Mucosal Immunity

Uncontrolled interferon γ (IFNγ)-mediated T-cell responses to commensal microbiota are a driver of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is crucial for controlling these T-cell responses, but the precise mechanism of inhibition remains unclear. A better understanding of how IL-10 exerts its suppressive function may allow identification of individuals with suboptimal IL-10 function among the heterogeneous population of IBD patients. Using cells from patients with an IL10RA deficiency or STAT3 mutations, we demonstrate that IL-10 signaling in monocyte-derived dendritic cells (moDCs), but not T cells, is essential for controlling IFNγ-secreting CD4+ T cells. Deficiency in IL-10 signaling dramatically increased IL-1β release by moDCs. IL-1β boosted IFNγ secretion by CD4+ T cells either directly or indirectly by stimulating moDCs to secrete IL-12. As predicted a signature of IL-10 dysfunction was observed in a subgroup of pediatric IBD patients having higher IL-1β expression in activated immune cells and macroscopically affected intestinal tissue. In agreement, reduced IL10RA expression was detected in peripheral blood mononuclear cells and a subgroup of pediatric IBD patients exhibited diminished IL-10 responsiveness. Our data unveil an important mechanism by which IL-10 controls IFNγ-secreting CD4+ T cells in humans and identifies IL-1β as a potential classifier for a subgroup of IBD patients.

Persistent immune activation in virologically suppressed HIV-1 patients, which may be the consequence of various factors including microbial translocation, is a major cause of comorbidities. We have previously shown that different profiles of immune activation may be distinguished in virological responders. Here, we tested the hypothesis that a particular profile might be the consequence of microbial translocation. To this aim, we measured 64 soluble and cell surface markers of inflammation and CD4+ and CD8+ T-cell, B cell, monocyte, NK cell, and endothelial activation in 140 adults under efficient antiretroviral therapy, and classified patients and markers using a double hierarchical clustering analysis. We also measured the plasma levels of the microbial translocation markers bacterial DNA, lipopolysaccharide binding protein (LBP), intestinal-fatty acid binding protein, and soluble CD14. We identified five different immune activation profiles. Patients with an immune activation profile characterized by a high percentage of CD38+CD8+ T-cells and a high level of the endothelial activation marker soluble Thrombomodulin, presented with higher LBP mean (± SEM) concentrations (33.3 ± 1.7 vs. 28.7 ± 0.9 μg/mL, p = 0.025) than patients with other profiles. Our data are consistent with the hypothesis that the immune activation profiles we described are the result of different etiological factors. We propose a model, where particular causes of immune activation, as microbia

Respiratory syncytial virus (RSV) is the most prevalent viral etiological agent of acute respiratory tract infection. Although RSV affects people of all ages, the disease is more severe in infants and causes significant morbidity and hospitalization in young children and in the elderly. Host factors, including an immature immune system in infants, low lymphocyte levels in patients under 5 years old, and low levels of RSV-specific neutralizing antibodies in the blood of adults over 65 years of age, can explain the high susceptibility to RSV infection in these populations. Other host factors that correlate with severe RSV disease include high concentrations of proinflammatory cytokines such as interleukins (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and thymic stromal lymphopoitein (TSLP), which are produced in the respiratory tract of RSV-infected individuals, accompanied by a strong neutrophil response. In addition, data from studies of RSV infections in humans and in animal models revealed that this virus suppresses adaptive immune responses that could eliminate it from the respiratory tract. Here, we examine host factors that contribute to RSV pathogenesis based on an exhaustive review of in vitro infection in humans and in animal models to provide insights into the design of vaccines and therapeutic tools that could prevent diseases caused by RSV.

Despite broad scientific interest in harnessing the power of Earth’s microbiomes, knowledge gaps hinder their efficient use for addressing urgent societal and environmental challenges. We argue that structuring research and technology developments around a design–build–test–learn (DBTL) cycle will advance microbiome engineering and spur new discoveries of the basic scientific principles governing microbiome function. In this Review, we present key elements of an iterative DBTL cycle for microbiome engineering, focusing on generalizable approaches, including top-down and bottom-up design processes, synthetic and self-assembled construction methods, and emerging tools to analyse microbiome function. These approaches can be used to harness microbiomes for broad applications related to medicine, agriculture, energy and the environment. We also discuss key challenges and opportunities of each approach and synthesize them into best practice guidelines for engineering microbiomes. We anticipate that adoption of a DBTL framework will rapidly advance microbiome-based biotechnologies aimed at improving human and animal health, agriculture and enabling the bioeconomy. Microbiome engineering has many potential applications, ranging from agriculture to medicine. In this Review, Lawson, McMahon and colleagues guide us through the design–build–test–learn cycle that has been successful in many disciplines and explain how it applies to microbiome engineering.

Citrobacter rodentium is an extracellular enteric mouse-specific pathogen used to model infections with human pathogenic Escherichia coli and inflammatory bowel disease. C. rodentium injects type III secretion system effectors into intestinal epithelial cells (IECs) to target inflammatory, metabolic and cell survival pathways and establish infection. While the host responds to infection by activating innate and adaptive immune signalling, required for clearance, the IECs respond by rapidly shifting bioenergetics to aerobic glycolysis, which leads to oxygenation of the epithelium, an instant expansion of mucosal-associated commensal Enterobacteriaceae and a decline of obligate anaerobes. Moreover, infected IECs reprogramme intracellular metabolic pathways, characterized by simultaneous activation of cholesterol biogenesis, import and efflux, leading to increased serum and faecal cholesterol levels. In this Review we summarize recent advances highlighting the intimate relationship between C. rodentium pathogenesis, metabolism and the gut microbiota. Citrobacter rodentium, an extracellular mouse-specific enteric pathogen, provides a robust model for the study of physiological host–pathogen–microbiota interactions. In this Review, Frankel and colleagues highlight how the C. rodentium model has advanced our understanding of enteric infections and inflammatory bowel disease, in particular changes to host metabolism and inflammation.

Hundreds of commensal bacterial species inhabit the gastrointestinal tract. This diverse microbial ecosystem plays a crucial role in the prevention and resolution of infectious diseases. In thi