Infection or immunization can reprogram innate immune cells generating memory responses with broad protection against subsequent infection, a process referred to as “trained immunity.” A new study by ...Stacy and colleagues demonstrates that, following acute infection, the commensal microbiota can also be “trained” to enhance colonization resistance against heterologous infection.
Infection or immunization can reprogram innate immune cells generating memory responses with broad protection against subsequent infection, a process referred to as “trained immunity.” A new study by Stacy and colleagues demonstrates that, following acute infection, the commensal microbiota can also be “trained” to enhance colonization resistance against heterologous infection.
Dendritic cells (DCs) play an important role in CD4(+) T helper (Th) cell differentiation and in the initiation of both protective and pathogenic immunity. Granulocyte/macrophage colony-stimulating ...factor (GM-CSF) is a DC growth factor critical for the induction of experimental autoimmune encephalomyelitis (EAE) and other autoimmune diseases, yet its mechanism of action in vivo is not fully defined. We show that GM-CSF is directly required for the accumulation of radiosensitive dermal-derived langerin(+)CD103(+) DCs in the skin and peripheral lymph nodes under steady-state and inflammatory conditions. Langerin(+)CD103(+) DCs stimulated naive myelin-reactive T cells to proliferate and produce IFN-gamma and IL-17. They were superior to other DC subsets in inducing expression of T-bet and promoting Th1 cell differentiation. Ablation of this subset in vivo conferred resistance to EAE. The current report reveals a previously unidentified role for GM-CSF in DC ontogeny and identifies langerin(+)CD103(+) DCs as an important subset in CD4(+) T cell-mediated autoimmune disease.
There is rapidly growing awareness of microbiome assembly and function in early-life gut health. Although many factors, such as antibiotic use and highly processed diets, impinge on this process, ...most research has focused on people residing in high-income countries. However, much of the world’s population lives in low- and middle-income countries (LMICs), where, in addition to erratic antibiotic use and suboptimal diets, these groups experience unique challenges. Indeed, many children in LMICs are infected with intestinal helminths. Although helminth infections are strongly associated with diverse developmental co-morbidities and induce profound microbiome changes, few studies have directly examined whether intersecting pathways between these components of the holobiont shape health outcomes in early life. Here, we summarize microbial colonization within the first years of human life, how helminth-mediated changes to the gut microbiome may affect postnatal growth, and why more research on this relationship may improve health across the lifespan.
Intestinal helminth infection and delayed gut microbiome maturation have known individual developmental and long-term adverse health outcomes. Yet, their combined effects in early life remain poorly described. Here, Bogza et al. detail these complex interactions and suggest experimental models to explore their emergent properties on immune, microbial, and infant development.
Plasticity of the intestinal epithelium is a source of host vulnerability for helminth manipulation.Intestinal helminths alter the function of epithelial cells at diverse stages of lineage ...differentiation.Organoid-based studies are emerging as a powerful experimental approach to studying direct helminth–host interactions under more physiological conditions.The investigation of direct helminth–host interactions at the epithelial interface is the next frontier of host–parasite interactions.
Intestinal helminths remain highly pervasive throughout the animal kingdom by modulating multiple aspects of the host immune response. The intestinal epithelium functions as a physical barrier as well as a sentinel innate immune tissue with the ability to sense and respond to infectious agents. Although helminths form intimate interactions with the epithelium, comprehensive knowledge about host–helminth interactions at this dynamic interface is lacking. In addition, little is known about the ability of helminths to directly shape the fate of this barrier tissue. Here, we review the diverse pathways by which helminths regulate the epithelium and highlight the emerging field of direct helminth regulation of intestinal stem cell (ISC) fate and function.
Since the vasculature is tasked with circulating blood from a central pump (the heart) to every tissue, it must be intricately branched. The celiac trunk supplies blood to the stomach, and the ...superior and inferior mesenteric arteries supply the small intestine, the proximal colon and distal colon, respectively. In response to pathogen invasion or loss of barrier integrity, both IECs and tissue-resident leukocytes secrete a host of factors such as cytokines, reactive oxygen species, and lipid mediators that increase endothelial cell expression of chemokine receptors and integrins that promote immune cell extravasation into the lamina propria. ...the tissue damage and requirements for host defense are unique to each parasite.
Dendritic cells (DCs) are potent inducers of T cell immunity, and autologous DC vaccination holds promise for the treatment of cancers and chronic infectious diseases. In practice, however, ...therapeutic vaccines of this type have had mixed success. In this article, we show that brief exposure to inhibitors of mechanistic target of rapamycin (mTOR) in DCs during the period that they are responding to TLR agonists makes them particularly potent activators of naive CD8+ T cells and able to enhance control of B16 melanoma in a therapeutic autologous vaccination model in the mouse. The improved performance of DCs in which mTOR has been inhibited is correlated with an extended life span after activation and prolonged, increased expression of costimulatory molecules. Therapeutic autologous vaccination with DCs treated with TLR agonists plus the mTOR inhibitor rapamycin results in improved generation of Ag-specific CD8+ T cells in vivo and improved antitumor immunity compared with that observed with DCs treated with TLR agonists alone. These findings define mTOR as a molecular target for augmenting DC survival and activation, and document a novel pharmacologic approach for enhancing the efficacy of therapeutic autologous DC vaccination.
Mechanisms regulating B cell development, activation, education in the germinal center (GC) and differentiation, underpin the humoral immune response. Protein arginine methyltransferase 5 (Prmt5), ...which catalyzes most symmetric dimethyl arginine protein modifications, is overexpressed in B cell lymphomas but its function in normal B cells is poorly defined. Here we show that Prmt5 is necessary for antibody responses and has essential but distinct functions in all proliferative B cell stages in mice. Prmt5 is necessary for B cell development by preventing p53-dependent and p53-independent blocks in Pro-B and Pre-B cells, respectively. By contrast, Prmt5 protects, via p53-independent pathways, mature B cells from apoptosis during activation, promotes GC expansion, and counters plasma cell differentiation. Phenotypic and RNA-seq data indicate that Prmt5 regulates GC light zone B cell fate by regulating transcriptional programs, achieved in part by ensuring RNA splicing fidelity. Our results establish Prmt5 as an essential regulator of B cell biology.
Parasitic helminths cause significant damage as they migrate through host tissues to complete their life cycle. While chronic helminth infections are characterized by a well-described Type 2 immune ...response, the early, tissue-invasive stages are not well understood. Here we investigate the immune pathways activated during the early stages of Heligmosomoides polygyrus bakeri (Hpb), a natural parasitic roundworm of mice. In contrast to the Type 2 immune response present at later stages of infection, a robust Type 1 immune signature including IFNg production was dominant at the time of parasite invasion and granuloma formation. This early response was associated with an accumulation of activated Natural Killer (NK) cells, with no increase of other innate lymphoid cell populations. Parabiosis and confocal microscopy studies indicated that NK cells were recruited from circulation to the small intestine, where they surrounded parasitic larvae. NK cell recruitment required IFNγ receptor signaling, but was independent of CXCR3 expression. The depletion of tissue-infiltrating NK cells altered neither worm burden nor parasite fitness, but increased vascular injury, suggesting a role for NK cells in mediating tissue protection. Together, these data identify an unexpected role for NK cells in promoting disease tolerance during the invasive stage of an enteric helminth infection.
Since the vast majority of species solely rely on innate immunity for host defense, it stands to reason that a critical evolutionary trait like immunological memory evolved in this primitive branch ...of our immune system. There is ample evidence that vaccines such as bacillus Calmette-Guérin (BCG) induce protective innate immune memory responses (trained immunity) against heterologous pathogens. Here we show that while BCG vaccination significantly reduces morbidity and mortality against influenza A virus (IAV), it fails to provide protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In contrast to IAV, SARS-CoV-2 infection leads to unique pulmonary vasculature damage facilitating viral dissemination to other organs, including the bone marrow (BM), a central site for BCG-mediated trained immunity. Finally, monocytes from BCG-vaccinated individuals mount an efficient cytokine response to IAV infection, while this response is minimal following SARS-CoV-2. Collectively, our data suggest that the protective capacity of BCG vaccination is contingent on viral pathogenesis and tissue tropism.
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•BCG vaccination provides significant protection against IAV in mice and hamsters•BCG provides no protection against SARS-CoV-2 in mice and hamsters•SARS-CoV-2 induces pulmonary hemorrhage and disseminates to the bone marrow•Monocytes from BCG-vaccinated humans induce more cytokines to IAV than SARS-CoV-2
Kaufmann et al. show that BCG vaccination protects mice and hamsters against influenza, but not SARS-CoV-2. The distinct tropism of SARS-CoV-2 for pulmonary endothelial cells may lead to lung hemorrhage and systemic viral dissemination. Thus, the protection of BCG against viral pathogens is mainly determined by pathogenesis of infections.
Abstract
Background
Inflammatory bowel diseases (IBDs) including Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by chronic and debilitating gut inflammation. Altered bacterial ...communities of the intestine are strongly associated with IBD initiation and progression. The gut virome, which is primarily composed of bacterial viruses (bacteriophages, phages), is thought to be an important factor regulating and shaping microbial communities in the gut. While alterations in the gut virome have been observed in IBD patients, the contribution of these viruses to alterations in the bacterial community and heightened inflammatory responses associated with IBD patients remains largely unknown.
Results
Here, we performed in vivo microbial cross-infection experiments to follow the effects of fecal virus-like particles (VLPs) isolated from UC patients and healthy controls on bacterial diversity and severity of experimental colitis in human microbiota-associated (HMA) mice. Shotgun metagenomics confirmed that several phages were transferred to HMA mice, resulting in treatment-specific alterations in the gut virome. VLPs from healthy and UC patients also shifted gut bacterial diversity of these mice, an effect that was amplified during experimental colitis. VLPs isolated from UC patients specifically altered the relative abundance of several bacterial taxa previously implicated in IBD progression. Additionally, UC VLP administration heightened colitis severity in HMA mice, as indicated by shortened colon length and increased pro-inflammatory cytokine production. Importantly, this effect was dependent on intact VLPs.
Conclusions
Our findings build on recent literature indicating that phages are dynamic regulators of bacterial communities in the gut and implicate the intestinal virome in modulating intestinal inflammation and disease.
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