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The involvement of host immunity in the gut microbiota-mediated colonization resistance to Clostridioides difficile infection (CDI) is incompletely understood. Here, we show that interleukin (IL)-22, induced by colonization of the gut microbiota, is crucial for the prevention of CDI in human microbiota-associated (HMA) mice. IL-22 signaling in HMA mice regulated host glycosylation, which enabled the growth of succinate-consuming bacteria Phascolarctobacterium spp. within the gut microbiome. Phascolarctobacterium reduced the availability of luminal succinate, a crucial metabolite for the growth of C. difficile , and therefore prevented the growth of C. difficile . IL-22-mediated host N -glycosylation is likely impaired in patients with ulcerative colitis (UC) and renders UC-HMA mice more susceptible to CDI. Transplantation of healthy human-derived microbiota or Phascolarctobacterium reduced luminal succinate levels and restored colonization resistance in UC-HMA mice. IL-22-mediated host glycosylation thus fosters the growth of commensal bacteria that compete with C. difficile for the nutritional niche. In germ-free mice colonized with human microbiota, mucosal IL-22 signaling promotes the growth of succinate-consuming commensal bacteria via host mucus glycosylation, and transplantation of these bacteria limits Clostridioides difficile infection.

Developing general principles of host–microorganism interactions necessitates a robust understanding of the eco-evolutionary processes that structure microbiota. Phylosymbiosis, or patterns of microbiome composition that can be predicted by host phylogeny, is a unique framework for interrogating these processes. Identifying the contexts in which phylosymbiosis does and does not occur facilitates an evaluation of the relative importance of different ecological processes in shaping the microbial community. In this Review, we summarize the prevalence of phylosymbiosis across the animal kingdom on the basis of the current literature and explore the microbial community assembly processes and related host traits that contribute to phylosymbiosis. We find that phylosymbiosis is less prevalent in taxonomically richer microbiomes and hypothesize that this pattern is a result of increased stochasticity in the assembly of complex microbial communities. We also note that despite hosting rich microbiomes, mammals commonly exhibit phylosymbiosis. We hypothesize that this pattern is a result of a unique combination of mammalian traits, including viviparous birth, lactation and the co-evolution of haemochorial placentas and the eutherian immune system, which compound to ensure deterministic microbial community assembly. Examining both the individual and the combined importance of these traits in driving phylosymbiosis provides a new framework for research in this area moving forward.In this Review, Mallott and Amato summarize the prevalence of phylosymbiosis across the animal kingdom and explore the microbial community assembly processes and related host traits that contribute to phylosymbiosis. They find that phylosymbiosis is less prevalent in taxonomically richer microbiomes across the animal kingdom, except in mammals, perhaps owing to a unique combination of mammalian traits that influence the microbiota.

The airway microbiome has an important role in asthma pathophysiology. However, little is known on the relationships between the airway microbiome of asthmatic children, loss of asthma control, and severe exacerbations. Here we report that the microbiota’s dynamic patterns and compositions are related to asthma exacerbations. We collected nasal blow samples (n = 319) longitudinally during a clinical trial at 2 time-points within one year: randomization when asthma is under control, and at time of early loss of asthma control (yellow zone (YZ)). We report that participants whose microbiota was dominated by the commensal Corynebacterium   +   Dolosigranulum cluster at RD experience the lowest rates of YZs (p = 0.005) and have longer time to develop at least 2 episodes of YZ (p = 0.03). The airway microbiota have changed from randomization to YZ. A switch from the Corynebacterium   +   Dolosigranulum cluster at randomization to the Moraxella- cluster at YZ poses the highest risk of severe asthma exacerbation (p = 0.04). Corynebacterium’s relative abundance at YZ is inversely associated with severe exacerbation (p = 0.002). How the airway microbiome influences asthma pathophysiology remains unclear. Here, the authors analyse nasal samples of cohort of school-age children with persistent asthma and find that the microbiota’s patterns and composition at time of early loss of asthma control associate with severe asthma exacerbations.

Circular RNAs (circRNAs) are new members of the long noncoding RNA families and have been identified in a variety of organisms, including plants, animals, and humans. Accumulating data indicate that circRNAs perform multiple functions in a variety of cellular processes associated with human diseases, such as Alzheimer’s disease and cancer; however, the roles of circRNAs in virus infection have been largely uninvestigated. Virus-host interactions are complicated processes, and multiple cellular proteins promote or inhibit viral replication through different mechanisms. Recent progress has implicated circular RNAs (circRNAs) in cancer biology and progression; however, the role of circRNAs in viral infection remains largely unclear. Here, we detected 11,620 circRNAs in A549 cells and found that 411 of them were differentially expressed in influenza virus-infected A549 cells. We characterized a novel intronic circRNA, AIVR, that was upregulated in influenza virus-infected A549 cells and found that silencing of AIVR significantly promoted influenza virus replication in A549 cells. We further found that AIVR predominantly localizes in the cytoplasm and works as a microRNA (miRNA) sponge. One of the miRNAs absorbed by AIVR binds the mRNA of CREBBP, which is an important component of the large nucleoprotein complex interferon beta (IFN-β) enhanceosome that accelerates IFN-β production. AIVR overexpression significantly increased the mRNA and protein levels of IFN-β in the influenza virus-infected A549 cells. Therefore, the upregulation of AIVR is a cellular antiviral strategy, with AIVR exerting its antiviral effect by absorbing miRNA and promoting the expression of CREBBP to facilitate IFN-β production. Our study provides new insights into the roles of circRNAs in the cellular innate antiviral response. IMPORTANCE Circular RNAs (circRNAs) are new members of the long noncoding RNA families and have been identified in a variety of organisms, including plants, animals, and humans. Accumulating data indicate that circRNAs perform multiple functions in a variety of cellular processes associated with human diseases, such as Alzheimer’s disease and cancer; however, the roles of circRNAs in virus infection have been largely uninvestigated. In this study, we investigated the cellular circRNA response upon influenza virus infection and found that 411 circRNAs were differentially expressed in the virus-infected cells. We identified a novel human intronic circRNA (we named AIVR) that antagonizes influenza virus replication. Upregulated circRNA AIVR absorbs an miRNA that binds the mRNA of CREBBP, leading to an increase in the cellular expression of CREBBP and then accelerating IFN-β production. This study advances the understanding of the roles of circRNAs in the cellular innate antiviral response.

Reciprocal, intimate relationships between the human microbiome and the host immune system are shaped by past microbial encounters and prepare the host for future ones. Antibiotics and other antimicrobials leave their mark on both the microbiome and host immunity. Antimicrobials alter the structure of the microbiota, expand the host-specific pool of antimicrobial-resistance genes and organisms, degrade the protective effects of the microbiota against invasion by pathogens, and may impair vaccine efficacy. Through these effects on the microbiome they may affect immune responses. Vaccines that exert protective or therapeutic effects against pathogens may reduce the use of antimicrobials, the development and spread of antimicrobial resistance, and the harmful impacts of these drugs on the microbiome. Other strategies involving manipulation of the microbiome to deplete antibiotic-resistant organisms or to enhance immune responses to vaccines may prove valuable in addressing antimicrobial resistance as well. This article describes the intersections of immunity, microbiome and antimicrobial exposure, and the use of vaccines and other alternative strategies for the control and management of antimicrobial resistance.

In the last century, life expectancy has increased considerably, thanks to the introduction of antibiotics, hygiene and vaccines that have contributed to the cure and prevention of many infectious diseases. The era of antimicrobial therapy started in the nineteenth century with the identification of chemical compounds with antimicrobial properties. However, immediately after the introduction of these novel drugs, microorganisms started to become resistant through different strategies. Although resistance mechanisms were already present before antibiotic introduction, their large-scale use and mis-use have increased the number of resistant microorganisms. Rapid spreading of mobile elements by horizontal gene transfer such as plasmids and integrative conjugative elements (ICE) carrying multiple resistance genes has dramatically increased the worldwide prevalence of relevant multi drug-resistant human pathogens such as , and . Today, antimicrobial resistance (AMR) remains one of the major global concerns to be addressed and only global efforts could help in finding a solution. In terms of magnitude the economic impact of AMR is estimated to be comparable to that of climate global change in 2030. Although antibiotics continue to be essential to treat such infections, non-antibiotic therapies will play an important role in limiting the increase of antibiotic resistant microorganisms. Among non-antibiotic strategies, vaccines and therapeutic monoclonal antibodies (mAbs) play a strategic role. In this review, we will summarize the evolution and the mechanisms of antibiotic resistance, and the impact of AMR on life expectancy and economics.

The regulatory noncoding small RNAs (sRNAs) of bacteria are key elements influencing gene expression; however, there has been little evidence that beneficial bacteria use these molecules to communicate with their animal hosts. We report here that the bacterial sRNA SsrA plays an essential role in the light-organ symbiosis between Vibrio fischeri and the squid Euprymna scolopes . The symbionts load SsrA into outer membrane vesicles, which are transported specifically into the epithelial cells surrounding the symbiont population in the light organ. Although an SsrA-deletion mutant (Δ ssrA ) colonized the host to a normal level after 24 h, it produced only 2/10 the luminescence per bacterium, and its persistence began to decline by 48 h. The host’s response to colonization by the Δ ssrA strain was also abnormal: the epithelial cells underwent premature swelling, and host robustness was reduced. Most notably, when colonized by the Δ ssrA strain, the light organ differentially up-regulated 10 genes, including several encoding heightened immune-function or antimicrobial activities. This study reveals the potential for a bacterial symbiont’s sRNAs not only to control its own activities but also to trigger critical responses promoting homeostasis in its host. In the absence of this communication, there are dramatic fitness consequences for both partners.

Salmonellosis and listeriosis together accounted for more than one third of foodborne illnesses in the United States and almost half the hospitalizations for gastrointestinal diseases in 2018 while tuberculosis afflicted over 10 million people worldwide causing almost 2 million deaths. Regardless of the intrinsic virulence differences among Listeria monocytogenes , Salmonella enterica and Mycobacterium tuberculosis , these intracellular pathogens share the ability to survive and persist inside the macrophage and other cells and thrive in iron rich environments. Interferon-gamma (IFN-γ) is a central cytokine in host defense against intracellular pathogens and has been shown to promote iron export in macrophages. We hypothesize that IFN-γ decreases iron availability to intracellular pathogens consequently limiting replication in these cells. In this study, we show that IFN-γ regulates the expression of iron-related proteins hepcidin, ferroportin, and ferritin to induce iron export from macrophages. Listeria monocytogenes , S . enterica , and M . tuberculosis infections significantly induce iron sequestration in human macrophages. In contrast, IFN-γ significantly reduces hepcidin secretion in S . enterica and M . tuberculosis infected macrophages. Similarly, IFN-γ-activated macrophages express higher ferroportin levels than untreated controls even after infection with L . monocytogenes bacilli; bacterial infection greatly down-regulates ferroportin expression. Collectively, IFN-γ significantly inhibits pathogen-associated intracellular iron sequestration in macrophages and consequently retards the growth of intracellular bacterial pathogens by decreasing iron availability.

Abstract Background BCG vaccination has beneficial nonspecific (heterologous) effects that protect against nonmycobacterial infections. We have previously reported that BCG vaccination at birth alters in vitro cytokine responses to heterologous stimulants in the neonatal period. This study investigated heterologous responses in 167 infants in the same trial 7 months after randomization. Methods A whole-blood assay was used to interrogate in vitro cytokine responses to heterologous stimulants (killed pathogens) and Toll-like receptor (TLR) ligands. Results Compared to BCG-naive infants, BCG-vaccinated infants had increased production of interferon gamma (IFN-γ) and monokine induced by gamma interferon (MIG) (CXCL9) in response to mycobacterial stimulation and decreased production of IFN-γ in response to heterologous stimulation and TLR ligands. Reduced IFN-γ responses were attributable to a decrease in the proportion of infants who mounted a detectable IFN-γ response. BCG-vaccinated infants also had increased production of MIG (CXCL9) and interleukin-8 (IL-8), and decreased production of IL-10, macrophage inflammatory protein-1α (MIP-1α), and MIP-1β, the pattern of which varied by stimulant. IL-1Ra responses following TLR1/2 (Pam3CYSK4) stimulation were increased in BCG-vaccinated infants. Both sex and maternal BCG vaccination status influenced the effect of neonatal BCG vaccination. Conclusions BCG vaccination leads to changes in IFN-γ responsiveness to heterologous stimulation. BCG-induced changes in other cytokine responses to heterologous stimulation vary by pathogen. Neonatal BCG vaccination results in a decreased proportion of infants mounting an IFN-γ response to heterologous stimulation at 7 months of age. Both sex and maternal BCG vaccination status influenced the effect of BCG vaccination on heterologous cytokine responses.

Animals use epithelial barriers to protect themselves from the commensal and pathogenic microorganisms they encounter. These epithelia adapt their function in response to microbial-derived signals, and impairments in these adaptive responses can lead to infection and inflammatory disorders. Improved understanding of the mechanisms underlying host adaptation to microbes can thus be expected to lead to new approaches for promoting health in humans and other animals. Here, we identify the epithelial transcription factor E74-like ETS transcription factor 3 (Elf3) as a mediator of host-microbe interactions in zebrafish. Functional genomic approaches indicated that Elf3 is upregulated by microbiota in both mouse and zebrafish. Using elf3 mutant zebrafish, we find that elf3 mediates induction of host immune responses in larval stages and protects against immune-related pathologies and health deterioration in adults. These results advance our understanding of the transcriptional mechanisms mediating host responses to microbes and provide a new Elf3 deficiency model of epithelial and immune pathology.