella, Bacteroides, Lactobacillus, Clostridia, and Bifidobacterium, examining the functions of predicted transport proteins. The overview synthesizes recent research efforts, highlighting how these transportomes influence host-microbe interactions and contribute to the microbial ecology of the gut., Key Messages: Transportomes are vital for the survival and adaptation of bacteria in the gut, enabling the import and export of various nutrients and molecules. The complex interplay of transport proteins not only supports bacterial growth and competition but also has implications for host health, potentially contributing to pathogenic processes. Understanding the pathogenic potential of transportomes in major gut bacterial species provides insights into gut health and disease, offering avenues for future research and therapeutic strategies., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Wolbachia are successful Gram-negative bacterial endosymbionts, globally infecting a large fraction of arthropod species and filarial nematodes. Efficient vertical transmission, the capacity for horizontal transmission, manipulation of host reproduction and enhancement of host fitness can promote the spread both within and between species. Wolbachia are abundant and can occupy extraordinary diverse and evolutionary distant host species, suggesting that they have evolved to engage and manipulate highly conserved core cellular processes. Here, we review recent studies identifying Wolbachia-host interactions at the molecular and cellular levels. We explore how Wolbachia interact with a wide array of host cytoplasmic and nuclear components in order to thrive in a diversity of cell types and cellular environments. This endosymbiont has also evolved the ability to precisely target and manipulate specific phases of the host cell cycle. The remarkable diversity of cellular interactions distinguishes Wolbachia from other endosymbionts and is largely responsible for facilitating its global propagation through host populations. Finally, we describe how insights into Wolbachia-host cellular interactions have led to promising applications in controlling insect-borne and filarial nematode-based diseases., (© 2023. Springer Nature Limited.)

Respiratory syncytial virus (RSV) has a significant health burden in children, older adults, and the immunocompromised. However, limited effort has been made to identify emergence of new RSV genotypes' frequency of infection and how the combination of nasopharyngeal microbiome and viral genotypes impact RSV disease outcomes. In an observational cohort designed to capture the first infant RSV infection, we employed multi-omics approaches to sequence 349 RSV complete genomes and matched nasopharyngeal microbiomes, during which the 2012/2013 season was dominated by RSV-A, whereas 2013 and 2014 was dominated by RSV-B. We found non-G-72nt-duplicated RSV-A strains were more frequent in male infants ( P  = 0.02), whereas G-72nt-duplicated genotypes (which is ON1 lineage) were seen equally in both males and females. DESeq2 testing of the nasal microbiome showed Haemophilus was significantly more abundant in infants with RSV-A infection compared to infants with RSV-B infection (adjusted P  = 0.002). In addition, the broad microbial clustering of the abundant genera was significantly associated with infant sex ( P  = 0.03). Overall, we show sex differences in infection by RSV genotype and host nasopharyngeal microbiome, suggesting an interaction between host genetics, virus genotype, and associated nasopharyngeal microbiome. IMPORTANCE Respiratory syncytial virus (RSV) is one of the leading causes of lower respiratory tract infections in young children and is responsible for high hospitalization rates and morbidity in infants and the elderly. To understand how the emergence of RSV viral genotypes and viral-respiratory microbiome interactions contribute to infection frequency and severity, we utilized an observational cohort designed to capture the first infant RSV infection we employed multi-omics approaches to sequence 349 RSV complete genomes and matched nasopharyngeal microbiomes. We found non-G-72nt-duplicated RSV-A genotypes were more frequent in male infants, whereas G-72nt-duplicated RSV-A strains (ON1 lineage) were seen equally in both males and females. Microbiome analysis show Haemophilus was significantly more abundant in infants with RSV-A compared to infants with RSV-B infection and the microbial clustering of the abundant genera was associated with infant sex. Overall, we show sex differences in RSV genotype-nasopharyngeal microbiome, suggesting an interaction host genetics-virus-microbiome interaction.

The three genomic and a single subgenomic RNA of Cowpea chlorotic mottle virus (CCMV), which is pathogenic to plants, is packaged into three morphologically indistinguishable icosahedral virions with T=3 symmetry. The two virion types, C1 V and C2 V , package genomic RNAs 1 (C1) and 2 (C2), respectively. The third virion type, C3+4 V , copackages genomic RNA3 and its subgenomic RNA (RNA4). In this study, we sought to evaluate how the alteration of native capsid dynamics by the host and viral replicase modulate the general biology of the virus. The application of a series of biochemical, molecular, and biological assays revealed the following. (i) Proteolytic analysis of the three virion types of CCMV assembled individually in planta revealed that, while retaining the structural integrity, C1 V and C2 V virions released peptide regions encompassing the N-terminal arginine-rich RNA binding motif. In contrast, a minor population of the C3+4 V virion type was sensitive to trypsin-releasing peptides encompassing the entire capsid protein region. (ii) The wild-type CCMV virions purified from cowpea are highly susceptible to trypsin digestion, while those from Nicotiana benthamiana remained resistant, and (iii) finally, the matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) analysis evaluated the relative dynamics of C3+4 V and B3+4 V virions assembled under the control of the homologous versus heterologous replicase. The role of viral replicase in modulating the capsid dynamics was evident by the differential sensitivity to protease exhibited by B3+4 V and C3+4 V virions assembled under the homologous versus heterologous replicase. Our results collectively conclude that constant modulation of capsid dynamics by the host and viral replicase is obligatory for successful infection. IMPORTANCE Infectious virus particles or virions are considered static structures and undergo various conformational transitions to replicate and infect many eukaryotic cells. In viruses, conformational changes are essential for establishing infection and evolution. Although viral capsid fluctuations, referred to as dynamics or breathing, have been well studied in RNA viruses pathogenic to animals, such information is limited among plant viruses. The primary focus of this study is to address how capsid dynamics of plant-pathogenic RNA viruses, namely, Cowpea chlorotic mottle (CCMV) and Brome mosaic virus (BMV), are modulated by the host and viral replicase. The results presented have improved and transformed our understanding of the functional relationship between capsid dynamics and the general biology of the virus. They are likely to provide stimulus to extend similar studies to viruses pathogenic to eukaryotic organisms.

Viral infections alter host cell metabolism and homeostasis; however, the mechanisms that regulate these processes have only begun to be elucidated. We report here that Zika virus (ZIKV) infection activates the antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2), which precedes oxidative stress. Downregulation of Nrf2 or inhibition of glutathione (GSH) synthesis resulted in significantly increased viral replication. Interestingly, 6-amino-nicotinamide (6-AN), a nicotinamide analog commonly used as an inhibitor of the pentose phosphate pathway (PPP), decreased viral replication by over 1,000-fold. This inhibition was neither recapitulated by the knockdown of PPP enzymes, glucose 6-phosphate dehydrogenase (G6PD), or 6-phosphogluconate dehydrogenase (6PGD), nor prevented by supplementation with ribose 5-phosphate. Instead, our metabolomics and metabolic phenotype studies support a mechanism in which 6-AN depletes cells of NAD(H) and impairs NAD(H)-dependent glycolytic steps resulting in inhibition of viral replication. The inhibitory effect of 6-AN was rescued with precursors of the salvage pathway but not with those of other NAD + biosynthesis pathways. Inhibition of glycolysis reduced viral protein levels, which were recovered transiently. This transient recovery in viral protein synthesis was prevented when oxidative metabolism was inhibited by blockage of the mitochondrial pyruvate carrier, fatty acid oxidation, or glutaminolysis, demonstrating a compensatory role of mitochondrial metabolism in ZIKV replication. These results establish an antagonistic role for the host cell Nrf2/GSH/NADPH-dependent antioxidant response against ZIKV and demonstrate the dependency of ZIKV replication on NAD(H). Importantly, our work suggests the potential use of NAD(H) antimetabolite therapy against the viral infection. IMPORTANCE Zika virus (ZIKV) is a major public health concern of international proportions. While the incidence of ZIKV infections has declined substantially in recent years, the potential for the reemergence or reintroduction remains high. Although viral infection alters host cell metabolism and homeostasis to promote its replication, deciphering the mechanism(s) involved in these processes is important for identifying therapeutic targets. The present work reveals the complexities of host cell redox regulation and metabolic dependency of ZIKV replication. An antagonistic effect of the Nrf2/GSH/NADP(H)-dependent antioxidant response against ZIKV infection and an essential role of NAD(H) metabolism and glycolysis for viral replication are established for the first time. These findings highlight the potential use of NAD(H) antimetabolites to counter ZIKV infection and pathogenesis.

Herpes simplex virus type 1 (HSV-1) is a ubiquitous human pathogen that can cause significant morbidity, primarily facial cold sores and herpes simplex encephalitis. Previous studies have shown that a variety of viruses can reprogram the metabolic profiles of host cells to facilitate self-replication. In order to further elucidate the metabolic interactions between the host cell and HSV-1, we used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze the metabolic profiles in human lung fibroblasts KMB17 infected with HSV-1. The results showed that 654 and 474 differential metabolites were identified in positive and negative ion modes, respectively, and 169 and 114 metabolic pathways that might be altered were screened. These altered metabolites are mainly involved in central carbon metabolism, choline metabolism, amino acid metabolism, purine and pyrimidine metabolism, cholesterol metabolism, bile secretion, and prolactin signaling pathway. Further, we confirmed that the addition of tryptophan metabolite kynurenine promotes HSV-1 replication, and the addition of 25-Hydroxycholesterol inhibits viral replication. Significantly, HSV-1 replication was obviously enhanced in the ChOKα (a choline metabolic rate-limiting enzyme) deficient mouse macrophages. These results indicated that HSV-1 induces the metabolic reprogramming of host cells to promote or resist viral replication. Taken together, these observations highlighted the significance of host cell metabolism in HSV-1 replication, which would help to clarify the pathogenesis of HSV-1 and identify new anti-HSV-1 therapeutic targets.

While pathogenic and mutualistic microbes are ubiquitous across ecosystems and often co-occur within hosts, how they interact to determine patterns of disease in genetically diverse wild populations is unknown. To test whether microbial mutualists provide protection against pathogens, and whether this varies among host genotypes, we conducted a field experiment in three naturally occurring epidemics of a fungal pathogen, Podosphaera plantaginis, infecting a host plant, Plantago lanceolata, in the Åland Islands, Finland. In each population, we collected epidemiological data on experimental plants from six allopatric populations that had been inoculated with a mixture of mutualistic arbuscular mycorrhizal fungi or a nonmycorrhizal control. Inoculation with arbuscular mycorrhizal fungi increased growth in plants from every population, but also increased host infection rate. Mycorrhizal effects on disease severity varied among host genotypes and strengthened over time during the epidemic. Host genotypes that were more susceptible to the pathogen received stronger protective effects from inoculation. Our results show that arbuscular mycorrhizal fungi introduce both benefits and risks to host plants, and shift patterns of infection in host populations under pathogen attack. Understanding how mutualists alter host susceptibility to disease will be important for predicting infection outcomes in ecological communities and in agriculture., (© 2022 The Authors. New Phytologist © 2022 New Phytologist Foundation.)

Viruses are important ecological, biogeochemical, and evolutionary drivers in every environment. Upon infection, they often cause the lysis of the host cell. However, some viruses exhibit alternative life cycles, such as chronic infections without cell lysis. The nature and the impact of chronic infections in prokaryotic host organisms remains largely unknown. Here, we characterize a novel haloarchaeal virus, Haloferax volcanii pleomorphic virus 1 (HFPV-1), which is currently the only virus infecting the model haloarchaeon Haloferax volcanii DS2, and demonstrate that HFPV-1 and H. volcanii are a great model system to study virus-host interactions in archaea. HFPV-1 is a pleomorphic virus that causes a chronic infection with continuous release of virus particles, but host and virus coexist without cell lysis or the appearance of resistant cells. Despite an only minor impact of the infection on host growth, we uncovered an extensive remodeling of the transcriptional program of the host (up to 1,049 differentially expressed genes). These changes are highlighted by a down-regulation of two endogenous provirus regions in the host genome, and we show that HFPV-1 infection is strongly influenced by a cross-talk between HFPV-1 and one of the proviruses mediated by a superinfection-like exclusion mechanism. Furthermore, HFPV-1 has a surprisingly wide host range among haloarchaea, and purified virus DNA can cause an infection after transformation into the host, making HFPV-1 a candidate for being developed into a genetic tool for a range of so far inaccessible haloarchaea.

Bacteria adapt to their constantly changing environments largely by transcriptional regulation through the activities of various transcription factors (TFs). However, techniques that monitor TF-promoter interactions in situ in living bacteria are lacking. Herein, we developed a whole-cell TF-promoter binding assay based on the intermolecular FRET between an unnatural amino acid, l-(7-hydroxycoumarin-4-yl) ethylglycine, which labels TFs with bright fluorescence through genetic encoding (donor fluorophore) and the live cell nucleic acid stain SYTO 9 (acceptor fluorophore). We show that this new FRET pair monitors the intricate TF-promoter interactions elicited by various types of signal transduction systems, including one-component (CueR) and two-component systems (BasSR and PhoPQ), in bacteria with high specificity and sensitivity. We demonstrate that robust CouA incorporation and FRET occurrence is achieved in all these regulatory systems based on either the crystal structures of TFs or their simulated structures, if 3D structures of the TFs were unavailable. Furthermore, using CueR and PhoPQ systems as models, we demonstrate that the whole-cell FRET assay is applicable for the identification and validation of complex regulatory circuit and novel modulators of regulatory systems of interest. Finally, we show that the FRET system is applicable for single-cell analysis and monitoring TF activities in Escherichia coli colonizing a Caenorhabditis elegans host. In conclusion, we established a tractable and sensitive TF-promoter binding assay, which not only complements currently available approaches for DNA-protein interactions but also provides novel opportunities for functional annotation of bacterial signal transduction systems and studies of the bacteria-host interface., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The mechanisms used by human adapted commensal Neisseria to shape and maintain a niche in their host are poorly defined. These organisms are common members of the mucosal microbiota and share many putative host interaction factors with Neisseria meningitidis and Neisseria gonorrhoeae. Evaluating the role of these shared factors during host carriage may provide insight into bacterial mechanisms driving both commensalism and asymptomatic infection across the genus. We identified host interaction factors required for niche development and maintenance through in vivo screening of a transposon mutant library of Neisseria musculi, a commensal of wild-caught mice which persistently and asymptomatically colonizes the oral cavity and gut of CAST/EiJ and A/J mice. Approximately 500 candidate genes involved in long-term host interaction were identified. These included homologs of putative N. meningitidis and N. gonorrhoeae virulence factors which have been shown to modulate host interactions in vitro. Importantly, many candidate genes have no assigned function, illustrating how much remains to be learned about Neisseria persistence. Many genes of unknown function are conserved in human adapted Neisseria species; they are likely to provide a gateway for understanding the mechanisms allowing pathogenic and commensal Neisseria to establish and maintain a niche in their natural hosts. Validation of a subset of candidate genes confirmed a role for a polysaccharide capsule in N. musculi persistence but not colonization. Our findings highlight the potential utility of the Neisseria musculi-mouse model as a tool for studying the pathogenic Neisseria; our work represents a first step towards the identification of novel host interaction factors conserved across the genus., Competing Interests: The authors have declared that no competing interests exist.

Dengue virus (DENV) is a mosquito-borne flavivirus responsible for dengue disease, a major human health concern for which no effective treatment is available. DENV relies heavily on the host cellular machinery for productive infection. Here, we show that the scaffold protein RACK1, which is part of the DENV replication complex, mediates infection by binding to the 40S ribosomal subunit. Mass spectrometry analysis of RACK1 partners coupled to an RNA interference screen-identified Vigilin and SERBP1 as DENV host-dependency factors. Both are RNA-binding proteins that interact with the DENV genome. Genetic ablation of Vigilin or SERBP1 rendered cells poorly susceptible to DENV, as well as related flaviviruses, by hampering the translation and replication steps. Finally, we established that a Vigilin or SERBP1 mutant lacking RACK1 binding but still interacting with the viral RNA is unable to mediate DENV infection. We propose that RACK1 recruits Vigilin and SERBP1, linking the DENV genome to the translation machinery for efficient infection. IMPORTANCE We recently identified the scaffolding RACK1 protein as an important host-dependency factor for dengue virus (DENV), a positive-stranded RNA virus responsible for the most prevalent mosquito-borne viral disease worldwide. Here, we have performed the first RACK1 interactome in human cells and identified Vigilin and SERBP1 as DENV host-dependency factors. Both are RNA-binding proteins that interact with the DENV RNA to regulate viral replication. Importantly, Vigilin and SERBP1 interact with RACK1 and the DENV viral RNA (vRNA) to mediate viral replication. Overall, our results suggest that RACK1 acts as a binding platform at the surface of the 40S ribosomal subunit to recruit Vigilin and SERBP1, which may therefore function as linkers between the viral RNA and the translation machinery to facilitate infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the largest RNA genome, approximately 30 kb, among RNA viruses. The DDX DEAD box RNA helicase is a multifunctional protein involved in all aspects of RNA metabolism. Therefore, host RNA helicases may regulate and maintain such a large viral RNA genome. In this study, I investigated the potential role of several host cellular RNA helicases in SARS-CoV-2 infection. Notably, DDX21 knockdown markedly accumulated intracellular viral RNA and viral production, as well as viral infectivity of SARS-CoV-2, indicating that DDX21 strongly restricts the SARS-CoV-2 infection. In addition, MOV10 RNA helicase also suppressed the SARS-CoV-2 infection. In contrast, DDX1, DDX5, and DDX6 RNA helicases were required for SARS-CoV-2 replication. Indeed, SARS-CoV-2 infection dispersed the P-body formation of DDX6 and MOV10 RNA helicases as well as XRN1 exonuclease, while the viral infection did not induce stress granule formation. Accordingly, the SARS-CoV-2 nucleocapsid (N) protein interacted with DDX1, DDX3, DDX5, DDX6, DDX21, and MOV10 and disrupted the P-body formation, suggesting that SARS-CoV-2 N hijacks DDX6 to carry out viral replication. Conversely, DDX21 and MOV10 restricted SARS-CoV-2 infection through an interaction of SARS-CoV-2 N with host cellular RNA helicases. Altogether, host cellular RNA helicases seem to regulate the SARS-CoV-2 infection. IMPORTANCE SARS-CoV-2 has a large RNA genome, of approximately 30 kb. To regulate and maintain such a large viral RNA genome, host RNA helicases may be involved in SARS-CoV-2 replication. In this study, I have demonstrated that DDX21 and MOV10 RNA helicases limit viral infection and replication. In contrast, DDX1, DDX5, and DDX6 are required for SARS-CoV-2 infection. Interestingly, SARS-CoV-2 infection disrupted P-body formation and attenuated or suppressed stress granule formation. Thus, SARS-CoV-2 seems to hijack host cellular RNA helicases to play a proviral role by facilitating viral infection and replication and by suppressing the host innate immune system.

In the past 2 years, the coronavirus disease 2019 (COVID-19) pandemic has driven investigational studies and controlled clinical trials on antiviral treatments and vaccines that have undergone regulatory approval. Now that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants may become endemic over time, there remains a need to identify drugs that treat the symptoms of COVID-19 and prevent progression toward severe cases, hospitalization, and death. Understanding the molecular mechanisms of SARS-CoV-2 infection is extremely important for the development of effective therapies against COVID-19. This review outlines the key pathways involved in the host response to SARS-CoV-2 infection and discusses the potential role of antioxidant and anti-inflammatory pharmacological approaches for the management of early mild-to-moderate COVID-19, using the examples of combined indomethacin, low-dose aspirin, omeprazole, hesperidin, quercetin, and vitamin C. The pharmacological targets of these substances are described here for their possible synergism in counteracting SARS-CoV-2 replication and progression of the infection from the upper respiratory airways to the blood, avoiding vascular complications and cytokine and bradykinin storms.

Urinary tract infections (UTIs) are the second most frequent bacterial infections worldwide, with Escherichia coli being the main causative agent. The increase of antibiotic-resistance determinants among isolates from clinical samples, including UTIs, makes the development of novel therapeutic strategies a necessity. In this context, the use of bacteriophages as a therapeutic alternative has been proposed, due to their ability to efficiently kill bacteria. In this work, we isolated and characterized three novel bacteriophages, microbes laboratory phage 1 (MLP1), MLP2, and MLP3, belonging to the Chaseviridae , Myoviridae , and Podoviridae families, respectively. These phages efficiently infect and kill laboratory reference strains and multidrug-resistant clinical E. coli isolates from patients with diagnosed UTIs. Interestingly, these phages are also able to infect intestinal pathogenic Escherichia coli strains, such as enteroaggregative E. coli and diffusely adherent E. coli. Our data show that the MLP phages recognize different regions of the lipopolysaccharide (LPS) molecule, an important virulence factor in bacteria that is also highly variable among different E. coli strains. Altogether, our results suggest that these phages may represent an interesting alternative for the treatment of antibiotic-resistant E. coli. IMPORTANCE Urinary tract infections affect approximately 150 million people annually. The current antibiotic resistance crisis demands the development of novel therapeutic alternatives. Our results show that three novel phages, MLP1, MLP2, and MLP3 are able to infect both laboratory and multidrug-resistant clinical isolates of Escherichia coli. Since these phages (i) efficiently kill antibiotic-resistant clinical isolates of uropathogenic Escherichia coli (UPEC), (ii) recognize different portions of the LPS molecule, and (iii) are able to efficiently infect intestinal pathogenic Escherichia coli hosts, we believe that these novel phages are good candidates to be used as a therapeutic alternative to treat antibiotic-resistant E. coli strains generating urinary tract and/or intestinal infections.

Dermatophytic pathogens are a source of disturbance to the host microbiome, but the temporal progression of these disturbances is unclear. Here, we determined how Snake Fungal Disease, caused by Ophidiomyces ophidiicola, resulted in disturbance to the host microbiome. To assess disease effects on the microbiome, 22 Common Watersnakes (Nerodia sipedon) were collected and half were inoculated with O. ophidiicola. Epidermal swabs were collected weekly for use in microbiome and pathogen load characterization. For the inoculated treatment only, we found a significant effect of disease progression on microbial richness and Shannon diversity consistent with the intermediate disturbance hypothesis. When explicitly accounting for differences in assemblage richness, we found that β-diversity among snakes was significantly affected by the interaction of time and treatment group, with assemblages becoming more dissimilar across time in the inoculated, but not the control group. Also, differences between treatments in average microbiome composition became greater with time, but this interactive effect was not evident when accounting for assemblage richness. These results suggest that changes in composition of the host microbiome associated with disease largely occur due to changes in microbial richness related to disease progression., (© 2022. The Author(s).)

Emerging microbe infections, such as Zika virus (ZIKV), pose an increasing threat to human health. Investigations on ZIKV replication have revealed the construction of replication complexes (RCs), but the role of cytoskeleton in this process is largely unknown. Here, we investigated the function of cytoskeletal intermediate filament protein vimentin in the life cycle of ZIKV infection. Using advanced imaging techniques, we uncovered that vimentin filaments undergo drastic reorganization upon viral protein synthesis to form a perinuclear cage-like structure that embraces and concentrates RCs. Genetic removal of vimentin markedly disrupted the integrity of RCs and resulted in fragmented subcellular dispersion of viral proteins. This led to reduced viral genome replication, viral protein production, and release of infectious virions, without interrupting viral binding and entry. Furthermore, mass spectrometry and RNA-sequencing screens identified interactions and interplay between vimentin and hundreds of endoplasmic reticulum (ER)-resident RNA-binding proteins. Among them, the cytoplasmic-region of ribosome receptor binding protein 1, an ER transmembrane protein that directly binds viral RNA, interacted with and was regulated by vimentin, resulting in modulation of ZIKV replication. Together, the data in our work reveal a dual role for vimentin as a structural element for RC integrity and as an RNA-binding-regulating hub during ZIKV infection, thus unveiling a layer of interplay between Zika virus and host cell., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Legume plants establish a nitrogen-fixing symbiosis with soil bacteria known as rhizobia. Compatibility between legumes and rhizobia is determined at species-specific level, but variations in the outcome of the symbiotic process are also influenced by the capacity of the plant to discriminate and select specific strains that are better partners. We compared the transcriptional response of two genetically diverse accessions of Phaseolus vulgaris from Mesoamerica and South Andes to Rhizobium etli strains that exhibit variable degrees of symbiotic affinities. Our results indicate that the plant genotype is the major determinant of the transcriptional reprogramming occurring in roots at early stages of the symbiotic interaction. Differentially expressed genes (DEGs) regulated in the Mesoamerican and the Andean accessions in response to specific strains are different, but they belong to the same functional categories. The common and strain-specific transcriptional responses to rhizobia involve distinct transcription factors  and cis-elements present in the promoters of DEGs in each accession, showing that diversification and domestication of common bean at different geographic regions influenced the evolution of symbiosis differently in each genetic pool. Quantitative PCR analysis validated our transcriptional datasets, which constitute a valuable source of coding and non-coding candidate genes to further unravel the molecular determinants governing the mechanisms by which plants select bacterial strains that produce a better symbiotic outcome., (© 2022. The Author(s).)

Omicron is a new variant of SARS-CoV-2, which is currently infecting people around the world. Spike glycoprotein, an important molecule in pathogenesis of infection has been modeled and the interaction of its Receptor Binding Domain with human ACE-receptor has been analysed by simulation studies. Structural analysis of Omicron spike glycoprotein shows the 30 mutations to be distributed over all domains of the trimeric protein, wherein the mutant residues are seen to be participating in higher number of intra-molecular interactions including two salt bridges emanating from mutant residues thereby stabilizing their conformation, as compared to wild type. Complex of Receptor Binding Domain (RBD) with human ACE-2 receptor shows seven mutations at interacting interface comprising of two ionic interactions, eight hydrogen bonds and seven Van der Waals interactions. The number and quality of these interactions along with other binding biophysical parameters suggests more potency of RBD domain to the receptor as compared to the wild type counterpart. Results of this study explains the high transmissibility of Omicron variant of SARS-CoV-2 that is currently observed across the world., Competing Interests: Declaration of competing interest Authors report no conflict of interest in this work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The emergence of new SARS-CoV-2 variants poses a threat to the human population where it is difficult to assess the severity of a particular variant of the virus. Spike protein and specifically its receptor binding domain (RBD) which makes direct interaction with the ACE2 receptor of the human has shown prominent amino acid substitutions in most of the Variants of Concern. Here, by using all-atom molecular dynamics simulations we compare the interaction of Wild-type RBD/ACE2 receptor complex with that of the latest Omicron variant of the virus. We observed a very interesting diversification of the charge, dynamics and energetics of the protein complex formed upon mutations. These results would help us in understanding the molecular basis of binding of the Omicron variant with that of SARS-CoV-2 Wild-type., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Plants benefit from their close association with soil microbes which assist in their response to abiotic and biotic stressors. Yet much of what we know about plant stress responses is based on studies where the microbial partners were uncontrolled and unknown. Under climate change, the soil microbial community will also be sensitive to and respond to abiotic and biotic stressors. Thus, facilitating plant adaptation to climate change will require a systems-based approach that accounts for the multi-dimensional nature of plant-microbe-environment interactions. In this perspective, we highlight some of the key factors influencing plant-microbe interactions under stress as well as new tools to facilitate the controlled study of their molecular complexity, such as fabricated ecosystems and synthetic communities. When paired with genomic and biochemical methods, these tools provide researchers with more precision, reproducibility, and manipulability for exploring plant-microbe-environment interactions under a changing climate., (© 2022 The Author(s).)

Four tailspike proteins (TSP1-4) of Escherichia coli O157:H7 bacteriophage CBA120 enable infection of multiple hosts. They form a branched complex that attaches to the tail baseplate. Each TSP recognizes a different lipopolysaccharide on the membrane of a different bacterial host. The 335 N-terminal residues of TSP4 promote the assembly of the TSP complex and anchor it to the tail baseplate. The crystal structure of TSP4-N 335 reveals a trimeric protein comprising four domains. The baseplate anchor domain (AD) contains an intertwined triple-stranded β-helix. The ensuing XD1, XD2 and XD3 β-sheet containing domains mediate the binding of TSP1-3 to TSP4. Each of the XD domains adopts the same fold as the respective XD domains of bacteriophage T4 gp10 baseplate protein, known to engage in protein-protein interactions via its XD2 and XD3 domains. The structural similarity suggests that XD2 and XD3 of TSP4 also function in protein-protein interactions. Analytical ultracentrifugation analyses of TSP4-N 335 and of domain deletion proteins showed how TSP4-N 335 promotes the formation of the TSP quaternary complex. TSP1 and TSP2 bind directly to TSP4 whereas TSP3 binding requires a pre-formed TSP4-N 335 :TSP2 complex. A 3-dimensional model of the bacteriophage CBA120 TSP complex has been developed based on the structural and ultracentrifuge information., (© 2022. The Author(s).)

Soil is a living ecosystem, the health of which depends on fine interactions among its abiotic and biotic components. These form a delicate equilibrium maintained through a multilayer network that absorbs certain perturbations and guarantees soil functioning. Deciphering the principles governing the interactions within soils is of critical importance for their management and conservation. Here, we focus on soil microbiota and discuss the complexity of interactions that impact the composition and function of soil microbiota and their interaction with plants. We discuss how physical aspects of soils influence microbiota composition and how microbiota-plant interactions support plant growth and responses to nutrient deficiencies. We predict that understanding the principles determining the configuration and functioning of soil microbiota will contribute to the design of microbiota-based strategies to preserve natural resources and develop more environmentally friendly agricultural practices., (© 2021 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

Gut microbial products direct growth, differentiation, and development in animal hosts. However, we lack system-wide understanding of cell-specific responses to the microbiome. We profiled cell transcriptomes from the intestine, and associated tissue, of zebrafish larvae raised in the presence or absence of a microbiome. We uncovered extensive cellular heterogeneity in the conventional zebrafish intestinal epithelium, including previously undescribed cell types with known mammalian homologs. By comparing conventional to germ-free profiles, we mapped microbial impacts on transcriptional activity in each cell population. We revealed intricate degrees of cellular specificity in host responses to the microbiome that included regulatory effects on patterning and on metabolic and immune activity. For example, we showed that the absence of microbes hindered pro-angiogenic signals in the developing vasculature, causing impaired intestinal vascularization. Our work provides a high-resolution atlas of intestinal cellular composition in the developing fish gut and details the effects of the microbiome on each cell type., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Microbes have been coevolving with their host for millions of years, exploiting host resources to their own benefit. We show that viral and bacterial pathogens convergently evolved to hijack cellular mitogen-activated protein kinase (MAPK) p90-ribosomal S6-kinases (RSKs). Theiler's virus leader (L) protein binds RSKs and prevents their dephosphorylation, thus maintaining the kinases active. Recruitment of RSKs enables L-protein-mediated inhibition of eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2 or PKR) and stress granule formation. Strikingly, ORF45 protein of Kaposi's sarcoma-associated herpesvirus (KSHV) and YopM protein of Yersinia use the same peptide motif as L to recruit and activate RSKs. All three proteins interact with a conserved surface-located loop of RSKs, likely acting as an allosteric regulation site. Some unrelated viruses and bacteria thus evolved to harness RSKs in a common fashion, yet to target distinct aspects of innate immunity. As documented for Varicella zoster virus ORF11, additional pathogens likely evolved to hijack RSKs, using a similar short linear motif., Competing Interests: Competing interest statement: Y.H. received a salary from Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan, while working as guest scientist at the Université Catholique de Louvain. The company had no influence on the research project., (Copyright © 2022 the Author(s). Published by PNAS.)

Background & Aims: Microbiota composition and mechanisms of host-microbiota interactions in the esophagus are unclear. We aimed to uncover fundamental information about the esophageal microbiome and its potential significance to eosinophilic esophagitis (EoE)., Methods: Microbiota composition, transplantation potential, and antibiotic responsiveness in the esophagus were established via 16S ribosomal RNA sequencing. Functional outcomes of microbiota colonization were assessed by RNA sequencing analysis of mouse esophageal epithelium and compared with the human EoE transcriptome. The impact of dysbiosis was assessed using a preclinical model of EoE., Results: We found that the murine esophagus is colonized with diverse microbial communities within the first month of life. The esophageal microbiota is distinct, dominated by Lactobacillales, and demonstrates spatial heterogeneity as the proximal and distal esophagus are enriched in Bifidobacteriales and Lactobacillales, respectively. Fecal matter transplantation restores the esophageal microbiota, demonstrating that the local environment drives diversity. Microbiota colonization modifies esophageal tissue morphology and gene expression that is enriched in pathways associated with epithelial barrier function and overlapping with genes involved in EoE, including POSTN, KLK5, and HIF1A. Finally, neonatal antibiotic treatment reduces the abundance of Lactobacillales and exaggerates type 2 inflammation in the esophagus. Clinical data substantiated loss of esophageal Lactobacillales in EoE compared with controls., Conclusions: The esophagus has a unique microbiome with notable differences between its proximal and distal regions. Fecal matter transplantation restores the esophageal microbiome. Antibiotic-induced dysbiosis exacerbates disease in a murine model of EoE. Collectively, these data establish the composition, transplantation potential, antibiotic responsiveness, and host-microbiota interaction in the esophagus and have implications for gastrointestinal health and disease., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Characteristics of the gut microbiome vary synchronously with changes in host diet. However, the underlying effects of these fluctuations remain unclear. Here, we performed fecal microbiota transplantation (FMT) of diet-specific feces from an endangered mammal (the giant panda) into a germ-free mouse model. We demonstrated that the butyrate-producing bacterium Clostridium butyricum was more abundant during shoot-eating season than during the leaf-eating season, congruent with the significant increase in host body mass. Following season-specific FMT, the microbiota of the mouse model resembled that of the donor, and mice transplanted with the microbiota from the shoot-eating season grew faster and stored more fat. Mechanistic investigations revealed that butyrate extended the upregulation of hepatic circadian gene Per2, subsequently increasing phospholipid biosynthesis. Validation experiments further confirmed this causal relationship. This study demonstrated that seasonal shifts in the gut microbiome affect growth performance, facilitating a deeper understanding of host-microbe interactions in wild mammals., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

As of July 2021, the outbreak of coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has led to more than 200 million infections and more than 4.2 million deaths globally. Complications of severe COVID-19 include acute kidney injury, liver dysfunction, cardiomyopathy, and coagulation dysfunction. Thus, there is an urgent need to identify proteins and genetic factors associated with COVID-19 susceptibility and outcome. We comprehensively reviewed recent findings of host-SARS-CoV-2 interactome analyses. To identify genetic variants associated with COVID-19, we focused on the findings from genome and transcriptome wide association studies (GWAS and TWAS) and bioinformatics analysis. We described established human proteins including ACE2, TMPRSS2, 40S ribosomal subunit, ApoA1, TOM70, HLA-A, and PALS1 interacting with SARS-CoV-2 based on cryo-electron microscopy results. Furthermore, we described approximately 1000 human proteins showing evidence of interaction with SARS-CoV-2 and highlighted host cellular processes such as innate immune pathways affected by infection. We summarized the evidence on more than 20 identified candidate genes in COVID-19 severity. Predicted deleterious and disruptive genetic variants with possible effects on COVID-19 infectivity have been also summarized. These findings provide novel insights into SARS-CoV-2 biology and infection as well as potential strategies for development of novel COVID therapeutic targets and drug repurposing., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Metabolites derived from symbionts have the potential to regulate host pathophysiological conditions, especially in the gut. In a recent issue of Nature, Oh et al. clarify unique molecular structures of α-galactosylceramides derived from B. fragilis and their immune-modulatory functions against host natural killer T (NKT) cells., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The clathrin coat assembly protein AP180 drives endocytosis, which is crucial for numerous physiological events, such as the internalization and recycling of receptors, uptake of neurotransmitters and entry of viruses, including SARS-CoV-2, by interacting with clathrin. Moreover, dysfunction of AP180 underlies the pathogenesis of Alzheimer's disease. Therefore, it is important to understand the mechanisms of assembly and, especially, disassembly of AP180/clathrin-containing cages. Here, we identified AP180 as a novel phosphatidic acid (PA)-binding protein from the mouse brain. Intriguingly, liposome binding assays using various phospholipids and PA species revealed that AP180 most strongly bound to 1-stearoyl-2-docosahexaenoyl-PA (18:0/22:6-PA) to a comparable extent as phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ), which is known to associate with AP180. An AP180 N-terminal homology domain (1-289 aa) interacted with 18:0/22:6-PA, and a lysine-rich motif (K38-K39-K40) was essential for binding. The 18:0/22:6-PA in liposomes in 100 nm diameter showed strong AP180-binding activity at neutral pH. Notably, 18:0/22:6-PA significantly attenuated the interaction of AP180 with clathrin. However, PI(4,5)P 2 did not show such an effect. Taken together, these results indicate the novel mechanism by which 18:0/22:6-PA selectively regulates the disassembly of AP180/clathrin-containing cages., Competing Interests: Declaration of competing interest All authors have declared no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Appended to the 5' end of nascent RNA polymerase II transcripts is 7-methyl guanosine (m 7 G-cap) that engages nuclear cap-binding complex (CBC) to facilitate messenger RNA (mRNA) maturation. Mature mRNAs exchange CBC for eIF4E, the rate-limiting translation factor that is controlled through mTOR. Experiments in immune cells have now documented HIV-1 incompletely processed transcripts exhibited hypermethylated m 7 G-cap and that the down-regulation of the trimethylguanosine synthetase-1-reduced HIV-1 infectivity and virion protein synthesis by several orders of magnitude. HIV-1 cap hypermethylation required nuclear RNA helicase A (RHA)/DHX9 interaction with the shape of the 5' untranslated region (UTR) primer binding site (PBS) segment. Down-regulation of RHA or the anomalous shape of the PBS segment abrogated hypermethylated caps and derepressed eIF4E binding for virion protein translation during global down-regulation of host translation. mTOR inhibition was detrimental to HIV-1 proliferation and attenuated Tat, Rev, and Nef synthesis. This study identified mutually exclusive translation pathways and the calibration of virion structural/accessory protein synthesis with de novo synthesis of the viral regulatory proteins. The hypermethylation of select, viral mRNA resulted in CBC exchange to heterodimeric CBP80/NCBP3 that expanded the functional capacity of HIV-1 in immune cells., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Nuclear pore complexes (NPC) regulate molecular traffics on nuclear envelope, which plays crucial roles during cell fate specification and diseases. The viral accessory protein NSP9 of SARS-CoV-2 is reported to interact with nucleoporin 62 (NUP62), a structural component of the NPC, but its biological impact on the host cell remain obscure. Here, we established new cell line models with ectopic NSP9 expression and determined the subcellular destination and biological functions of NSP9. Confocal imaging identified NSP9 to be largely localized in close proximity to the endoplasmic reticulum. In agreement with the subcellular distribution of NSP9, association of NSP9 with NUP62 was observed in cytoplasm. Furthermore, the overexpression of NSP9 correlated with a reduction of NUP62 expression on the nuclear envelope, suggesting that attenuating NUP62 expression might have contributed to defective NPC formation. Importantly, the loss of NUP62 impaired translocation of p65, a subunit of NF-κB, upon TNF-α stimulation. Concordantly, NSP9 over-expression blocked p65 nuclear transport. Taken together, these data shed light on the molecular mechanisms underlying the modulation of host cells during SARS-CoV-2 infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Research on oxidants and electrophiles has shifted from focusing on damage to biomolecules to the more fine-grained physiological arena. Redox transitions as excursions from a steady-state redox set point are continually ongoing in maintenance of redox balance. Current excitement on these topics results from the fact that recent research provided mechanistic insight, which gives rise to more concrete and differentiated questions. This Commentary focuses on redox eustress and the feedback restoration of steady state as concepts in active maintenance of physiological health, with brief discussion of redox stress response to viral infection, exemplified by COVID-19., (© 2021 The Authors. IUBMB Life published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

MicroRNAs (miRNAs) involved host-virus interaction, affecting the replication or pathogenesis of several viruses. Although avian leukosis virus subgroup J (ALV-J) has been one of the most studied avian viruses, the effects of various host miRNAs on ALV-J infection and its underlying molecular mechanisms are still unclear. Here, we reported that gga-miR-200b-3p acts as a positive host factor enhancing ALV-J replication. We found that gga-miR-200b-3p was increased in response to ALV-J infection in host cells, and that gga-miR-200b-3p effectively enhanced ALV-J replication via targeting host protein dual-specificity phosphatase 1 (DUSP1). Collectively, these findings highlight a crucial role of gga-miR-200b-3p in ALV-J replication., (Copyright © 2021 Elsevier B.V. All rights reserved.)