Publications by authors named "Amiran Dzutsev"

45 Publications

Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients.

Science 2021 02;371(6529):595-602

Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.

Anti-programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti-PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti-PD-1 in patients with PD-1-refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti-PD-1, increased CD8 T cell activation, and decreased frequency of interleukin-8-expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma.
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http://dx.doi.org/10.1126/science.abf3363DOI Listing
February 2021

Transkingdom interactions between Lactobacilli and hepatic mitochondria attenuate western diet-induced diabetes.

Nat Commun 2021 01 4;12(1):101. Epub 2021 Jan 4.

Veterinary Medicine, Oregon State University, Corvallis, OR, USA.

Western diet (WD) is one of the major culprits of metabolic disease including type 2 diabetes (T2D) with gut microbiota playing an important role in modulating effects of the diet. Herein, we use a data-driven approach (Transkingdom Network analysis) to model host-microbiome interactions under WD to infer which members of microbiota contribute to the altered host metabolism. Interrogation of this network pointed to taxa with potential beneficial or harmful effects on host's metabolism. We then validate the functional role of the predicted bacteria in regulating metabolism and show that they act via different host pathways. Our gene expression and electron microscopy studies show that two species from Lactobacillus genus act upon mitochondria in the liver leading to the improvement of lipid metabolism. Metabolomics analyses revealed that reduced glutathione may mediate these effects. Our study identifies potential probiotic strains for T2D and provides important insights into mechanisms of their action.
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http://dx.doi.org/10.1038/s41467-020-20313-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782853PMC
January 2021

Integrative genomic analysis implicates ERCC6 and its interaction with ERCC8 in susceptibility to breast cancer.

Sci Rep 2020 12 4;10(1):21276. Epub 2020 Dec 4.

Cancer Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Up to 30% of all breast cancer cases may be inherited and up to 85% of those may be due to segregation of susceptibility genes with low and moderate risk [odds ratios (OR) ≤ 3] for (mostly peri- and post-menopausal) breast cancer. The majority of low/moderate-risk genes, particularly those with minor allele frequencies (MAF) of < 30%, have not been identified and/or validated due to limitations of conventional association testing approaches, which include the agnostic nature of Genome Wide Association Studies (GWAS). To overcome these limitations, we used a hypothesis-driven integrative genomics approach to test the association of breast cancer with candidate genes by analyzing multi-omics data. Our candidate-gene association analyses of GWAS datasets suggested an increased risk of breast cancer with ERCC6 (main effect: 1.29 ≤ OR ≤ 2.91, 0.005 ≤ p ≤ 0.04, 11.8 ≤ MAF ≤ 40.9%), and implicated its interaction with ERCC8 (joint effect: 3.03 ≤ OR ≤ 5.31, 0.01 ≤ p ≤ 0.03). We found significant upregulation of ERCC6 (p = 7.95 × 10) and ERCC8 (p = 4.67 × 10) in breast cancer and similar frequencies of ERCC6 (1.8%) and ERCC8 (0.3%) mutations in breast tumors to known breast cancer susceptibility genes such as BLM (1.9%) and LSP1 (0.3%). Our integrative genomics approach suggests that ERCC6 may be a previously unreported low- to moderate-risk breast cancer susceptibility gene, which may also interact with ERCC8.
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http://dx.doi.org/10.1038/s41598-020-77037-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718875PMC
December 2020

Distinct contributions of cathelin-related antimicrobial peptide (CRAMP) derived from epithelial cells and macrophages to colon mucosal homeostasis.

J Pathol 2021 Mar 19;253(3):339-350. Epub 2021 Jan 19.

Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.

The cathelin-related antimicrobial peptide CRAMP protects the mouse colon from inflammation, inflammation-associated carcinogenesis, and disrupted microbiome balance, as shown in systemic Cnlp mice (also known as Camp mice). However, the mechanistic basis for the role and the cellular source of CRAMP in colon pathophysiology are ill defined. This study, using either epithelial or myeloid conditional Cnlp mice, demonstrated that epithelial cell-derived CRAMP played a major role in supporting normal development of colon crypts, mucus production, and repair of injured mucosa. On the other hand, myeloid cell-derived CRAMP potently supported colon epithelial resistance to bacterial invasion during acute inflammation with exacerbated mucosal damage and higher rate of mouse mortality. Therefore, a well concerted cooperation of epithelial- and myeloid-derived CRAMP is essential for colon mucosal homeostasis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898386PMC
March 2021

Human NK cells prime inflammatory DC precursors to induce Tc17 differentiation.

Blood Adv 2020 08;4(16):3990-4006

Laboratory of Integrative Cancer Immunology, Center for Cancer Research, and.

Adaptive immune responses are acknowledged to evolve from innate immunity. However, limited information exists regarding whether encounters between innate cells direct the generation of specialized T-cell subsets. We aim to understand how natural killer (NK) cells modulate cell-mediated immunity in humans. We found that human CD14+CD16- monocytes that differentiate into inflammatory dendritic cells (DCs) are shaped at the early stages of differentiation by cell-to-cell interactions with NK cells. Although a fraction of monocytes is eliminated by NK-cell-mediated cytotoxicity, the polarization of interferon-γ (IFN-γ) at the NKp30-stabilized synapses triggers a stable IFN-γ signature in surviving monocytes that persists after their differentiation into DCs. Notably, NK-cell-instructed DCs drive the priming of type 17 CD8+ T cells (Tc17) with the capacity to produce IFN-γ and interleukin-17A. Compared with healthy donors, this cellular network is impaired in patients with classical NK-cell deficiency driven by mutations in the GATA2 gene. Our findings reveal a previously unrecognized connection by which Tc17-mediated immunity might be regulated by NK-cell-mediated tuning of antigen-presenting cells.
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http://dx.doi.org/10.1182/bloodadvances.2020002084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448590PMC
August 2020

Microbial DNA signature in plasma enables cancer diagnosis.

Nat Rev Clin Oncol 2020 08;17(8):453-454

Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1038/s41571-020-0391-1DOI Listing
August 2020

Multi-omics: Differential expression of IFN-γ results in distinctive mechanistic features linking chronic inflammation, gut dysbiosis, and autoimmune diseases.

J Autoimmun 2020 07 24;111:102436. Epub 2020 Mar 24.

Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, USA. Electronic address:

Low grade, chronic inflammation is a critical risk factor for immunologic dysfunction including autoimmune diseases. However, the multiplicity of complex mechanisms and lack of relevant murine models limit our understanding of the precise role of chronic inflammation. To address these hurdles, we took advantage of multi-omics data and a unique murine model with a low but chronic expression of IFN-γ, generated by replacement of the AU-rich element (ARE) in the 3' UTR region of IFN-γ mRNA with random nucleotides. Herein, we demonstrate that low but differential expression of IFN-γ in mice by homozygous or heterozygous ARE replacement triggers distinctive gut microbial alterations, of which alteration is female-biased with autoimmune-associated microbiota. Metabolomics data indicates that gut microbiota-dependent metabolites have more robust sex-differences than microbiome profiling, particularly those involved in fatty acid oxidation and nuclear receptor signaling. More importantly, homozygous ARE-Del mice have dramatic changes in tryptophan metabolism, bile acid and long-chain lipid metabolism, which interact with gut microbiota and nuclear receptor signaling similarly with sex-dependent metabolites. Consistent with these findings, nuclear receptor signaling, encompassing molecules such as PPARs, FXR, and LXRs, was detectable as a top canonical pathway in comparison of blood and tissue-specific gene expression between female homozygous vs heterozygous ARE-Del mice. Further analysis implies that dysregulated autophagy in macrophages is critical for breaking self-tolerance and gut homeostasis, while pathways interact with nuclear receptor signaling to regulate inflammatory responses. Overall, pathway-based integration of multi-omics data provides systemic and cellular insights about how chronic inflammation driven by IFN-γ results in the development of autoimmune diseases with specific etiopathological features.
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http://dx.doi.org/10.1016/j.jaut.2020.102436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266723PMC
July 2020

Author Correction: Interaction between the microbiome and TP53 in human lung cancer.

Genome Biol 2020 Feb 20;21(1):41. Epub 2020 Feb 20.

Laboratory of Human Carcinogenesis, Center for Cancer, Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr., Rm 3068A, MSC 4258, Bethesda, MD, 20892-4258, USA.

Following publication of the original paper [1], the authors submitted a new Additional file 5 to replace the one containing formatting issues. The updated Additional file 5 is published in this correction.
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http://dx.doi.org/10.1186/s13059-020-01961-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033853PMC
February 2020

Mucosal vaccine efficacy against intrarectal SHIV is independent of anti-Env antibody response.

J Clin Invest 2019 03 18;129(3):1314-1328. Epub 2019 Feb 18.

Vaccine Branch, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA.

It is widely believed that protection against acquisition of HIV or SIV infection requires anti-envelope (anti-Env) antibodies, and that cellular immunity may affect viral loads but not acquisition, except in special cases. Here we provide evidence to the contrary. Mucosal immunization may enhance HIV vaccine efficacy by eliciting protective responses at portals of exposure. Accordingly, we vaccinated macaques mucosally with HIV/SIV peptides, modified vaccinia Ankara-SIV (MVA-SIV), and HIV-gp120-CD4 fusion protein plus adjuvants, which consistently reduced infection risk against heterologous intrarectal SHIVSF162P4 challenge, both high dose and repeated low dose. Surprisingly, vaccinated animals exhibited no anti-gp120 humoral responses above background and Gag- and Env-specific T cells were induced but failed to correlate with viral acquisition. Instead, vaccine-induced gut microbiome alteration and myeloid cell accumulation in colorectal mucosa correlated with protection. Ex vivo stimulation of the myeloid cell-enriched population with SHIV led to enhanced production of trained immunity markers TNF-α and IL-6, as well as viral coreceptor agonist MIP1α, which correlated with reduced viral Gag expression and in vivo viral acquisition. Overall, our results suggest mechanisms involving trained innate mucosal immunity together with antigen-specific T cells, and also indicate that vaccines can have critical effects on the gut microbiome, which in turn can affect resistance to infection. Strategies to elicit similar responses may be considered for vaccine designs to achieve optimal protective efficacy.
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http://dx.doi.org/10.1172/JCI122110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391089PMC
March 2019

Cell-Type-Specific Responses to Interleukin-1 Control Microbial Invasion and Tumor-Elicited Inflammation in Colorectal Cancer.

Immunity 2019 01;50(1):166-180.e7

Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. Electronic address:

Chronic inflammation drives the progression of colorectal cancer (CRC). Increased expression of interleukin (IL)-17A is associated with poor prognosis, and IL-17A blockade curbs tumor progression in preclinical models of CRC. Here we examined the impact of IL-1 signaling, a key regulator of the IL-17 pathway, in different cell types within the CRC microenvironment. Genetic deletion of the IL-1 receptor (IL-1R1) in epithelial cells alleviated tumorigenesis in the APC model of CRC, demonstrating a cell-autonomous role for IL-1 signaling in early tumor seed outgrowth. T cell specific ablation of IL-1R1 decreased tumor-elicited inflammation dependent on IL-17 and IL-22, thereby reducing CRC progression. The pro-tumorigenic roles of IL-1 were counteracted by its effects on myeloid cells, particularly neutrophils, where IL-1R1 ablation resulted in bacterial invasion into tumors, heightened inflammation and aggressive CRC progression. Thus, IL-1 signaling elicits cell-type-specific responses, which, in aggregate, set the inflammatory tone of the tumor microenvironment and determine the propensity for disease progression.
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http://dx.doi.org/10.1016/j.immuni.2018.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490968PMC
January 2019

An Interleukin-23-Interleukin-22 Axis Regulates Intestinal Microbial Homeostasis to Protect from Diet-Induced Atherosclerosis.

Immunity 2018 11 30;49(5):943-957.e9. Epub 2018 Oct 30.

Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. Electronic address:

Although commensal flora is involved in the regulation of immunity, the interplay between cytokine signaling and microbiota in atherosclerosis remains unknown. We found that interleukin (IL)-23 and its downstream target IL-22 restricted atherosclerosis by repressing pro-atherogenic microbiota. Inactivation of IL-23-IL-22 signaling led to deterioration of the intestinal barrier, dysbiosis, and expansion of pathogenic bacteria with distinct biosynthetic and metabolic properties, causing systemic increase in pro-atherogenic metabolites such as lipopolysaccharide (LPS) and trimethylamine N-oxide (TMAO). Augmented disease in the absence of the IL-23-IL-22 pathway was mediated in part by pro-atherogenic osteopontin, controlled by microbial metabolites. Microbiota transfer from IL-23-deficient mice accelerated atherosclerosis, whereas microbial depletion or IL-22 supplementation reduced inflammation and ameliorated disease. Our work uncovers the IL-23-IL-22 signaling as a regulator of atherosclerosis that restrains expansion of pro-atherogenic microbiota and argues for informed use of cytokine blockers to avoid cardiovascular side effects driven by microbiota and inflammation.
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http://dx.doi.org/10.1016/j.immuni.2018.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257980PMC
November 2018

MAVS deficiency induces gut dysbiotic microbiota conferring a proallergic phenotype.

Proc Natl Acad Sci U S A 2018 10 24;115(41):10404-10409. Epub 2018 Sep 24.

Centre International de Recherche en Infectiologie, INSERM U1111-CNRS UMR5308, 69365 Lyon Cedex 07, France;

Prominent changes in the gut microbiota (referred to as "dysbiosis") play a key role in the development of allergic disorders, but the underlying mechanisms remain unknown. Study of the delayed-type hypersensitivity (DTH) response in mice contributed to our knowledge of the pathophysiology of human allergic contact dermatitis. Here we report a negative regulatory role of the RIG-I-like receptor adaptor mitochondrial antiviral signaling (MAVS) on DTH by modulating gut bacterial ecology. Cohousing and fecal transplantation experiments revealed that the dysbiotic microbiota of mice conferred a proallergic phenotype that is communicable to wild-type mice. DTH sensitization coincided with increased intestinal permeability and bacterial translocation within lymphoid organs that enhanced DTH severity. Collectively, we unveiled an unexpected impact of RIG-I-like signaling on the gut microbiota with consequences on allergic skin disease outcome. Primarily, these data indicate that manipulating the gut microbiota may help in the development of therapeutic strategies for the treatment of human allergic skin pathologies.
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http://dx.doi.org/10.1073/pnas.1722372115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187193PMC
October 2018

Interaction between the microbiome and TP53 in human lung cancer.

Genome Biol 2018 08 24;19(1):123. Epub 2018 Aug 24.

Laboratory of Human Carcinogenesis, Center for Cancer, Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr., Rm 3068A, MSC 4258, Bethesda, MD, 20892-4258, USA.

Background: Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesize that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from 33 controls and 143 cancer cases, we conduct 16S ribosomal RNA (rRNA) bacterial gene sequencing, with RNA-sequencing data from lung cancer cases in The Cancer Genome Atlas serving as the validation cohort.

Results: Overall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma specifically, a separate group of taxa are identified, in which Acidovorax is enriched in smokers. Acidovorax temporans is identified within tumor sections by fluorescent in situ hybridization and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax, exhibit higher abundance among the subset of squamous cell carcinoma cases with TP53 mutations, an association not seen in adenocarcinomas.

Conclusions: The results of this comprehensive study show both microbiome-gene and microbiome-exposure interactions in squamous cell carcinoma lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can impair epithelial function, have a unique bacterial consortium that is higher in relative abundance in smoking-associated tumors of this type. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection.
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http://dx.doi.org/10.1186/s13059-018-1501-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109311PMC
August 2018

The innate immune receptor TREM-1 promotes liver injury and fibrosis.

J Clin Invest 2018 11 2;128(11):4870-4883. Epub 2018 Oct 2.

Molecular Oncology and Biomarkers Program, Georgia Cancer Center, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.

Inflammation occurs in all tissues in response to injury or stress and is the key process underlying hepatic fibrogenesis. Targeting chronic and uncontrolled inflammation is one strategy to prevent liver injury and fibrosis progression. Here, we demonstrate that triggering receptor expressed on myeloid cells 1 (TREM-1), an amplifier of inflammation, promotes liver disease by intensifying hepatic inflammation and fibrosis. In the liver, TREM-1 expression was limited to liver macrophages and monocytes and was highly upregulated on Kupffer cells, circulating monocytes, and monocyte-derived macrophages in a mouse model of chronic liver injury and fibrosis induced by carbon tetrachloride (CCl4) administration. TREM-1 signaling promoted proinflammatory cytokine production and mobilization of inflammatory cells to the site of injury. Deletion of Trem1 reduced liver injury, inflammatory cell infiltration, and fibrogenesis. Reconstitution of Trem1-deficient mice with Trem1-sufficient Kupffer cells restored the recruitment of inflammatory monocytes and the severity of liver injury. Markedly increased infiltration of liver fibrotic areas with TREM-1-positive Kupffer cells and monocytes/macrophages was found in patients with hepatic fibrosis. Our data support a role of TREM-1 in liver injury and hepatic fibrogenesis and suggest that TREM-1 is a master regulator of Kupffer cell activation, which escalates chronic liver inflammatory responses, activates hepatic stellate cells, and reveals a mechanism of promotion of liver fibrosis.
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http://dx.doi.org/10.1172/JCI98156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205377PMC
November 2018

Influence of gut microbiome on mucosal immune activation and SHIV viral transmission in naive macaques.

Mucosal Immunol 2018 07 1;11(4):1219-1229. Epub 2018 Jun 1.

Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

It is unknown whether the gut microbiome affects HIV transmission. In our recent SHIV vaccine study, we found that the naive rhesus macaques from two different sources had significantly different rates of infection against repeated low-dose intrarectal challenge with SHIV virus. Exploring causes, we found that the more susceptible group of seven macaques had significantly more activated CD4CCR5Ki67 T cells in the rectal mucosa than the more resistant group of 11 macaques from a different source. The prevalence of pre-challenge activated rectal CD4 T cells in the naive macaques correlated inversely with the number of challenges required to infect. Because the two naive groups came from different sources, we hypothesized that their microbiomes may differ and might explain the activation difference. Indeed, after sequencing 16s rRNA, we found differences between the two naive groups that correlated with immune activation status. Distinct gut microbiota induced different levels of immune activation ex vivo. Significantly lower ratios of Bacteroides to Prevotella, and significantly lower levels of Firmicutes were found in the susceptible cohort, which were also inversely correlated with high levels of immune activation in the rectal mucosa. Thus, host-microbiome interactions might influence HIV/SIV mucosal transmission through effects on mucosal immune activation.
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http://dx.doi.org/10.1038/s41385-018-0029-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030500PMC
July 2018

The Antimicrobial Peptide CRAMP Is Essential for Colon Homeostasis by Maintaining Microbiota Balance.

J Immunol 2018 03 12;200(6):2174-2185. Epub 2018 Feb 12.

Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702;

Commensal bacteria are critical for physiological functions in the gut, and dysbiosis in the gut may cause diseases. In this article, we report that mice deficient in cathelin-related antimicrobial peptide (CRAMP) were defective in the development of colon mucosa and highly sensitive to dextran sulfate sodium (DSS)-elicited colitis, as well as azoxymethane-mediated carcinogenesis. Pretreatment of CRAMP mice with antibiotics markedly reduced the severity of DSS-induced colitis, suggesting CRAMP as a limiting factor on dysbiosis in the colon. This was supported by observations that wild-type (WT) mice cohoused with CRAMP mice became highly sensitive to DSS-induced colitis, and the composition of fecal microbiota was skewed by CRAMP deficiency. In particular, several bacterial species that are typically found in oral microbiota, such as , , and , were increased in feces of CRAMP mice and were transferred to WT mice during cohousing. When littermates of CRAMP parents were examined, the composition of the fecal microbiota of WT pups and heterozygous parents was similar. In contrast, although the difference in fecal microbiota between CRAMP and WT pups was small early on after weaning and single mouse housing, there was an increasing divergence with prolonged single housing. These results indicate that CRAMP is critical in maintaining colon microbiota balance and supports mucosal homeostasis, anti-inflammatory responses, and protection from carcinogenesis.
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http://dx.doi.org/10.4049/jimmunol.1602073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931736PMC
March 2018

Non-classical Immunity Controls Microbiota Impact on Skin Immunity and Tissue Repair.

Cell 2018 02 18;172(4):784-796.e18. Epub 2018 Jan 18.

Mucosal Immunology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD 20892, USA. Electronic address:

Mammalian barrier surfaces are constitutively colonized by numerous microorganisms. We explored how the microbiota was sensed by the immune system and the defining properties of such responses. Here, we show that a skin commensal can induce T cell responses in a manner that is restricted to non-classical MHC class I molecules. These responses are uncoupled from inflammation and highly distinct from pathogen-induced cells. Commensal-specific T cells express a defined gene signature that is characterized by expression of effector genes together with immunoregulatory and tissue-repair signatures. As such, non-classical MHCI-restricted commensal-specific immune responses not only promoted protection to pathogens, but also accelerated skin wound closure. Thus, the microbiota can induce a highly physiological and pleiotropic form of adaptive immunity that couples antimicrobial function with tissue repair. Our work also reveals that non-classical MHC class I molecules, an evolutionarily ancient arm of the immune system, can promote homeostatic immunity to the microbiota.
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http://dx.doi.org/10.1016/j.cell.2017.12.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034182PMC
February 2018

White Adipose Tissue Is a Reservoir for Memory T Cells and Promotes Protective Memory Responses to Infection.

Immunity 2017 12 5;47(6):1154-1168.e6. Epub 2017 Dec 5.

Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; NIAID Microbiome Program, NIH, Bethesda, MD 20892, USA. Electronic address:

White adipose tissue bridges body organs and plays a fundamental role in host metabolism. To what extent adipose tissue also contributes to immune surveillance and long-term protective defense remains largely unknown. Here, we have shown that at steady state, white adipose tissue contained abundant memory lymphocyte populations. After infection, white adipose tissue accumulated large numbers of pathogen-specific memory T cells, including tissue-resident cells. Memory T cells in white adipose tissue expressed a distinct metabolic profile, and white adipose tissue from previously infected mice was sufficient to protect uninfected mice from lethal pathogen challenge. Induction of recall responses within white adipose tissue was associated with the collapse of lipid metabolism in favor of antimicrobial responses. Our results suggest that white adipose tissue represents a memory T cell reservoir that provides potent and rapid effector memory responses, positioning this compartment as a potential major contributor to immunological memory.
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http://dx.doi.org/10.1016/j.immuni.2017.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773068PMC
December 2017

Differential T cell homing to colon vs. small intestine is imprinted by local CD11c APCs that determine homing receptors.

J Leukoc Biol 2017 12 26;102(6):1381-1388. Epub 2017 Sep 26.

Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

Mechanisms that imprint T cell homing to the small intestine have been well studied; however, those for homing to the colon are poorly understood. Recently, we found that these are distinct subcompartments of the gut mucosal immune system, which implies differential homing. Here, we show that colonic CD11c APCs imprint CD8 T cell preferential homing to the colon, in contrast to those from the small intestine that imprint CD8 T cell homing to the small intestine, and that the differences are related to the variable ability of APCs to induce α4β7-integrin and CCR9 expression on T cells. Colon APCs also expressed lower levels of retinoic acid-producing enzymes that are known to control the mucosal homing of T cells. These findings are the first to our knowledge to directly demonstrate that colon APCs imprint T cells to selectively home to the large bowel, which is critical for the design of successful T cell-based therapies and vaccines, such as colon cancer immunotherapy and HIV vaccines.
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http://dx.doi.org/10.1189/jlb.1A1116-463RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669635PMC
December 2017

Longitudinal profiling reveals a persistent intestinal dysbiosis triggered by conventional anti-tuberculosis therapy.

Microbiome 2017 07 7;5(1):71. Epub 2017 Jul 7.

Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 33, Room 1W10A, 33 North Drive, MSC 3202, Bethesda, MD, 20892-3202, USA.

Background: Effective treatment of Mycobacterium tuberculosis (Mtb) infection requires at least 6 months of daily therapy with multiple orally administered antibiotics. Although this drug regimen is administered annually to millions worldwide, the impact of such intensive antimicrobial treatment on the host microbiome has never been formally investigated. Here, we characterized the longitudinal outcome of conventional isoniazid-rifampin-pyrazinamide (HRZ) TB drug administration on the diversity and composition of the intestinal microbiota in Mtb-infected mice by means of 16S rRNA sequencing. We also investigated the effects of each of the individual antibiotics alone and in different combinations.

Results: While inducing only a transient decrease in microbial diversity, HRZ treatment triggered a marked, immediate and reproducible alteration in community structure that persisted for the entire course of therapy and for at least 3 months following its cessation. Members of order Clostridiales were among the taxa that decreased in relative frequencies during treatment and family Porphyromonadaceae significantly increased post treatment. Experiments comparing monotherapy and different combination therapies identified rifampin as the major driver of the observed alterations induced by the HRZ cocktail but also revealed unexpected effects of isoniazid and pyrazinamide in certain drug pairings.

Conclusions: This report provides the first detailed analysis of the longitudinal changes in the intestinal microbiota due to anti-tuberculosis therapy. Importantly, many of the affected taxa have been previously shown in other systems to be associated with modifications in immunologic function. Together, our findings reveal that the antibiotics used in conventional TB treatment induce a distinct and long lasting dysbiosis. In addition, they establish a murine model for studying the potential impact of this dysbiosis on host resistance and physiology.
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http://dx.doi.org/10.1186/s40168-017-0286-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501520PMC
July 2017

Microbes and Cancer.

Annu Rev Immunol 2017 04 30;35:199-228. Epub 2017 Jan 30.

Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, email:

Commensal microorganisms (the microbiota) live on all the surface barriers of our body and are particularly abundant and diverse in the distal gut. The microbiota and its larger host represent a metaorganism in which the cross talk between microbes and host cells is necessary for health, survival, and regulation of physiological functions locally, at the barrier level, and systemically. The ancestral molecular and cellular mechanisms stemming from the earliest interactions between prokaryotes and eukaryotes have evolved to mediate microbe-dependent host physiology and tissue homeostasis, including innate and adaptive resistance to infections and tissue repair. Mostly because of its effects on metabolism, cellular proliferation, inflammation, and immunity, the microbiota regulates cancer at the level of predisposing conditions, initiation, genetic instability, susceptibility to host immune response, progression, comorbidity, and response to therapy. Here, we review the mechanisms underlying the interaction of the microbiota with cancer and the evidence suggesting that the microbiota could be targeted to improve therapy while attenuating adverse reactions.
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http://dx.doi.org/10.1146/annurev-immunol-051116-052133DOI Listing
April 2017

Proteus mirabilis: The Enemy Within.

Immunity 2015 Apr;42(4):602-4

Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address:

The organism needs to tailor the intestinal inflammatory response to pathogenic bacteria and to pathobionts that are only occasionally pathogenic. In this issue of Immunity, Seo et al. (2015) show that the pathobiont Proteus mirabilis induces NLRP3 inflammasome-dependent interleukin-1β (IL-1β) release from CCR2(+) Ly6C(high) inflammatory monocytes.
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http://dx.doi.org/10.1016/j.immuni.2015.04.004DOI Listing
April 2015

Microbiota modulation of myeloid cells in cancer therapy.

Cancer Immunol Res 2015 Feb;3(2):103-9

Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.

Myeloid cells represent a major component of the tumor microenvironment, where they play divergent dual roles. They can induce antitumor immune responses, but mostly they promote immune evasion, tumor progression, and metastasis formation. Thus, strategies aiming at reprogramming the tumor microenvironment represent a promising immunotherapy approach. Myeloid cells respond to environmental factors including signals derived from commensal microbes. In this Cancer Immunology at the Crossroads overview, we discuss recent advances on the effects of the commensal microbiota on myeloid-cell functions and how they affect the response to cancer therapy.
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http://dx.doi.org/10.1158/2326-6066.CIR-14-0225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324508PMC
February 2015

Uncovering effects of antibiotics on the host and microbiota using transkingdom gene networks.

Gut 2015 Nov 22;64(11):1732-43. Epub 2015 Jan 22.

College of Veterinary Medicine, Oregon State University, Corvallis, Oregon, USA Ghost Lab, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Objective: Despite widespread use of antibiotics for the treatment of life-threatening infections and for research on the role of commensal microbiota, our understanding of their effects on the host is still very limited.

Design: Using a popular mouse model of microbiota depletion by a cocktail of antibiotics, we analysed the effects of antibiotics by combining intestinal transcriptome together with metagenomic analysis of the gut microbiota. In order to identify specific microbes and microbial genes that influence the host phenotype in antibiotic-treated mice, we developed and applied analysis of the transkingdom network.

Results: We found that most antibiotic-induced alterations in the gut can be explained by three factors: depletion of the microbiota; direct effects of antibiotics on host tissues and the effects of remaining antibiotic-resistant microbes. Normal microbiota depletion mostly led to downregulation of different aspects of immunity. The two other factors (antibiotic direct effects on host tissues and antibiotic-resistant microbes) primarily inhibited mitochondrial gene expression and amounts of active mitochondria, increasing epithelial cell death. By reconstructing and analysing the transkingdom network, we discovered that these toxic effects were mediated by virulence/quorum sensing in antibiotic-resistant bacteria, a finding further validated using in vitro experiments.

Conclusions: In addition to revealing mechanisms of antibiotic-induced alterations, this study also describes a new bioinformatics approach that predicts microbial components that regulate host functions and establishes a comprehensive resource on what, why and how antibiotics affect the gut in a widely used mouse model of microbiota depletion by antibiotics.
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http://dx.doi.org/10.1136/gutjnl-2014-308820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5166700PMC
November 2015

Interleukin-1 and interferon-γ orchestrate β-glucan-activated human dendritic cell programming via IκB-ζ modulation.

PLoS One 2014 4;9(12):e114516. Epub 2014 Dec 4.

Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America; The Trans-NIH Center for Human Immunology, Bethesda, Maryland, United States of America.

Recognition of microbial components via innate receptors including the C-type lectin receptor Dectin-1, together with the inflammatory environment, programs dendritic cells (DCs) to orchestrate the magnitude and type of adaptive immune responses. The exposure to β-glucan, a known Dectin-1 agonist and component of fungi, yeasts, and certain immune support supplements, activates DCs to induce T helper (Th)17 cells that are essential against fungal pathogens and extracellular bacteria but may trigger inflammatory pathology or autoimmune diseases. However, the exact mechanisms of DC programming by β-glucan have not yet been fully elucidated. Using a gene expression/perturbation approach, we demonstrate that in human DCs β-glucan transcriptionally activates via an interleukin (IL)-1- and inflammasome-mediated positive feedback late-induced genes that bridge innate and adaptive immunity. We report that in addition to its known ability to directly prime T cells toward the Th17 lineage, IL-1 by promoting the transcriptional cofactor inhibitor of κB-ζ (IκB-ζ) also programs β-glucan-exposed DCs to express cell adhesion and migration mediators, antimicrobial molecules, and Th17-polarizing factors. Interferon (IFN)-γ interferes with the IL-1/IκB-ζ axis in β-glucan-activated DCs and promotes T cell-mediated immune responses with increased release of IFN-γ and IL-22, and diminished production of IL-17. Thus, our results identify IL-1 and IFN-γ as regulators of DC programming by β-glucan. These molecular networks provide new insights into the regulation of the Th17 response as well as new targets for the modulation of immune responses to β-glucan-containing microorganisms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114516PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256441PMC
December 2015

The role of the microbiota in inflammation, carcinogenesis, and cancer therapy.

Eur J Immunol 2015 Jan 13;45(1):17-31. Epub 2014 Nov 13.

Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA; Leidos Biomedical Research, Inc, Frederick, MD, USA.

Commensal microorganisms colonize barrier surfaces of all multicellular organisms, including those of humans. For more than 500 million years, commensal microorganisms and their hosts have coevolved and adapted to each other. As a result, the commensal microbiota affects many immune and nonimmune functions of their hosts, and de facto the two together comprise one metaorganism. The commensal microbiota communicates with the host via biologically active molecules. Recently, it has been reported that microbial imbalance may play a critical role in the development of multiple diseases, such as cancer, autoimmune conditions, and increased susceptibility to infection. In this review, we focus on the role of the commensal microbiota in the development, progression, and immune evasion of cancer, as well as some modulatory effects on the treatment of cancer. In particular, we discuss the mechanisms of microbiota-mediated regulation of innate and adaptive immune responses to tumors, and the consequences on cancer progression and whether tumors subsequently become resistant or susceptible to different anticancer therapeutic regiments.
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http://dx.doi.org/10.1002/eji.201444972DOI Listing
January 2015

Nucleotide excision repair/transcription gene defects in the fetus and impaired TFIIH-mediated function in transcription in placenta leading to preeclampsia.

BMC Genomics 2014 May 15;15:373. Epub 2014 May 15.

Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, State University of New York (SUNY), Rensselaer, NY 12144, USA.

Background: Preeclampsia is a significant cause of maternal and fetal mortality and morbidity worldwide. We previously reported associations between trichothiodystrophy (TTD) nucleotide excision repair (NER) and transcription gene mutations in the fetus and the risk of gestational complications including preeclampsia. TTD NER/transcription genes, XPD, XPB and TTD-A, code for subunits of Transcription Factor (TF)IIH. Interpreting XPD mutations in the context of available biochemical data led us to propose adverse effects on CDK-activating kinase (CAK) subunit of TFIIH and TFIIH-mediated functions as a relevant mechanism in preeclampsia. In order to gain deeper insight into the underlying biologic mechanisms involving TFIIH-mediated functions in placenta, we analyzed NER/transcription and global gene expression profiles of normal and preeclamptic placentas and studied gene regulatory networks.

Results: We found high expression of TTD NER/transcription genes in normal human placenta, above the mean of their expression in all organs. XPD and XPB were consistently expressed from 14 to 40 weeks gestation while expression of TTD-A was strongly negatively correlated (r=-0.7, P<0.0001) with gestational age. Analysis of gene expression patterns of placentas from a case-control study of preeclampsia using Algorithm for Reconstruction of Accurate Cellular Networks (ARACNE) revealed GTF2E1, a component of TFIIE which modulates TFIIH, among major regulators of differentially-expressed genes in preeclampsia. The basal transcription pathway was among the largest dysregulated protein-protein interaction networks in this preeclampsia dataset. Within the basal transcription pathway, significantly down-regulated genes besides GTF2E1 included those coding for the CAK complex of TFIIH, namely CDK7, CCNH, and MNAT1. Analysis of other relevant gene expression and gene regulatory network data also underscored the involvement of transcription pathways and identified JUNB and JUND (components of transcription factor AP-1) as transcription regulators of the network involving the TTD genes, GTF2E1, and selected gene regulators implicated in preeclampsia.

Conclusions: Our results indicate that TTD NER/transcription genes are expressed in placenta during gestational periods critical to preeclampsia development. Our overall findings suggest that impairment of TFIIH-mediated function in transcription in placenta is a likely mechanism leading to preeclampsia and provide etiologic clues which may be translated into therapeutic and preventive measures.
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http://dx.doi.org/10.1186/1471-2164-15-373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229886PMC
May 2014

Cell depletion in mice that express diphtheria toxin receptor under the control of SiglecH encompasses more than plasmacytoid dendritic cells.

J Immunol 2014 May 28;192(9):4409-16. Epub 2014 Mar 28.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;

Plasmacytoid dendritic cells (pDC) produce IFN-I in response to viruses and are routinely identified in mice by SiglecH expression. SiglecH is a sialic acid-binding Ig-like lectin that has an immunomodulatory role during viral infections. In this study, we evaluated the impact of SiglecH deficiency on cytokine responses in the presence and absence of pDC. We found that lack of SiglecH enhanced IFN-I responses to viral infection, regardless of whether pDC were depleted. We also examined the expression pattern of SiglecH and observed that it was expressed by specialized macrophages and progenitors of classical dendritic cells and pDC. Accordingly, marginal zone macrophages and pDC precursors were eliminated in newly generated SiglecH-diphtheria toxin receptor (DTR)-transgenic (Tg) mice but not in CLEC4C-DTR-Tg mice after diphtheria toxin (DT) treatment. Using two bacterial models, we found that SiglecH-DTR-Tg mice injected with DT had altered bacterial uptake and were more susceptible to lethal Listeria monocytogenes infection than were DT-treated CLEC4C-DTR-Tg mice. Taken together, our findings suggest that lack of SiglecH may affect cytokine responses by cell types other than pDC during viral infections, perhaps by altering viral distribution or burden, and that cell depletion in SiglecH-DTR-Tg mice encompasses more than pDC.
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http://dx.doi.org/10.4049/jimmunol.1303135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194082PMC
May 2014

Host immune response to infection and cancer: unexpected commonalities.

Cell Host Microbe 2014 Mar;15(3):295-305

Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA. Electronic address:

Both microbes and tumors activate innate resistance, tissue repair, and adaptive immunity. Unlike acute infection, tumor growth is initially unapparent; however, inflammation and immunity affect all phases of tumor growth from initiation to progression and dissemination. Here, we discuss the shared features involved in the immune response to infection and cancer including modulation by commensal microbiota, reactive hematopoiesis, chronic immune responses and regulatory mechanisms to prevent collateral tissue damage. This comparative analysis of immunity to infection and cancer furthers our understanding of the basic mechanisms underlying innate resistance and adaptive immunity and their translational application to the design of new therapeutic approaches.
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http://dx.doi.org/10.1016/j.chom.2014.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996827PMC
March 2014

Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment.

Science 2013 Nov;342(6161):967-70

Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA.

The gut microbiota influences both local and systemic inflammation. Inflammation contributes to development, progression, and treatment of cancer, but it remains unclear whether commensal bacteria affect inflammation in the sterile tumor microenvironment. Here, we show that disruption of the microbiota impairs the response of subcutaneous tumors to CpG-oligonucleotide immunotherapy and platinum chemotherapy. In antibiotics-treated or germ-free mice, tumor-infiltrating myeloid-derived cells responded poorly to therapy, resulting in lower cytokine production and tumor necrosis after CpG-oligonucleotide treatment and deficient production of reactive oxygen species and cytotoxicity after chemotherapy. Thus, optimal responses to cancer therapy require an intact commensal microbiota that mediates its effects by modulating myeloid-derived cell functions in the tumor microenvironment. These findings underscore the importance of the microbiota in the outcome of disease treatment.
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http://dx.doi.org/10.1126/science.1240527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709532PMC
November 2013