Publications by authors named "Ian A Myles"

31 Publications

Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3.

PLoS One 2021 4;16(3):e0248011. Epub 2021 Mar 4.

Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, Maryland, United States of America.

Keloids are a type of disordered scar formation which not only show heterogeneity between individuals and within the scar itself, but also share common features of hyperproliferation, abnormal extra-cellular matrix deposition and degradation, as well as altered expression of the molecular markers of wound healing. Numerous reports have established that cells from keloid scars display Warburg metabolism-a form of JAK2/STAT3-induced metabolic adaptation typical of rapidly dividing cells in which glycolysis becomes the predominant source of ATP over oxidative phosphorylation (OxPhos). Using the JAK1/2 inhibitor ruxolitinib, along with cells from patients with STAT3 loss of function (STA3 LOF; autosomal dominant hyper IgE syndrome) we examined the role of JAK/STAT signaling in the hyperproliferation and metabolic dysregulation seen in keloid fibroblasts. Although ruxolitinib inhibited hyperactivity in the scratch assay in keloid fibroblasts, it paradoxically exacerbated the hyper-glycolytic state, possibly by further limiting OxPhos via alterations in mitochondrial phosphorylated STAT3 (pSTAT3Ser727). In healthy volunteer fibroblasts, folic acid exposure recapitulated the exaggerated closure and hyper-glycolytic state of keloid fibroblasts through JAK1/2- and STAT3-dependent pathways. Although additional studies are needed before extrapolating from a representative cell line to keloids writ large, our results provide novel insights into the metabolic consequences of STAT3 dysfunction, suggest a possible role for folate metabolism in the pathogenesis of keloid scars, and offer in vitro pre-clinical data supporting considerations of clinical trials for ruxolitinib in keloid disorder.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248011PLOS
March 2021

USPHS Corps Care : Force Health Protection for Public Health Officers During the Ebola and COVID-19 Responses.

Public Health Rep 2021 Mar-Apr;136(2):148-153. Epub 2021 Feb 4.

Commissioned Corps (permanent), Rockville, MD, USA.

Force health protection (FHP) is defined as "the prevention of disease and injury in order to protect the strength and capabilities" of any service population. FHP was the foundational principal of the US Public Health Service (USPHS). President John Adams' signing of An Act for Sick and Disabled Seamen on July 16, 1798, marked the first dedication of US federal resources to ensuring the well-being of US civilian sailors and Naval service members. On January 4, 1889, President Cleveland enacted the USPHS Commissioned Corps, creating the world's first (and still only) uniformed service dedicated to promoting, protecting, and advancing the health and safety of the United States and the world. Building on the lessons of the 2014-2015 response to the Ebola virus pandemic, the Corps Care program was formalized in 2017 to establish and implement a uniform and comprehensive strategy to meet the behavioral health, medical, and spiritual needs of all Commissioned Corps officers. Its role was expanded in response to the coronavirus disease 2019 (COVID-19) pandemic, which has placed unprecedented demands on health care workers and spotlighted the need for FHP strategies. We describe the FHP roles of the Corps Care program for the resiliency of Commission Corps officers in general and the Corps' impact during the response to the COVID-19 pandemic. Qualitative analysis of FHP discussions with deployed officers highlights the unique challenges to FHP presented by the pandemic response.
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http://dx.doi.org/10.1177/0033354920984775DOI Listing
February 2021

Aberrant type 1 immunity drives susceptibility to mucosal fungal infections.

Science 2021 01;371(6526)

Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, USA.

Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.
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http://dx.doi.org/10.1126/science.aay5731DOI Listing
January 2021

Tumor Necrosis Factor Receptors: Pleiotropic Signaling Complexes and Their Differential Effects.

Front Immunol 2020 25;11:585880. Epub 2020 Nov 25.

Epithelial Therapeutics Unit, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, United States.

Since its discovery in 1975, TNFα has been a subject of intense study as it plays significant roles in both immunity and cancer. Such attention is well deserved as TNFα is unique in its engagement of pleiotropic signaling its two receptors: TNFR1 and TNFR2. Extensive research has yielded mechanistic insights into how a single cytokine can provoke a disparate range of cellular responses, from proliferation and survival to apoptosis and necrosis. Understanding the intracellular signaling pathways induced by this single cytokine its two receptors is key to further revelation of its exact functions in the many disease states and immune responses in which it plays a role. In this review, we describe the signaling complexes formed by TNFR1 and TNFR2 that lead to each potential cellular response, namely, canonical and non-canonical NF-κB activation, apoptosis and necrosis. This is followed by a discussion of data from mouse and human studies to examine the differential impacts of TNFR1 versus TNFR2 signaling.
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http://dx.doi.org/10.3389/fimmu.2020.585880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723893PMC
November 2020

Therapeutic responses to in atopic dermatitis may involve lipid-mediated TNF-related epithelial repair.

Sci Transl Med 2020 09;12(560)

Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA.

Dysbiosis of the skin microbiota is increasingly implicated as a contributor to the pathogenesis of atopic dermatitis (AD). We previously reported first-in-human safety and clinical activity results from topical application of the commensal skin bacterium for the treatment of AD in 10 adults and 5 children older than 9 years of age. Here, we examined the potential mechanism of action of treatment and its impact on children with AD less than 7 years of age, the most common age group for children with AD. In 15 children with AD, treatment was associated with amelioration of disease severity, improvement in epithelial barrier function, reduced burden on the skin, and a reduction in topical steroid requirements without severe adverse events. Our observed response rates to treatment were greater than those seen in historical placebo control groups in prior AD studies. Skin improvements and colonization by persisted for up to 8 months after cessation of treatment. Analyses of cellular scratch assays and the MC903 mouse model of AD suggested that production of sphingolipids by , cholinergic signaling, and flagellin expression may have contributed to therapeutic impact through induction of a TNFR2-mediated epithelial-to-mesenchymal transition. These results suggest that a randomized, placebo-controlled trial of treatment in individuals with AD is warranted and implicate commensals in the maintenance of the skin epithelial barrier.
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http://dx.doi.org/10.1126/scitranslmed.aaz8631DOI Listing
September 2020

Frontline Science: Breast milk confers passive cellular immunity via CD8-dependent mechanisms.

J Leukoc Biol 2020 Sep 2. Epub 2020 Sep 2.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Most modern research into the immune effects of breast milk has focused on the impacts of immunoglobulin or oligosaccharide content. However, immediately prior to parturition, the cell populations of breast milk become selectively enriched for CD8+ T cells of an effector memory subtype. Despite this observation that the cellular content of breast milk contains a distinct leukocyte population when compared to peripheral blood, the physiologic role of these CD8+ effector memory cells is unknown. Research encompassing animal models and humans has demonstrated that leukocytes are capable of transferring antigen-specific immunity even when lysed, dialyzed to enrich for fractions less than 10 kDa, and orally administered. Our previous work built upon these reports to elucidate several aspects of this dialyzable leukocyte extract (DLE) activity: only DLE from T effector memory CD8+ cells was capable of transferring antigen-specific immunity; the DLE activity was TCRβ dependent; dendritic cells (DCs) were the cellular target of DLE; and DLE enhanced immune activity in epithelial challenge models via induction of IL-6 from DCs. Herein, we reveal that breast milk dialysate activates similar cytokine and genetic pathways as DLE taken from peripheral blood and murine spleens through TCRβ- and CD8-dependent mechanisms. These findings suggest that the CD8+ memory T cells enriched in breast milk, even after potential lysis in the infant gut, may represent a mechanism for passive transfer of cellular immunity from mother to child.
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http://dx.doi.org/10.1002/JLB.3HI0820-406RRDOI Listing
September 2020

Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome.

J Clin Invest 2020 08;130(8):4167-4181

Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular Medicine Branch.

There are more than 7000 described rare diseases, most lacking specific treatment. Autosomal-dominant hyper-IgE syndrome (AD-HIES, also known as Job's syndrome) is caused by mutations in STAT3. These patients present with immunodeficiency accompanied by severe nonimmunological features, including skeletal, connective tissue, and vascular abnormalities, poor postinfection lung healing, and subsequent pulmonary failure. No specific therapies are available for these abnormalities. Here, we investigated underlying mechanisms in order to identify therapeutic targets. Histological analysis of skin wounds demonstrated delayed granulation tissue formation and vascularization during skin-wound healing in AD-HIES patients. Global gene expression analysis in AD-HIES patient skin fibroblasts identified deficiencies in a STAT3-controlled transcriptional network regulating extracellular matrix (ECM) remodeling and angiogenesis, with hypoxia-inducible factor 1α (HIF-1α) being a major contributor. Consistent with this, histological analysis of skin wounds and coronary arteries from AD-HIES patients showed decreased HIF-1α expression and revealed abnormal organization of the ECM and altered formation of the coronary vasa vasorum. Disease modeling using cell culture and mouse models of angiogenesis and wound healing confirmed these predicted deficiencies and demonstrated therapeutic benefit of HIF-1α-stabilizing drugs. The study provides mechanistic insights into AD-HIES pathophysiology and suggests potential treatment options for this rare disease.
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http://dx.doi.org/10.1172/JCI135490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410079PMC
August 2020

Cutaneous barrier leakage and gut inflammation drive skin disease in Omenn syndrome.

J Allergy Clin Immunol 2020 Nov 18;146(5):1165-1179.e11. Epub 2020 Apr 18.

Milan Unit, Institute for Genetic and Biomedical Research (IRGB) National Research Council (CNR), Milan, Italy; Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy. Electronic address:

Background: Severe early-onset erythroderma and gut inflammation, with massive tissue infiltration of oligoclonal activated T cells are the hallmark of Omenn syndrome (OS).

Objective: The impact of altered gut homeostasis in the cutaneous manifestations of OS remains to be clarified.

Methods: We analyzed a cohort of 15 patients with OS and the 129Sv/C57BL/6 knock-in Rag2 (Rag2) mouse model. Homing phenotypes of circulating lymphocytes were analyzed by flow cytometry. Inflammatory cytokines and chemokines were examined in the sera by ELISA and in skin biopsies by immunohistochemistry and in situ RNA hybridization. Experimental colitis was induced in mice by dextran sulfate sodium salt.

Results: We show that memory/activated T cells from patients with OS and from the Rag2 mouse model of OS abundantly express the skin homing receptors cutaneous lymphocyte associated antigen and CCR4 (Ccr4), associated with high levels of chemokine C-C motif ligands 17 and 22. Serum levels of LPS are also elevated. A broad T1/T2/T17 inflammatory signature is detected in the periphery and in the skin. Increased Tlr4 expression in the skin of Rag2 mice is associated with enhanced cutaneous inflammation on local and systemic administration of LPS. Likewise, boosting colitis in Rag2 mice results in increased frequency of Ccr4 splenic T cells and worsening of skin inflammation, as indicated by epidermal thickening, enhanced epithelial cell activation, and dermal infiltration by T1 effector T cells.

Conclusions: These results support the existence of an interplay between gut and skin that can sustain skin inflammation in OS.
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http://dx.doi.org/10.1016/j.jaci.2020.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649331PMC
November 2020

Allergy as a Disease of Dysbiosis: Is It Time to Shift the Treatment Paradigm?

Authors:
Ian A Myles

Front Cell Infect Microbiol 2019 7;9:50. Epub 2019 Mar 7.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.

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http://dx.doi.org/10.3389/fcimb.2019.00050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416200PMC
November 2019

Differing Virulence of Healthy Skin Commensals in Mouse Models of Infection.

Front Cell Infect Microbiol 2018 21;8:451. Epub 2019 Jan 21.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.

As therapies for atopic dermatitis (AD) based on live biotherapeutic products (LBP) are developed, the potential displacement of biotherapeutic strains, and species to mucosal sites where they are not naturally found is of investigative interest. However, formal assessment of the toxicity potential of healthy skin commensal organisms has not been reported in the literature. Our previous research indicates that topical application of live to treat AD was associated with clinical benefit on the skin, but the effects of exposure via inhalation, eye inoculation, and ingestion were unknown. Herein we report our findings from mice inoculated with commensal strains of , coagulase negative (CNS), and . Bacterial isolates were collected under clinical trial NCT03018275, however these results do not represent an interventional clinical trial. Our tested R. mucosa isolates did not display significant infection or inflammation. However, neutropenic mice inoculated with CNS had infection without major inflammation in pulmonary models. In contrast, systemic infection generated hepatic and splenic pathology for and CNS, which was worsened by the presence of neutropenia. Our results suggest that LBP derived from bacteria without significant infectivity histories, such as , may represent safer options than known pathobionts like and spp. Overall, these results suggest that topically applied LBP from select skin commensals are likely to present safe therapeutic options and reinforce our prior clinical findings.
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http://dx.doi.org/10.3389/fcimb.2018.00451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348709PMC
September 2019

Prolonging culture of primary human keratinocytes isolated from suction blisters with the Rho kinase inhibitor Y-27632.

PLoS One 2018 12;13(9):e0198862. Epub 2018 Sep 12.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, United States of America.

Keratinocytes are the most abundant cell type in the epidermis. They prevent desiccation and provide immunological and barrier defense against potential pathogens such as Staphylococcus aureus and Candida albicans. The study of this first line of immune defense may be hindered by invasive isolation methods and/or improper culture conditions to support stem cell maintenance and other potential mechanisms contributing to long-term subcultivation in vitro. Primary keratinocytes have been successfully isolated from blister roofs induced by negative pressure, which separates the epidermis from the dermis in vivo in human subjects. This method allows collection of pure epidermal cells without dermal contamination in a minimally invasive manner. However, the isolated keratinocytes differentiate and senesce when cultured in vitro beyond five passages. Here, we present evidence that the Rho kinase (ROCK) inhibitor Y-27632 can be used to effectively increase the proliferative capabilities of keratinocytes isolated using the suction blister method, similar to what has been previously reported for primary keratinocytes isolated using alternative methods. We show that the increase in passage number is directly correlated to delayed differentiation, and that cells passaged long term with the inhibitor retain their ability to stratify in organotypic raft cultures and respond to cytokine treatment; additionally, the late passage cells have a heterogeneous mix of differentiated and non-differentiated cells which may be predicted by a ratio of select differentiation markers. The described method presents a minimally invasive procedure for keratinocyte isolation and prolonged culture that allows analysis of keratinocyte function in both healthy volunteers and patients with dermatologic diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198862PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135349PMC
February 2019

TNF overproduction impairs epithelial staphylococcal response in hyper IgE syndrome.

J Clin Invest 2018 08 23;128(8):3595-3604. Epub 2018 Jul 23.

Laboratory of Clinical Immunology and Microbiology, and.

Autosomal dominant hyper IgE syndrome (AD-HIES), or Job's syndrome, is a primary immune deficiency caused by dominant-negative mutations in STAT3. Recurrent Staphylococcus aureus skin abscesses are a defining feature of this syndrome. A widely held hypothesis that defects in peripheral Th17 differentiation confer this susceptibility has never been directly evaluated. To assess the cutaneous immune response in AD-HIES, we induced suction blisters in healthy volunteers (HVs) and patients with AD-HIES and then challenged the wound with lethally irradiated bacteria. We show that cutaneous production of IL-17A and IL-17F was normal in patients with AD-HIES. Overproduction of TNF-α differentiated the responses in AD-HIES from HVs. This was associated with reduced IL-10 family signaling in blister-infiltrating cells and defective epithelial cell function. Mouse models of AD-HIES recapitulated these aberrant epithelial responses to S. aureus and involved defective epithelial-to-mesenchymal transition (EMT) rather than a failure of bacterial killing. Defective responses in mouse models of AD-HIES and primary keratinocyte cultures from patients with AD-HIES could be reversed by TNF-α blockade and by drugs with reported modulatory effects on EMT. Our results identify these as potential therapeutic approaches in patients with AD-HIES suffering S. aureus infections.
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http://dx.doi.org/10.1172/JCI121486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063472PMC
August 2018

Therefore, When I Grow Up I Want to Become an Aspirin Tablet.

Authors:
Ian A Myles

Front Public Health 2018 5;6:169. Epub 2018 Jun 5.

Bacterial Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, United Stated Public Health Service Commissioned Corps, Bethesda, MD, United States.

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http://dx.doi.org/10.3389/fpubh.2018.00169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996830PMC
June 2018

First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis.

JCI Insight 2018 05 3;3(9). Epub 2018 May 3.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.

The underlying pathology of atopic dermatitis (AD) includes impaired skin barrier function, susceptibility to Staphylococcus aureus skin infection, immune dysregulation, and cutaneous dysbiosis. Our recent investigation into the potential role of Gram-negative skin bacteria in AD revealed that isolates of one particular commensal, Roseomonas mucosa, collected from healthy volunteers (HVs) improved outcomes in mouse and cell culture models of AD. In contrast, isolates of R. mucosa from patients with AD worsened outcomes in these models. These preclinical results suggested that interventions targeting the microbiome could provide therapeutic benefit for patients with AD. As a first test of this hypothesis in humans, 10 adult and 5 pediatric patients were enrolled in an open-label phase I/II safety and activity trial (the Beginning Assessment of Cutaneous Treatment Efficacy for Roseomonas in Atopic Dermatitis trial; BACTERiAD I/II). Treatment with R. mucosa was associated with significant decreases in measures of disease severity, topical steroid requirement, and S. aureus burden. There were no adverse events or treatment complications. We additionally evaluated differentiating bacterial metabolites and topical exposures that may contribute to the skin dysbiosis associated with AD and/or influence future microbiome-based treatments. These early results support continued evaluation of R. mucosa therapy with a placebo-controlled trial.
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http://dx.doi.org/10.1172/jci.insight.120608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6012572PMC
May 2018

CD8 T cell dialyzable extract activity is dependent on TCR and MHC-I.

J Leukoc Biol 2017 09;102(3):566-567

Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

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http://dx.doi.org/10.1189/jlb.3LT0517-187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608050PMC
September 2017

Contrasting academic and lay press print coverage of the 2013-2016 Ebola Virus Disease outbreak.

PLoS One 2017 22;12(6):e0179356. Epub 2017 Jun 22.

Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

Under a traditional paradigm, only those with the expected background knowledge consume academic literature. The lay press, as well as government and non-government agencies, play a complementary role of extracting findings of high interest or importance and translating them for general viewing. The need for accurate reporting and public advising is paramount when attempting to tackle epidemic outbreaks through behavior change. Yet, public trust in media outlets is at a historic low. The Crisis and Emergency Risk Communication (CERC) model for media reporting on public health emergencies was established in 2005 and has subsequently been used to analyze media reporting on outbreaks of influenza and measles as well as smoking habits and medication compliance. However, no media analysis had yet been performed on the 2013-2016 Ebola Virus Disease (EVD) outbreak. This study compared the EVD information relayed by lay press sources with general review articles in the academic literature through a mixed-methods analysis. These findings suggest that comprehensive review articles could not serve as a source to clarify and contextualize the uncertainties around the EVD outbreak, perhaps due to adherence to technical accuracy at the expense of clarity within the context of outbreak conditions. This finding does not imply inferiority of the academic literature, nor does it draw direct causation between confusion in review articles and public misunderstanding. Given the erosion of the barriers siloing academia, combined with the demands of today's fast-paced media environment, contemporary researchers should realize that no study is outside the public forum and to therefore consider shifting the paradigm to take personal responsibility in the process of accurately translating their scientific words into public policy actions to best serve as a source of clarity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179356PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480889PMC
September 2017

Molecular Typing of Staphylococcus aureus Isolated from Patients with Autosomal Dominant Hyper IgE Syndrome.

Pathogens 2017 Jun 6;6(2). Epub 2017 Jun 6.

Bacterial Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Autosomal dominant hyper IgE syndrome (AD-HIES) is a primary immunodeficiency caused by a loss-of-function mutation in the Signal Transducer and Activator of Transcription 3 (STAT3). This immune disorder is clinically characterized by increased susceptibility to cutaneous and sinopulmonary infections, in particular with and . It has recently been recognized that the skin microbiome of patients with AD-HIES is altered with an overrepresentation of certain Gram-negative bacteria and Gram-positive staphylococci. However, these alterations have not been characterized at the species- and strain-level. Since infections are influenced by strain-specific expression of virulence factors, information on colonizing strain characteristics may provide insights into host-pathogen interactions and help guide management strategies for treatment and prophylaxis. The aim of this study was to determine whether the immunodeficiency of AD-HIES selects for unique strains of colonizing . Using multi-locus sequence typing (MLST), protein A (spa) typing, and PCR-based detection of toxin genes, we performed a detailed analysis of the isolates ( = 13) found on the skin of twenty-one patients with AD-HIES. We found a low diversity of sequence types, and an abundance of strains that expressed methicillin resistance, Panton-Valentine leukocidin (PVL), and staphylococcal enterotoxins K and Q (SEK, SEQ). Our results indicate that patients with AD-HIES may often carry antibiotic-resistant strains that harbor key virulence factors.
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http://dx.doi.org/10.3390/pathogens6020023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488657PMC
June 2017

CD8+ T cells produce a dialyzable antigen-specific activator of dendritic cells.

J Leukoc Biol 2017 01 11;101(1):307-320. Epub 2016 Aug 11.

Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Cellular lysates from PPD donors have been reported to transfer tuberculin reactivity to naïve recipients, but not diphtheria reactivity, and vice versa. A historically controversial topic, the terms "transfer factor" and "DLE" were used to characterize the reactivity-transferring properties of lysates. Intrigued by these reported phenomena, we found that the cellular extract derived from antigen-specific memory CD8 T cells induces IL-6 from antigen-matched APCs. This ultimately elicits IL-17 from bystander memory CD8 T cells. We have identified that dialyzable peptide sequences, S100a9, and the TCR β chain from CD8 T cells contribute to the molecular nature of this activity. We further show that extracts from antigen-targeted T cells enhance immunity to Staphylococcus aureus and Candida albicans These effects are sensitive to immunization protocols and extraction methodology in ways that may explain past discrepancies in the reproducibility of passive cellular immunity.
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http://dx.doi.org/10.1189/jlb.3A0216-082RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5166436PMC
January 2017

Transplantation of human skin microbiota in models of atopic dermatitis.

JCI Insight 2016 Jul;1(10)

Bacterial Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Maryland, USA.

Atopic dermatitis (AD) is characterized by reduced barrier function, reduced innate immune activation, and susceptibility to . Host susceptibility factors are suggested by monogenic disorders associated with AD-like phenotypes and can be medically modulated. contributes to AD pathogenesis and can be mitigated by antibiotics and bleach baths. Recent work has revealed that the skin microbiome differs significantly between healthy controls and patients with AD, including decreased Gram-negative bacteria in AD. However, little is known about the potential therapeutic benefit of microbiome modulation. To evaluate whether parameters of AD pathogenesis are altered after exposure to different culturable Gram-negative bacteria (CGN) collected from human skin, CGN were collected from healthy controls and patients with AD. Then, effects on cellular and culture-based models of immune, epithelial, and bacterial function were evaluated. Representative strains were evaluated in the MC903 mouse model of AD. We found that CGN taken from healthy volunteers but not from patients with AD were associated with enhanced barrier function, innate immunity activation, and control of . Treatment with CGN from healthy controls improved outcomes in a mouse model of AD. These findings suggest that a live-biotherapeutic approach may hold promise for treatment of patients with AD.
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http://dx.doi.org/10.1172/jci.insight.86955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963067PMC
July 2016

A method for culturing Gram-negative skin microbiota.

BMC Microbiol 2016 Apr 6;16:60. Epub 2016 Apr 6.

Bacterial Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Background: Commensal Gram-negative (CGN) microbiota have been identified on human skin by DNA sequencing; however, methods to reliably culture viable Gram-negative skin organisms have not been previously described.

Results: Through the use of selective antibiotics and minimal media we developed methods to culture CGN from skin swabs. We identified several previously uncharacterized CGN at the species level by optimizing growth conditions and limiting the inhibitory effects of nutrient shock, temperature, and bacterial competition, factors that may have previously limited CGN isolation from skin cultures.

Conclusions: Our protocol will permit future functional studies on the influences of CGN on skin homeostasis and disease.
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http://dx.doi.org/10.1186/s12866-016-0684-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823881PMC
April 2016

Allergen Immunotherapy in an HIV+ Patient with Allergic Fungal Rhinosinusitis.

Case Reports Immunol 2015 14;2015:875260. Epub 2015 Apr 14.

Allergy/Immunology/Immunization Service, Department of Medicine, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA.

Patients with HIV/AIDS can present with multiple types of fungal rhinosinusitis, fungal balls, granulomatous invasive fungal rhinosinusitis, acute or chronic invasive fungal rhinosinusitis, or allergic fungal rhinosinusitis (AFRS). Given the variable spectrum of immune status and susceptibility to severe infection from opportunistic pathogens it is extremely important that clinicians distinguish aggressive fungal invasive fungal disease from the much milder forms such as AFRS. Here we describe a patient with HIV and AFRS to both remind providers of the importance of ruling out invasive fungal disease and outline the other unique features of fungal sinusitis treatment in the HIV-positive population. Additionally we discuss the evidence for and against use of allergen immunotherapy (AIT) for fungal disease in general, as well as the evidence for AIT in the HIV population.
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http://dx.doi.org/10.1155/2015/875260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4411455PMC
May 2015

Strain Specific Phage Treatment for Staphylococcus aureus Infection Is Influenced by Host Immunity and Site of Infection.

PLoS One 2015 24;10(4):e0124280. Epub 2015 Apr 24.

Bacterial Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

The response to multi-drug resistant bacterial infections must be a global priority. While mounting resistance threatens to create what the World Health Organization has termed a "post-antibiotic era", the recent discovery that antibiotic use may adversely impact the microbiome adds further urgency to the need for new developmental approaches for anti-pathogen treatments. Methicillin-resistant Staphylococcus aureus (MRSA), in particular, has declared itself a serious threat within the United States and abroad. A potential solution to the problem of antibiotic resistance may not entail looking to the future for completely novel treatments, but instead looking into our history of bacteriophage therapy. This study aimed to test the efficacy, safety, and commercial viability of the use of phages to treat Staphylococcus aureus infections using the commercially available phage SATA-8505. We found that SATA-8505 effectively controls S. aureus growth and reduces bacterial viability both in vitro and in a skin infection mouse model. However, this killing effect was not observed when phage was cultured in the presence of human whole blood. SATA-8505 did not induce inflammatory responses in peripheral blood mononuclear cultures. However, phage did induce IFN gamma production in primary human keratinocyte cultures and induced inflammatory responses in our mouse models, particularly in a mouse model of chronic granulomatous disease. Our findings support the potential efficacy of phage therapy, although regulatory and market factors may limit its wider investigation and use.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124280PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409319PMC
January 2016

Fast food fever: reviewing the impacts of the Western diet on immunity.

Authors:
Ian A Myles

Nutr J 2014 Jun 17;13:61. Epub 2014 Jun 17.

Bacterial Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike Building 33, Room 2W10A, Bethesda, MD, 20892, Maryland.

While numerous changes in human lifestyle constitute modern life, our diet has been gaining attention as a potential contributor to the increase in immune-mediated diseases. The Western diet is characterized by an over consumption and reduced variety of refined sugars, salt, and saturated fat. Herein our objective is to detail the mechanisms for the Western diet's impact on immune function. The manuscript reviews the impacts and mechanisms of harm for our over-indulgence in sugar, salt, and fat, as well as the data outlining the impacts of artificial sweeteners, gluten, and genetically modified foods; attention is given to revealing where the literature on the immune impacts of macronutrients is limited to either animal or in vitro models versus where human trials exist. Detailed attention is given to the dietary impact on the gut microbiome and the mechanisms by which our poor dietary choices are encoded into our gut, our genes, and are passed to our offspring. While today's modern diet may provide beneficial protection from micro- and macronutrient deficiencies, our over abundance of calories and the macronutrients that compose our diet may all lead to increased inflammation, reduced control of infection, increased rates of cancer, and increased risk for allergic and auto-inflammatory disease.
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http://dx.doi.org/10.1186/1475-2891-13-61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074336PMC
June 2014

Effects of parental omega-3 fatty acid intake on offspring microbiome and immunity.

PLoS One 2014 29;9(1):e87181. Epub 2014 Jan 29.

Bacterial Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

The "Western diet" is characterized by increased intake of saturated and omega-6 (n-6) fatty acids with a relative reduction in omega-3 (n-3) consumption. These fatty acids can directly and indirectly modulate the gut microbiome, resulting in altered host immunity. Omega-3 fatty acids can also directly modulate immunity through alterations in the phospholipid membranes of immune cells, inhibition of n-6 induced inflammation, down-regulation of inflammatory transcription factors, and by serving as pre-cursors to anti-inflammatory lipid mediators such as resolvins and protectins. We have previously shown that consumption by breeder mice of diets high in saturated and n-6 fatty acids have inflammatory and immune-modulating effects on offspring that are at least partially driven by vertical transmission of altered gut microbiota. To determine if parental diets high in n-3 fatty acids could also affect offspring microbiome and immunity, we fed breeding mice an n-3-rich diet with 40% calories from fat and measured immune outcomes in their offspring. We found offspring from mice fed diets high in n-3 had altered gut microbiomes and modestly enhanced anti-inflammatory IL-10 from both colonic and splenic tissue. Omega-3 pups were protected during peanut oral allergy challenge with small but measurable alterations in peanut-related serologies. However, n-3 pups displayed a tendency toward worsened responses during E. coli sepsis and had significantly worse outcomes during Staphylococcus aureus skin infection. Our results indicate excess parental n-3 fatty acid intake alters microbiome and immune response in offspring.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087181PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906117PMC
October 2014

Parental dietary fat intake alters offspring microbiome and immunity.

J Immunol 2013 Sep 9;191(6):3200-9. Epub 2013 Aug 9.

Bacterial Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892.

Mechanisms underlying modern increases in prevalence of human inflammatory diseases remain unclear. The hygiene hypothesis postulates that decreased microbial exposure has, in part, driven this immune dysregulation. However, dietary fatty acids also influence immunity, partially through modulation of responses to microbes. Prior reports have described the direct effects of high-fat diets on the gut microbiome and inflammation, and some have additionally shown metabolic consequences for offspring. Our study sought to expand on these previous observations to identify the effects of parental diet on offspring immunity using mouse models to provide insights into challenging aspects of human health. To test the hypothesis that parental dietary fat consumption during gestation and lactation influences offspring immunity, we compared pups of mice fed either a Western diet (WD) fatty acid profile or a standard low-fat diet. All pups were weaned onto the control diet to specifically test the effects of early developmental fat exposure on immune development. Pups from WD breeders were not obese or diabetic, but still had worse outcomes in models of infection, autoimmunity, and allergic sensitization. They had heightened colonic inflammatory responses, with increased circulating bacterial LPS and muted systemic LPS responsiveness. These deleterious impacts of the WD were associated with alterations of the offspring gut microbiome. These results indicate that parental fat consumption can leave a "lard legacy" impacting offspring immunity and suggest inheritable microbiota may contribute to the modern patterns of human health and disease.
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http://dx.doi.org/10.4049/jimmunol.1301057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831371PMC
September 2013

Signaling via the IL-20 receptor inhibits cutaneous production of IL-1β and IL-17A to promote infection with methicillin-resistant Staphylococcus aureus.

Nat Immunol 2013 Aug 23;14(8):804-11. Epub 2013 Jun 23.

Bacterial Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Staphylococcus aureus causes most infections of human skin and soft tissue and is a major infectious cause of mortality. Host defense mechanisms against S. aureus are incompletely understood. Interleukin 19 (IL-19), IL-20 and IL-24 signal through type I and type II IL-20 receptors and are associated with inflammatory skin diseases such as psoriasis and atopic dermatitis. We found here that those cytokines promoted cutaneous infection with S. aureus in mice by downregulating IL-1β- and IL-17A-dependent pathways. We noted similar effects of those cytokines in human keratinocytes after exposure to S. aureus, and antibody blockade of the IL-20 receptor improved outcomes in infected mice. Our findings identify an immunosuppressive role for IL-19, IL-20 and IL-24 during infection that could be therapeutically targeted to alter susceptibility to infection.
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http://dx.doi.org/10.1038/ni.2637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721434PMC
August 2013

Preserving immunogenicity of lethally irradiated viral and bacterial vaccine epitopes using a radio- protective Mn2+-Peptide complex from Deinococcus.

Cell Host Microbe 2012 Jul;12(1):117-124

Department of Pathology, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.

Although pathogen inactivation by γ-radiation is an attractive approach for whole-organism vaccine development, radiation doses required to ensure sterility also destroy immunogenic protein epitopes needed to mount protective immune responses. We demonstrate the use of a reconstituted manganous peptide complex from the radiation-resistant bacterium Deinococcus radiodurans to protect protein epitopes from radiation-induced damage and uncouple it from genome damage and organism killing. The Mn(2+) complex preserved antigenic structures in aqueous preparations of bacteriophage lambda, Venezuelan equine encephalitis virus, and Staphylococcus aureus during supralethal irradiation (25-40 kGy). An irradiated vaccine elicited both antibody and Th17 responses, and induced B and T cell-dependent protection against methicillin-resistant S. aureus (MRSA) in mice. Structural integrity of viruses and bacteria are shown to be preserved at radiation doses far above those which abolish infectivity. This approach could expedite vaccine production for emerging and established pathogens for which no protective vaccines exist.
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http://dx.doi.org/10.1016/j.chom.2012.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073300PMC
July 2012

Staphylococcus aureus: an introduction.

Semin Immunopathol 2012 Mar 27;34(2):181-4. Epub 2012 Jan 27.

Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

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http://dx.doi.org/10.1007/s00281-011-0301-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324845PMC
March 2012

Impulse oscillometry in the evaluation of diseases of the airways in children.

Ann Allergy Asthma Immunol 2011 Mar 6;106(3):191-9. Epub 2011 Jan 6.

Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1960, USA.

Objective: To provide an overview of impulse oscillometry and its application to the evaluation of children with diseases of the airways.

Data Sources: Medline and PubMed search, limited to English language and human disease, with keywords forced oscillation, impulse oscillometry, and asthma.

Study Selections: The opinions of the authors were used to select studies for inclusion in this review.

Results: Impulse oscillometry is a noninvasive and rapid technique requiring only passive cooperation by the patient. Pressure oscillations are applied at the mouth to measure pulmonary resistance and reactance. It is employed by health care professionals to help diagnose pediatric pulmonary diseases such asthma and cystic fibrosis; assess therapeutic responses; and measure airway resistance during provocation testing.

Conclusions: Impulse oscillometry provides a rapid, noninvasive measure of airway impedance. It may be easily employed in the diagnosis and management of diseases of the airways in children.
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http://dx.doi.org/10.1016/j.anai.2010.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401927PMC
March 2011

Phantom rhinitis.

Authors:
Ian A Myles

Int Arch Allergy Immunol 2010 18;153(4):424-7. Epub 2010 Jun 18.

Department of Allergy and Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Sensitivity to strong odors has a broad differential diagnosis. A presentation is made of a 60-year-old man with lifelong mild allergic rhinitis and a superimposed 4-year history of sensitivity to smells. He had no response to medical treatments or allergic immunotherapy. His physical examination was unremarkable. After obtaining a detailed history, a definitive imaging study was performed and the patient underwent corrective treatment for his potentially life-threatening disorder. A detailed differential and strong clinical history is sometimes required to uncover the etiology of non-allergic rhinitis. Overwhelming sensations of strong odors may be a sign of a more serious condition and require investigation. This presentation discusses the differential diagnosis and suggested evaluation for patients with abnormalities in olfaction.
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http://dx.doi.org/10.1159/000316355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2945267PMC
March 2011