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1.
Annu Rev Immunol ; 36: 73-101, 2018 04 26.
Article in English | MEDLINE | ID: mdl-29144836

ABSTRACT

The cellular degradative pathway of autophagy has a fundamental role in immunity. Here, we review the function of autophagy and autophagy proteins in inflammation. We discuss how the autophagy machinery controls the burden of infectious agents while simultaneously limiting inflammatory pathologies, which often involves processes that are distinct from conventional autophagy. Among the newly emerging processes we describe are LC3-associated phagocytosis and targeting by autophagy proteins, both of which require many of the same proteins that mediate conventional autophagy. We also discuss how autophagy contributes to differentiation of myeloid and lymphoid cell types, coordinates multicellular immunity, and facilitates memory responses. Together, these functions establish an intimate link between autophagy, mucosal immunity, and chronic inflammatory diseases. Finally, we offer our perspective on current challenges and barriers to translation.


Subject(s)
Autophagy , Disease Susceptibility , Inflammation/etiology , Animals , Biomarkers , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immune System/cytology , Immune System/immunology , Immune System/metabolism , Immunomodulation , Inflammation/diagnosis , Inflammation/metabolism , Signal Transduction
2.
Nat Immunol ; 25(7): 1270-1282, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38877178

ABSTRACT

The relative and synergistic contributions of genetics and environment to interindividual immune response variation remain unclear, despite implications in evolutionary biology and medicine. Here we quantify interactive effects of genotype and environment on immune traits by investigating C57BL/6, 129S1 and PWK/PhJ inbred mice, rewilded in an outdoor enclosure and infected with the parasite Trichuris muris. Whereas cellular composition was shaped by interactions between genotype and environment, cytokine response heterogeneity including IFNγ concentrations was primarily driven by genotype with consequence on worm burden. In addition, we show that other traits, such as expression of CD44, were explained mostly by genetics on T cells, whereas expression of CD44 on B cells was explained more by environment across all strains. Notably, genetic differences under laboratory conditions were decreased following rewilding. These results indicate that nonheritable influences interact with genetic factors to shape immune variation and parasite burden.


Subject(s)
Gene-Environment Interaction , Mice, Inbred C57BL , Trichuriasis , Trichuris , Animals , Trichuris/immunology , Trichuriasis/immunology , Trichuriasis/parasitology , Mice , Hyaluronan Receptors/genetics , Hyaluronan Receptors/metabolism , B-Lymphocytes/immunology , Genotype , Interferon-gamma/metabolism , T-Lymphocytes/immunology , Female , Male
3.
Cell ; 179(7): 1441-1445, 2019 Dec 12.
Article in English | MEDLINE | ID: mdl-31835023

ABSTRACT

Despite being a staple of our science, the process of pre-publication peer review has few agreed-upon standards defining its goals or ideal execution. As a community of reviewers and authors, we assembled an evaluation format and associated specific standards for the process as we think it should be practiced. We propose that we apply, debate, and ultimately extend these to improve the transparency of our criticism and the speed with which quality data and ideas become public.


Subject(s)
Peer Review/standards , Biomedical Research/standards , Peer Review/methods , Periodicals as Topic/standards , Quality Improvement
4.
Cell ; 175(1): 36-37, 2018 09 20.
Article in English | MEDLINE | ID: mdl-30241612

ABSTRACT

Following an infection, a subset of individuals can remain disease free despite harboring a pathogen for a prolonged period. In this issue of Cell, Sanchez et al. demonstrate that a metabolically favorable host response can drive an otherwise lethal bacterial pathogen to abandon virulence and become a commensal microorganism.


Subject(s)
Asymptomatic Infections , Sugars , Bacteria , Humans , Symbiosis , Virulence
5.
Immunity ; 55(2): 237-253.e8, 2022 02 08.
Article in English | MEDLINE | ID: mdl-35081371

ABSTRACT

The Th17 cell-lineage-defining cytokine IL-17A contributes to host defense and inflammatory disease by coordinating multicellular immune responses. The IL-17 receptor (IL-17RA) is expressed by diverse intestinal cell types, and therapies targeting IL-17A induce adverse intestinal events, suggesting additional tissue-specific functions. Here, we used multiple conditional deletion models to identify a role for IL-17A in secretory epithelial cell differentiation in the gut. Paneth, tuft, goblet, and enteroendocrine cell numbers were dependent on IL-17A-mediated induction of the transcription factor ATOH1 in Lgr5+ intestinal epithelial stem cells. Although dispensable at steady state, IL-17RA signaling in ATOH1+ cells was required to regenerate secretory cells following injury. Finally, IL-17A stimulation of human-derived intestinal organoids that were locked into a cystic immature state induced ATOH1 expression and rescued secretory cell differentiation. Our data suggest that the cross talk between immune cells and stem cells regulates secretory cell lineage commitment and the integrity of the mucosa.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Intestinal Mucosa/cytology , Receptors, G-Protein-Coupled/metabolism , Receptors, Interleukin-17/metabolism , Stem Cells/metabolism , Animals , Cell Communication , Cell Differentiation/drug effects , Cell Lineage/drug effects , Colitis/chemically induced , Colitis/metabolism , Colitis/pathology , Dextran Sulfate/adverse effects , Humans , Interleukin-17/metabolism , Interleukin-17/pharmacology , Intestinal Mucosa/metabolism , Intestines/drug effects , Intestines/metabolism , Intestines/pathology , Mice , Mice, Knockout , NF-kappa B/metabolism , Receptors, Interleukin-17/deficiency , SOX9 Transcription Factor/metabolism , Signal Transduction , Stem Cells/cytology
6.
Nature ; 627(8004): 620-627, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38448595

ABSTRACT

The fungus Candida albicans frequently colonizes the human gastrointestinal tract, from which it can disseminate to cause systemic disease. This polymorphic species can transition between growing as single-celled yeast and as multicellular hyphae to adapt to its environment. The current dogma of C. albicans commensalism is that the yeast form is optimal for gut colonization, whereas hyphal cells are detrimental to colonization but critical for virulence1-3. Here, we reveal that this paradigm does not apply to multi-kingdom communities in which a complex interplay between fungal morphology and bacteria dictates C. albicans fitness. Thus, whereas yeast-locked cells outcompete wild-type cells when gut bacteria are absent or depleted by antibiotics, hyphae-competent wild-type cells outcompete yeast-locked cells in hosts with replete bacterial populations. This increased fitness of wild-type cells involves the production of hyphal-specific factors including the toxin candidalysin4,5, which promotes the establishment of colonization. At later time points, adaptive immunity is engaged, and intestinal immunoglobulin A preferentially selects against hyphal cells1,6. Hyphal morphotypes are thus under both positive and negative selective pressures in the gut. Our study further shows that candidalysin has a direct inhibitory effect on bacterial species, including limiting their metabolic output. We therefore propose that C. albicans has evolved hyphal-specific factors, including candidalysin, to better compete with bacterial species in the intestinal niche.


Subject(s)
Candida albicans , Fungal Proteins , Gastrointestinal Microbiome , Hyphae , Intestines , Mycotoxins , Symbiosis , Animals , Female , Humans , Male , Mice , Bacteria/growth & development , Bacteria/immunology , Candida albicans/growth & development , Candida albicans/immunology , Candida albicans/metabolism , Candida albicans/pathogenicity , Fungal Proteins/metabolism , Gastrointestinal Microbiome/immunology , Hyphae/growth & development , Hyphae/immunology , Hyphae/metabolism , Immunoglobulin A/immunology , Intestines/immunology , Intestines/microbiology , Mycotoxins/metabolism , Virulence
7.
Immunity ; 53(2): 398-416.e8, 2020 08 18.
Article in English | MEDLINE | ID: mdl-32814028

ABSTRACT

Paneth cells are the primary source of C-type lysozyme, a ß-1,4-N-acetylmuramoylhydrolase that enzymatically processes bacterial cell walls. Paneth cells are normally present in human cecum and ascending colon, but are rarely found in descending colon and rectum; Paneth cell metaplasia in this region and aberrant lysozyme production are hallmarks of inflammatory bowel disease (IBD) pathology. Here, we examined the impact of aberrant lysozyme production in colonic inflammation. Targeted disruption of Paneth cell lysozyme (Lyz1) protected mice from experimental colitis. Lyz1-deficiency diminished intestinal immune responses to bacterial molecular patterns and resulted in the expansion of lysozyme-sensitive mucolytic bacteria, including Ruminococcus gnavus, a Crohn's disease-associated pathobiont. Ectopic lysozyme production in colonic epithelium suppressed lysozyme-sensitive bacteria and exacerbated colitis. Transfer of R. gnavus into Lyz1-/- hosts elicited a type 2 immune response, causing epithelial reprograming and enhanced anti-colitogenic capacity. In contrast, in lysozyme-intact hosts, processed R. gnavus drove pro-inflammatory responses. Thus, Paneth cell lysozyme balances intestinal anti- and pro-inflammatory responses, with implications for IBD.


Subject(s)
Clostridiales/immunology , Colitis, Ulcerative/pathology , Muramidase/genetics , Muramidase/metabolism , Paneth Cells/metabolism , Animals , Clostridiales/genetics , Colitis, Ulcerative/microbiology , Crohn Disease/pathology , Female , Gastrointestinal Microbiome/genetics , Goblet Cells/cytology , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , STAT6 Transcription Factor/genetics
8.
Nature ; 610(7932): 547-554, 2022 10.
Article in English | MEDLINE | ID: mdl-36198790

ABSTRACT

Loss of Paneth cells and their antimicrobial granules compromises the intestinal epithelial barrier and is associated with Crohn's disease, a major type of inflammatory bowel disease1-7. Non-classical lymphoid cells, broadly referred to as intraepithelial lymphocytes (IELs), intercalate the intestinal epithelium8,9. This anatomical position has implicated them as first-line defenders in resistance to infections, but their role in inflammatory disease pathogenesis requires clarification. The identification of mediators that coordinate crosstalk between specific IEL and epithelial subsets could provide insight into intestinal barrier mechanisms in health and disease. Here we show that the subset of IELs that express γ and δ T cell receptor subunits (γδ IELs) promotes the viability of Paneth cells deficient in the Crohn's disease susceptibility gene ATG16L1. Using an ex vivo lymphocyte-epithelium co-culture system, we identified apoptosis inhibitor 5 (API5) as a Paneth cell-protective factor secreted by γδ IELs. In the Atg16l1-mutant mouse model, viral infection induced a loss of Paneth cells and enhanced susceptibility to intestinal injury by inhibiting the secretion of API5 from γδ IELs. Therapeutic administration of recombinant API5 protected Paneth cells in vivo in mice and ex vivo in human organoids with the ATG16L1 risk allele. Thus, we identify API5 as a protective γδ IEL effector that masks genetic susceptibility to Paneth cell death.


Subject(s)
Apoptosis Regulatory Proteins , Crohn Disease , Genetic Predisposition to Disease , Intraepithelial Lymphocytes , Nuclear Proteins , Paneth Cells , Animals , Humans , Mice , Apoptosis Regulatory Proteins/metabolism , Cell Death , Crohn Disease/genetics , Crohn Disease/metabolism , Crohn Disease/pathology , Genetic Predisposition to Disease/genetics , Intestinal Mucosa/pathology , Nuclear Proteins/metabolism , Paneth Cells/pathology , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Intraepithelial Lymphocytes/immunology , Intraepithelial Lymphocytes/metabolism , Cell Survival , Organoids , Alleles
9.
Immunity ; 49(1): 16-18, 2018 07 17.
Article in English | MEDLINE | ID: mdl-30021142

ABSTRACT

How type 2 immune responses are initiated is obscure. Nadjsombati et al. (2018), along with two other studies (Lei et al., 2018; Schneider et al., 2018), show that tuft cells can initiate type 2 responses by recognizing the metabolite succinate produced by intestinal parasites.


Subject(s)
Diabetes Mellitus, Type 2 , Parasites , Animals , Intestines , Succinic Acid , Taste
10.
Nature ; 579(7798): 260-264, 2020 03.
Article in English | MEDLINE | ID: mdl-32132711

ABSTRACT

The production of pore-forming toxins that disrupt the plasma membrane of host cells is a common virulence strategy for bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA)1-3. It is unclear, however, whether host species possess innate immune mechanisms that can neutralize pore-forming toxins during infection. We previously showed that the autophagy protein ATG16L1 is necessary for protection against MRSA strains encoding α-toxin4-a pore-forming toxin that binds the metalloprotease ADAM10 on the surface of a broad range of target cells and tissues2,5,6. Autophagy typically involves the targeting of cytosolic material to the lysosome for degradation. Here we demonstrate that ATG16L1 and other ATG proteins mediate protection against α-toxin through the release of ADAM10 on exosomes-extracellular vesicles of endosomal origin. Bacterial DNA and CpG DNA induce the secretion of ADAM10-bearing exosomes from human cells as well as in mice. Transferred exosomes protect host cells in vitro by serving as scavengers that can bind multiple toxins, and improve the survival of mice infected with MRSA in vivo. These findings indicate that ATG proteins mediate a previously unknown form of defence in response to infection, facilitating the release of exosomes that serve as decoys for bacterially produced toxins.


Subject(s)
Autophagy-Related Proteins/metabolism , Bacterial Toxins/metabolism , Exosomes/metabolism , A549 Cells , ADAM10 Protein/metabolism , Animals , Bacterial Toxins/pharmacology , Cell Survival/drug effects , DNA, Bacterial/pharmacology , Exosomes/drug effects , Exosomes/ultrastructure , Female , HEK293 Cells , Humans , Male , Methicillin-Resistant Staphylococcus aureus/pathogenicity , Methicillin-Resistant Staphylococcus aureus/physiology , Mice , Mice, Inbred C57BL , Staphylococcal Infections/mortality
11.
EMBO J ; 40(19): e108863, 2021 10 01.
Article in English | MEDLINE | ID: mdl-34459017

ABSTRACT

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.


Subject(s)
Autophagy , Disease Susceptibility , Animals , Autophagy/drug effects , Autophagy/genetics , Autophagy/immunology , Biomarkers , Gene Expression Regulation , Genetic Predisposition to Disease , Homeostasis , Host-Pathogen Interactions , Humans , Organ Specificity , Signal Transduction
12.
PLoS Pathog ; 19(9): e1011647, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37738244

ABSTRACT

The bacterial microbiota promotes the life cycle of the intestine-dwelling whipworm Trichuris by mediating hatching of parasite eggs ingested by the mammalian host. Despite the enormous disease burden associated with Trichuris colonization, the mechanisms underlying this transkingdom interaction have been obscure. Here, we used a multiscale microscopy approach to define the structural events associated with bacteria-mediated hatching of eggs for the murine model parasite Trichuris muris. Through the combination of scanning electron microscopy (SEM) and serial block face SEM (SBFSEM), we visualized the outer surface morphology of the shell and generated 3D structures of the egg and larva during the hatching process. These images revealed that exposure to hatching-inducing bacteria catalyzed asymmetric degradation of the polar plugs prior to exit by the larva. Unrelated bacteria induced similar loss of electron density and dissolution of the structural integrity of the plugs. Egg hatching was most efficient when high densities of bacteria were bound to the poles. Consistent with the ability of taxonomically distant bacteria to induce hatching, additional results suggest chitinase released from larva within the eggs degrade the plugs from the inside instead of enzymes produced by bacteria in the external environment. These findings define at ultrastructure resolution the evolutionary adaptation of a parasite for the microbe-rich environment of the mammalian gut.


Subject(s)
Microbiota , Trichuris , Mice , Animals , Microscopy, Electron, Scanning , Bacteria , Larva , Ovum , Mammals
13.
PLoS Biol ; 20(3): e3001592, 2022 03.
Article in English | MEDLINE | ID: mdl-35358182

ABSTRACT

Gastrointestinal effects associated with Coronavirus Disease 2019 (COVID-19) are highly variable for reasons that are not understood. In this study, we used intestinal organoid-derived cultures differentiated from primary human specimens as a model to examine interindividual variability. Infection of intestinal organoids derived from different donors with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) resulted in orders of magnitude differences in virus replication in small intestinal and colonic organoid-derived monolayers. Susceptibility to infection correlated with angiotensin I converting enzyme 2 (ACE2) expression level and was independent of donor demographic or clinical features. ACE2 transcript levels in cell culture matched the amount of ACE2 in primary tissue, indicating that this feature of the intestinal epithelium is retained in the organoids. Longitudinal transcriptomics of organoid-derived monolayers identified a delayed yet robust interferon signature, the magnitude of which corresponded to the degree of SARS-CoV-2 infection. Interestingly, virus with the Omicron variant spike (S) protein infected the organoids with the highest infectivity, suggesting increased tropism of the virus for intestinal tissue. These results suggest that heterogeneity in SARS-CoV-2 replication in intestinal tissues results from differences in ACE2 levels, which may underlie variable patient outcomes.


Subject(s)
COVID-19 , Angiotensin-Converting Enzyme 2/genetics , Humans , Organoids , SARS-CoV-2
14.
PLoS Biol ; 20(9): e3001754, 2022 09.
Article in English | MEDLINE | ID: mdl-36099266

ABSTRACT

Extracellular vesicles of endosomal origin, exosomes, mediate intercellular communication by transporting substrates with a variety of functions related to tissue homeostasis and disease. Their diagnostic and therapeutic potential has been recognized for diseases such as cancer in which signaling defects are prominent. However, it is unclear to what extent exosomes and their cargo inform the progression of infectious diseases. We recently defined a subset of exosomes termed defensosomes that are mobilized during bacterial infection in a manner dependent on autophagy proteins. Through incorporating protein receptors on their surface, defensosomes mediated host defense by binding and inhibiting pore-forming toxins secreted by bacterial pathogens. Given this capacity to serve as decoys that interfere with surface protein interactions, we investigated the role of defensosomes during infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of Coronavirus Disease 2019 (COVID-19). Consistent with a protective function, exosomes containing high levels of the viral receptor ACE2 in bronchoalveolar lavage fluid (BALF) from critically ill COVID-19 patients was associated with reduced intensive care unit (ICU) and hospitalization times. We found ACE2+ exosomes were induced by SARS-CoV-2 infection and activation of viral sensors in cell culture, which required the autophagy protein ATG16L1, defining these as defensosomes. We further demonstrate that ACE2+ defensosomes directly bind and block viral entry. These findings suggest that defensosomes may contribute to the antiviral response against SARS-CoV-2 and expand our knowledge on the regulation and effects of extracellular vesicles during infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 , Humans , Peptidyl-Dipeptidase A/metabolism , Receptors, Virus , SARS-CoV-2
15.
Cell ; 141(7): 1135-45, 2010 Jun 25.
Article in English | MEDLINE | ID: mdl-20602997

ABSTRACT

It is unclear why disease occurs in only a small proportion of persons carrying common risk alleles of disease susceptibility genes. Here we demonstrate that an interaction between a specific virus infection and a mutation in the Crohn's disease susceptibility gene Atg16L1 induces intestinal pathologies in mice. This virus-plus-susceptibility gene interaction generated abnormalities in granule packaging and unique patterns of gene expression in Paneth cells. Further, the response to injury induced by the toxic substance dextran sodium sulfate was fundamentally altered to include pathologies resembling aspects of Crohn's disease. These pathologies triggered by virus-plus-susceptibility gene interaction were dependent on TNFalpha and IFNgamma and were prevented by treatment with broad spectrum antibiotics. Thus, we provide a specific example of how a virus-plus-susceptibility gene interaction can, in combination with additional environmental factors and commensal bacteria, determine the phenotype of hosts carrying common risk alleles for inflammatory disease.


Subject(s)
Carrier Proteins/genetics , Crohn Disease/genetics , Crohn Disease/virology , Genetic Predisposition to Disease , Ileum/pathology , Norovirus , Animals , Autophagy-Related Proteins , Crohn Disease/pathology , Gene Expression Profiling , Humans , Interferon-gamma/metabolism , Mice , Paneth Cells/metabolism , Paneth Cells/virology , Tumor Necrosis Factor-alpha/metabolism
16.
Immunity ; 42(5): 805-13, 2015 May 19.
Article in English | MEDLINE | ID: mdl-25992857

ABSTRACT

The mammalian virome includes diverse commensal and pathogenic viruses that evoke a broad range of immune responses from the host. Sustained viral immunomodulation is implicated in a variety of inflammatory diseases, but also confers unexpected benefits to the host. These outcomes of viral infections are often dependent on host genotype. Moreover, it is becoming clear that the virome is part of a dynamic network of microorganisms that inhabit the body. Therefore, viruses can be viewed as a component of the microbiome, and interactions with commensal bacteria and other microbial agents influence their behavior. This piece is a review of our current understanding of how the virome, together with other components of the microbiome, affects the function of the host immune system to regulate health and disease.


Subject(s)
Health , Microbiota/physiology , Virus Diseases , Virus Physiological Phenomena/immunology , Humans , Immunomodulation , Virus Diseases/immunology , Virus Diseases/virology
18.
Immunity ; 41(2): 311-24, 2014 Aug 21.
Article in English | MEDLINE | ID: mdl-25088769

ABSTRACT

Nod2 has been extensively characterized as a bacterial sensor that induces an antimicrobial and inflammatory gene expression program. Therefore, it is unclear why Nod2 mutations that disrupt bacterial recognition are paradoxically among the highest risk factors for Crohn's disease, which involves an exaggerated immune response directed at intestinal bacteria. Here, we identified several abnormalities in the small-intestinal epithelium of Nod2(-/-) mice including inflammatory gene expression and goblet cell dysfunction, which were associated with excess interferon-γ production by intraepithelial lymphocytes and Myd88 activity. Remarkably, these abnormalities were dependent on the expansion of a common member of the intestinal microbiota Bacteroides vulgatus, which also mediated exacerbated inflammation in Nod2(-/-) mice upon small-intestinal injury. These results indicate that Nod2 prevents inflammatory pathologies by controlling the microbiota and support a multihit disease model involving specific gene-microbe interactions.


Subject(s)
Bacteroides/immunology , Disease Susceptibility/immunology , Enteritis/immunology , Intestine, Small/immunology , Nod2 Signaling Adaptor Protein/genetics , Animals , Bacterial Typing Techniques , Crohn Disease/immunology , Enteritis/genetics , Goblet Cells/pathology , Inflammation/genetics , Inflammation/immunology , Interferon-gamma/biosynthesis , Intestinal Mucosa/immunology , Intestine, Small/microbiology , Lymphocytes/immunology , Mice , Mice, Knockout , Microbiota/immunology , Myeloid Differentiation Factor 88/immunology , Receptor-Interacting Protein Serine-Threonine Kinase 2 , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Signal Transduction/immunology
19.
Immunity ; 41(4): 579-91, 2014 Oct 16.
Article in English | MEDLINE | ID: mdl-25308334

ABSTRACT

Atg16L1 mediates the cellular degradative process of autophagy and is considered a critical regulator of inflammation based on its genetic association with inflammatory bowel disease. Here we find that Atg16L1 deficiency leads to an exacerbated graft-versus-host disease (GVHD) in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Atg16L1-deficient allo-HSCT recipients with GVHD displayed increased T cell proliferation due to increased dendritic cell (DC) numbers and costimulatory molecule expression. Reduced autophagy within DCs was associated with lysosomal abnormalities and decreased amounts of A20, a negative regulator of DC activation. These results broaden the function of Atg16L1 and the autophagy pathway to include a role in limiting a DC-mediated response during inflammatory disease, such as GVHD.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Carrier Proteins/immunology , Dendritic Cells/immunology , Graft vs Host Disease/immunology , Animals , Autophagy/immunology , Autophagy-Related Proteins , B7-1 Antigen/biosynthesis , B7-2 Antigen/biosynthesis , CD40 Antigens/biosynthesis , Carrier Proteins/genetics , Cell Proliferation , Cells, Cultured , Colitis/immunology , Cysteine Endopeptidases/biosynthesis , Disease Models, Animal , Female , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Hematopoietic Stem Cell Transplantation , Homeodomain Proteins/genetics , Immediate-Early Proteins/biosynthesis , Inflammation/immunology , Intracellular Signaling Peptides and Proteins/biosynthesis , Lymphocyte Activation/immunology , Lysosomes/pathology , Membrane Proteins/biosynthesis , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Receptors, Antigen, T-Cell, gamma-delta/immunology , Transplantation, Homologous , Tumor Necrosis Factor alpha-Induced Protein 3
20.
Gastroenterology ; 160(4): 1050-1066, 2021 03.
Article in English | MEDLINE | ID: mdl-33347881

ABSTRACT

The intestinal microbiota comprises diverse fungal and viral components, in addition to bacteria. These microbes interact with the immune system and affect human physiology. Advances in metagenomics have associated inflammatory and autoimmune diseases with alterations in fungal and viral species in the gut. Studies of animal models have found that commensal fungi and viruses can activate host-protective immune pathways related to epithelial barrier integrity, but can also induce reactions that contribute to events associated with inflammatory bowel disease. Changes in our environment associated with modernization and the COVID-19 pandemic have exposed humans to new fungi and viruses, with unknown consequences. We review the lessons learned from studies of animal viruses and fungi commonly detected in the human gut and how these might affect health and intestinal disease.


Subject(s)
Gastrointestinal Microbiome/physiology , Immunity/immunology , Inflammatory Bowel Diseases/etiology , Mycobiome/physiology , Virome/physiology , Animals , COVID-19/complications , Fecal Microbiota Transplantation , Humans , Lectins, C-Type/physiology , SARS-CoV-2 , Th1 Cells/immunology
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