Publications by authors named "Emily K Cope"

20 Publications

  • Page 1 of 1

Do the Bugs in Your Gut Eat Your Memories? Relationship between Gut Microbiota and Alzheimer's Disease.

Brain Sci 2020 Nov 3;10(11). Epub 2020 Nov 3.

The Pathogen and Microbiome Institute, Center for Applied Microbiome Science, Northern Arizona University, Flagstaff, AZ 86011, USA.

The human microbiota is composed of trillions of microbial cells inhabiting the oral cavity, skin, gastrointestinal (GI) tract, airways, and reproductive organs. The gut microbiota is composed of dynamic communities of microorganisms that communicate bidirectionally with the brain via cytokines, neurotransmitters, hormones, and secondary metabolites, known as the gut microbiota-brain axis. The gut microbiota-brain axis is suspected to be involved in the development of neurological diseases, including Alzheimer's disease (AD), Parkinson's disease, and Autism Spectrum Disorder. AD is an irreversible, neurodegenerative disease of the central nervous system (CNS), characterized by amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Microglia and astrocytes, the resident immune cells of the CNS, play an integral role in AD development, as neuroinflammation is a driving factor of disease severity. The gut microbiota-brain axis is a novel target for Alzheimer's disease therapeutics to modulate critical neuroimmune and metabolic pathways. Potential therapeutics include probiotics, prebiotics, fecal microbiota transplantation, and dietary intervention. This review summarizes our current understanding of the role of the gut microbiota-brain axis and neuroinflammation in the onset and development of Alzheimer's disease, limitations of current research, and potential for gut microbiota-brain axis targeted therapies.
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http://dx.doi.org/10.3390/brainsci10110814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693835PMC
November 2020

Microbiotyping the Sinonasal Microbiome.

Front Cell Infect Microbiol 2020 8;10:137. Epub 2020 Apr 8.

Department of Otolaryngology, Head and Neck Surgery, University of Adelaide, Adelaide, SA, Australia.

This study offers a novel description of the sinonasal microbiome, through an unsupervised machine learning approach combining dimensionality reduction and clustering. We apply our method to the International Sinonasal Microbiome Study (ISMS) dataset of 410 sinus swab samples. We propose three main sinonasal "microbiotypes" or "states": the first is -dominated, the second is -dominated, and the third dominated by the other core genera of the sinonasal microbiome (, and ). The prevalence of the three microbiotypes studied did not differ between healthy and diseased sinuses, but differences in their distribution were evident based on geography. We also describe a potential reciprocal relationship between species and , suggesting that a certain microbial equilibrium between various players is reached in the sinuses. We validate our approach by applying it to a separate 16S rRNA gene sequence dataset of 97 sinus swabs from a different patient cohort. Sinonasal microbiotyping may prove useful in reducing the complexity of describing sinonasal microbiota. It may drive future studies aimed at modeling microbial interactions in the sinuses and in doing so may facilitate the development of a tailored patient-specific approach to the treatment of sinus disease in the future.
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http://dx.doi.org/10.3389/fcimb.2020.00137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156599PMC
April 2020

The international sinonasal microbiome study: A multicentre, multinational characterization of sinonasal bacterial ecology.

Allergy 2020 08 30;75(8):2037-2049. Epub 2020 Mar 30.

Department of Otolaryngology, Head and Neck Surgery, University of Adelaide, Adelaide, SA, Australia.

The sinonasal microbiome remains poorly defined, with our current knowledge based on a few cohort studies whose findings are inconsistent. Furthermore, the variability of the sinus microbiome across geographical divides remains unexplored. We characterize the sinonasal microbiome and its geographical variations in both health and disease using 16S rRNA gene sequencing of 410 individuals from across the world. Although the sinus microbial ecology is highly variable between individuals, we identify a core microbiome comprised of Corynebacterium, Staphylococcus, Streptococcus, Haemophilus and Moraxella species in both healthy and chronic rhinosinusitis (CRS) cohorts. Corynebacterium (mean relative abundance = 44.02%) and Staphylococcus (mean relative abundance = 27.34%) appear particularly dominant in the majority of patients sampled. Amongst patients suffering from CRS with nasal polyps, a statistically significant reduction in relative abundance of Corynebacterium (40.29% vs 50.43%; P = .02) was identified. Despite some measured differences in microbiome composition and diversity between some of the participating centres in our cohort, these differences would not alter the general pattern of core organisms described. Nevertheless, atypical or unusual organisms reported in short-read amplicon sequencing studies and that are not part of the core microbiome should be interpreted with caution. The delineation of the sinonasal microbiome and standardized methodology described within our study will enable further characterization and translational application of the sinus microbiota.
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http://dx.doi.org/10.1111/all.14276DOI Listing
August 2020

Author Correction: Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2.

Authors:
Evan Bolyen Jai Ram Rideout Matthew R Dillon Nicholas A Bokulich Christian C Abnet Gabriel A Al-Ghalith Harriet Alexander Eric J Alm Manimozhiyan Arumugam Francesco Asnicar Yang Bai Jordan E Bisanz Kyle Bittinger Asker Brejnrod Colin J Brislawn C Titus Brown Benjamin J Callahan Andrés Mauricio Caraballo-Rodríguez John Chase Emily K Cope Ricardo Da Silva Christian Diener Pieter C Dorrestein Gavin M Douglas Daniel M Durall Claire Duvallet Christian F Edwardson Madeleine Ernst Mehrbod Estaki Jennifer Fouquier Julia M Gauglitz Sean M Gibbons Deanna L Gibson Antonio Gonzalez Kestrel Gorlick Jiarong Guo Benjamin Hillmann Susan Holmes Hannes Holste Curtis Huttenhower Gavin A Huttley Stefan Janssen Alan K Jarmusch Lingjing Jiang Benjamin D Kaehler Kyo Bin Kang Christopher R Keefe Paul Keim Scott T Kelley Dan Knights Irina Koester Tomasz Kosciolek Jorden Kreps Morgan G I Langille Joslynn Lee Ruth Ley Yong-Xin Liu Erikka Loftfield Catherine Lozupone Massoud Maher Clarisse Marotz Bryan D Martin Daniel McDonald Lauren J McIver Alexey V Melnik Jessica L Metcalf Sydney C Morgan Jamie T Morton Ahmad Turan Naimey Jose A Navas-Molina Louis Felix Nothias Stephanie B Orchanian Talima Pearson Samuel L Peoples Daniel Petras Mary Lai Preuss Elmar Pruesse Lasse Buur Rasmussen Adam Rivers Michael S Robeson Patrick Rosenthal Nicola Segata Michael Shaffer Arron Shiffer Rashmi Sinha Se Jin Song John R Spear Austin D Swafford Luke R Thompson Pedro J Torres Pauline Trinh Anupriya Tripathi Peter J Turnbaugh Sabah Ul-Hasan Justin J J van der Hooft Fernando Vargas Yoshiki Vázquez-Baeza Emily Vogtmann Max von Hippel William Walters Yunhu Wan Mingxun Wang Jonathan Warren Kyle C Weber Charles H D Williamson Amy D Willis Zhenjiang Zech Xu Jesse R Zaneveld Yilong Zhang Qiyun Zhu Rob Knight J Gregory Caporaso

Nat Biotechnol 2019 Sep;37(9):1091

Center for Applied Microbiome Science, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41587-019-0252-6DOI Listing
September 2019

Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2.

Authors:
Evan Bolyen Jai Ram Rideout Matthew R Dillon Nicholas A Bokulich Christian C Abnet Gabriel A Al-Ghalith Harriet Alexander Eric J Alm Manimozhiyan Arumugam Francesco Asnicar Yang Bai Jordan E Bisanz Kyle Bittinger Asker Brejnrod Colin J Brislawn C Titus Brown Benjamin J Callahan Andrés Mauricio Caraballo-Rodríguez John Chase Emily K Cope Ricardo Da Silva Christian Diener Pieter C Dorrestein Gavin M Douglas Daniel M Durall Claire Duvallet Christian F Edwardson Madeleine Ernst Mehrbod Estaki Jennifer Fouquier Julia M Gauglitz Sean M Gibbons Deanna L Gibson Antonio Gonzalez Kestrel Gorlick Jiarong Guo Benjamin Hillmann Susan Holmes Hannes Holste Curtis Huttenhower Gavin A Huttley Stefan Janssen Alan K Jarmusch Lingjing Jiang Benjamin D Kaehler Kyo Bin Kang Christopher R Keefe Paul Keim Scott T Kelley Dan Knights Irina Koester Tomasz Kosciolek Jorden Kreps Morgan G I Langille Joslynn Lee Ruth Ley Yong-Xin Liu Erikka Loftfield Catherine Lozupone Massoud Maher Clarisse Marotz Bryan D Martin Daniel McDonald Lauren J McIver Alexey V Melnik Jessica L Metcalf Sydney C Morgan Jamie T Morton Ahmad Turan Naimey Jose A Navas-Molina Louis Felix Nothias Stephanie B Orchanian Talima Pearson Samuel L Peoples Daniel Petras Mary Lai Preuss Elmar Pruesse Lasse Buur Rasmussen Adam Rivers Michael S Robeson Patrick Rosenthal Nicola Segata Michael Shaffer Arron Shiffer Rashmi Sinha Se Jin Song John R Spear Austin D Swafford Luke R Thompson Pedro J Torres Pauline Trinh Anupriya Tripathi Peter J Turnbaugh Sabah Ul-Hasan Justin J J van der Hooft Fernando Vargas Yoshiki Vázquez-Baeza Emily Vogtmann Max von Hippel William Walters Yunhu Wan Mingxun Wang Jonathan Warren Kyle C Weber Charles H D Williamson Amy D Willis Zhenjiang Zech Xu Jesse R Zaneveld Yilong Zhang Qiyun Zhu Rob Knight J Gregory Caporaso

Nat Biotechnol 2019 08;37(8):852-857

Center for Applied Microbiome Science, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, USA.

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http://dx.doi.org/10.1038/s41587-019-0209-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015180PMC
August 2019

Domestic canines do not display evidence of gut microbial dysbiosis in the presence of Clostridioides (Clostridium) difficile, despite cellular susceptibility to its toxins.

Anaerobe 2019 Aug 1;58:53-72. Epub 2019 Apr 1.

Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA; Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ, 86011, USA. Electronic address:

Clostridioides difficile infection (CDI) is an emerging public health threat and C. difficile is the most common cause of antimicrobial-associated diarrhea worldwide and the leading cause of hospital-associated infections in the US, yet the burden of community-acquired infections (CAI) is poorly understood. Characterizing C. difficile isolated from canines is important for understanding the role that canines may play in CAI. In addition, several studies have suggested that canines carry toxigenic C. difficile asymptomatically, which may imply that there are mechanisms responsible for resistance to CDI in canines that could be exploited to help combat human CDI. To assess the virulence potential of canine-derived C. difficile, we tested whether toxins TcdA and TcdB (hereafter toxins) derived from a canine isolate were capable of causing tight junction disruptions to colonic epithelial cells. Additionally, we addressed whether major differences exist between human and canine cells regarding C. difficile pathogenicity by exposing them to identical toxins. We then examined the canine gut microbiome associated with C. difficile carriage using 16S rRNA gene sequencing and searched for deviations from homeostasis as an indicator of CDI. Finally, we queried 16S rRNA gene sequences for bacterial taxa that may be associated with resistance to CDI in canines. Clostridioides difficile isolated from a canine produced toxins that reduced tight junction integrity in both human and canine cells in vitro. However, canine guts were not dysbiotic in the presence of C. difficile. These findings support asymptomatic carriage in canines and, furthermore, suggest that there are features of the gut microbiome and/or a canine-specific immune response that may protect canines against CDI. We identified two biologically relevant bacteria that may aid in CDI resistance in canines: 1) Clostridium hiranonis, which synthesizes secondary bile acids that have been shown to provide resistance to CDI in mice; and 2) Sphingobacterium faecium, which produces sphingophospholipids that may be associated with regulating homeostasis in the canine gut. Our findings suggest that canines may be cryptic reservoirs for C. difficile and, furthermore, that mechanisms of CDI resistance in the canine gut could provide insights into targeted therapeutics for human CDI.
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http://dx.doi.org/10.1016/j.anaerobe.2019.03.017DOI Listing
August 2019

Loss of Microbial Niche Specificity Between the Upper and Lower Airways in Patients With Cystic Fibrosis.

Laryngoscope 2019 03 3;129(3):544-550. Epub 2018 Oct 3.

Pathogen and Microbiome Institute, Department of Biological Sciences, Northern Arizona University, Flagstaff, Arizona, U.S.A.

Objectives/hypothesis: To determine the relationship between mucosal-associated sinus and bronchial microbiota in cystic fibrosis (CF) patients compared to non-CF patients with chronic rhinosinusitis (CRS).

Study Design: Case series.

Methods: We examined the microbial composition of 52 paired sinus and bronchial brushings from 26 patients with CRS. Paired airway samples from nine subjects with CF were compared with samples from 17 non-CF-CRS disease control patients. The Illumina MiSeq platform was used to sequence the V4 region of the 16S rRNA gene. Sequences were analyzed using QIIME 1.9.0.

Results: CF patients demonstrate increased severity of sinus inflammation (Lund-Mackay score 16.3 vs. 12.4, P = .023) and diminished diversity of microbial communities in both the sinuses (Shannon diversity 0.98 vs. 3.3, P = .009) and lungs (Shannon diversity 2.2 vs. 4.0, P = .042) relative to non-CF-CRS. Non-CF-CRS sinus and lung microbiota were distinct and clustered by niche (sinus vs. lung, P = .004). However, CF airway microbiota demonstrated a loss of niche specificity (sinus vs. lung, P = .492). Two CF patients underwent lung transplantation at 4.5 and 9 months prior to sampling. Sinus and lung samples from these two patients demonstrated distinct microbial communities.

Conclusions: Patients with CF undergoing surgery for CRS exhibit substantial bacterial community collapse in the sinuses and a loss of niche specificity between the upper and lower airways compared to non-CF patients with CRS. These results extend previous studies elucidating the lower airway microbiome in cystic fibrosis and provide support for the concept of microbial translocation in the cystic fibrosis airways.

Level Of Evidence: 4 Laryngoscope, 129:544-550, 2019.
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http://dx.doi.org/10.1002/lary.27454DOI Listing
March 2019

Heterogeneity of Microbiota Dysbiosis in Chronic Rhinosinusitis: Potential Clinical Implications and Microbial Community Mechanisms Contributing to Sinonasal Inflammation.

Front Cell Infect Microbiol 2018 23;8:168. Epub 2018 May 23.

Department of Biological Sciences, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, United States.

Recent studies leveraging next-generation sequencing and functional approaches to understand the human microbiota have demonstrated the presence of diverse, niche-specific microbial communities at nearly every mucosal surface. These microbes contribute to the development and function of physiologic and immunological features that are key to host health status. Not surprisingly, several chronic inflammatory diseases have been attributed to dysbiosis of microbiota composition or function, including chronic rhinosinusitis (CRS). CRS is a heterogeneous disease characterized by inflammation of the sinonasal cavity and mucosal microbiota dysbiosis. Inflammatory phenotypes and bacterial community compositions vary considerably across individuals with CRS, complicating current studies that seek to address causality of a dysbiotic microbiome as a driver or initiator of persistent sinonasal inflammation. Murine models have provided some experimental evidence that alterations in local microbial communities and microbially-produced metabolites influence health status. In this perspective, we will discuss the clinical implications of distinct microbial compositions and community-level functions in CRS and how mucosal microbiota relate to the diverse inflammatory endotypes that are frequently observed. We will also describe specific microbial interactions that can deterministically shape the pattern of co-colonizers and the resulting metabolic products that drive or exacerbate host inflammation. These findings are discussed in the context of CRS-associated inflammation and in other chronic inflammatory diseases that share features observed in CRS. An improved understanding of CRS patient stratification offers the opportunity to personalize therapeutic regimens and to design novel treatments aimed at manipulation of the disease-associated microbiota to restore sinus health.
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http://dx.doi.org/10.3389/fcimb.2018.00168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974464PMC
July 2019

Host-Microbe Interactions in Airway Disease: toward Disease Mechanisms and Novel Therapeutic Strategies.

Authors:
Emily K Cope

mSystems 2018 Mar-Apr;3(2). Epub 2018 Mar 13.

Department of Biological Sciences, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, Arizona, USA.

Despite growing efforts to understand the role of the microbiota in airway disease, mechanisms that link microbial community dysbiosis to chronic inflammation remain elusive. Our laboratory is interested in how altered microbiota composition or function influences airway inflammatory diseases, including chronic rhinosinusitis, asthma, and cystic fibrosis. Given the tight interplay between host-associated microbes and host immunity, the potential for translational microbiome research to guide clinical decisions and novel therapeutics is becoming better appreciated. We hope to advance our understanding of the ecology of airway disease through integrating multiple omics assays and and experimental validation. An increased understanding of the role of the microbiota in chronic airway inflammation will ultimately lead to the rational development of therapeutics aimed at manipulation of microbiota composition or activity to treat these important and costly diseases. In this perspective, I discuss our current research investigating the microbiology and ecology of the airway microbiome.
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http://dx.doi.org/10.1128/mSystems.00158-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850075PMC
March 2018

Fungal Microbiota in Chronic Airway Inflammatory Disease and Emerging Relationships with the Host Immune Response.

Front Microbiol 2017 12;8:2477. Epub 2017 Dec 12.

Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, United States.

The respiratory tract is a complex system that is inhabited by niche-specific communities of microbes including bacteria, fungi, and viruses. These complex microbial assemblages are in constant contact with the mucosal immune system and play a critical role in airway health and immune homeostasis. Changes in the composition and diversity of airway microbiota are frequently observed in patients with chronic inflammatory diseases including chronic rhinosinusitis (CRS), cystic fibrosis, allergy, and asthma. While the bacterial microbiome of the upper and lower airways has been the focus of many recent studies, the contribution of fungal microbiota to inflammation is an emerging research interest. Within the context of allergic airway disease, fungal products are important allergens and fungi are potent inducers of inflammation. In addition, murine models have provided experimental evidence that fungal microbiota in peripheral organs, notably the gastrointestinal (GI) tract, influence pulmonary health. In this review, we explore the role of the respiratory and GI microbial communities in chronic airway inflammatory disease development with a specific focus on fungal microbiome interactions with the airway immune system and fungal-bacterial interactions that likely contribute to inflammatory disease. These findings are discussed in the context of clinical and immunological features of fungal-mediated disease in CRS, allergy, and asthmatic patients. While this field is still nascent, emerging evidence suggests that dysbiotic fungal and bacterial microbiota interact to drive or exacerbate chronic airway inflammatory disease.
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http://dx.doi.org/10.3389/fmicb.2017.02477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733051PMC
December 2017

Compositionally and functionally distinct sinus microbiota in chronic rhinosinusitis patients have immunological and clinically divergent consequences.

Microbiome 2017 05 12;5(1):53. Epub 2017 May 12.

Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, 94143, USA.

Background: Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by persistent sinonasal inflammation and sinus microbiome dysbiosis. The basis of this heterogeneity is poorly understood. We sought to address the hypothesis that a limited number of compositionally distinct pathogenic bacterial microbiota exist in CRS patients and invoke discrete immune responses and clinical phenotypes in CRS patients.

Results: Sinus brushings from patients with CRS (n = 59) and healthy individuals (n = 10) collected during endoscopic sinus surgery were analyzed using 16S rRNA gene sequencing, predicted metagenomics, and RNA profiling of the mucosal immune response. We show that CRS patients cluster into distinct sub-groups (DSI-III), each defined by specific pattern of bacterial co-colonization (permutational multivariate analysis of variance (PERMANOVA); p = 0.001, r  = 0.318). Each sub-group was typically dominated by a pathogenic family: Streptococcaceae (DSI), Pseudomonadaceae (DSII), Corynebacteriaceae [DSIII(a)], or Staphylococcaceae [DSIII(b)]. Each pathogenic microbiota was predicted to be functionally distinct (PERMANOVA; p = 0.005, r  = 0.217) and encode uniquely enriched gene pathways including ansamycin biosynthesis (DSI), tryptophan metabolism (DSII), two-component response [DSIII(b)], and the PPAR-γ signaling pathway [DSIII(a)]. Each is also associated with significantly distinct host immune responses; DSI, II, and III(b) invoked a variety of pro-inflammatory, T1 responses, while DSIII(a), which exhibited significantly increased incidence of nasal polyps (Fisher's exact; p = 0.034, relative risk = 2.16), primarily induced IL-5 expression (Kruskal Wallis; q = 0.045).

Conclusions: A large proportion of CRS patient heterogeneity may be explained by the composition of their sinus bacterial microbiota and related host immune response-features which may inform strategies for tailored therapy in this patient population.
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http://dx.doi.org/10.1186/s40168-017-0266-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427582PMC
May 2017

Mapping and comparing bacterial microbiota in the sinonasal cavity of healthy, allergic rhinitis, and chronic rhinosinusitis subjects.

Int Forum Allergy Rhinol 2017 06 8;7(6):561-569. Epub 2017 May 8.

Translational Genomics Research Institute, Flagstaff, AZ.

Background: The role of microbiota in sinonasal inflammation can be further understood by targeted sampling of healthy and diseased subjects. We compared the microbiota of the middle meatus (MM) and inferior meatus (IM) in healthy, allergic rhinitis (AR), and chronic rhinosinusitis (CRS) subjects to characterize intrasubject, intersubject, and intergroup differences.

Methods: Subjects were recruited in the office, and characterized into healthy, AR, and CRS groups. Endoscopically-guided swab samples were obtained from the MM and IM bilaterally. Bacterial microbiota were characterized by sequencing the V3-V4 region of the 16S ribosomal RNA (rRNA) gene.

Results: Intersubject microbiome analyses were conducted in 65 subjects: 8 healthy, 11 AR, and 46 CRS (25 CRS with nasal polyps [CRSwNP]; 21 CRS without nasal polyps [CRSsNP]). Intrasubject analyses were conducted for 48 individuals (4 controls, 11 AR, 8 CRSwNP, and 15 CRSwNP). There was considerable intersubject microbiota variability, but intrasubject profiles were similar (p = 0.001, nonparametric t test). Intrasubject bacterial diversity was significantly reduced in MM of CRSsNP subjects compared to IM samples (p = 0.022, nonparametric t test). CRSsNP MM samples were enriched in Streptococcus, Haemophilus, and Fusobacterium spp. but exhibited loss of diversity compared to healthy, CRSwNP, and AR subject-samples (p < 0.05; nonparametric t test). CRSwNP patients were enriched in Staphylococcus, Alloiococcus, and Corynebacterium spp.

Conclusion: This study presents the sinonasal microbiome profile in one of the larger populations of non-CRS and CRS subjects, and is the first office-based cohort in the literature. In contrast to healthy, AR, and CRSwNP subjects, CRSsNP MM samples exhibited decreased microbiome diversity and anaerobic enrichment. CRSsNP MM samples had reduced diversity compared to same-subject IM samples, a novel finding.
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http://dx.doi.org/10.1002/alr.21934DOI Listing
June 2017

A chronic rhinosinusitis-derived isolate of Pseudomonas aeruginosa induces acute and pervasive effects on the murine upper airway microbiome and host immune response.

Int Forum Allergy Rhinol 2016 12 6;6(12):1229-1237. Epub 2016 Sep 6.

Division of Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA.

Background: Diverse microbial communities colonize healthy sinus mucosa and specific species within these communities are capable of protecting the host from pathogenic infection. However, little is known of the dynamics of upper airway infection and the role of the sinus mucosal microbiome in short- and longer-term outcomes using clinical isolates from patients with chronic rhinosinusitis.

Methods: We examine microbiome and immune dynamics after murine sinus infection with Pseudomonas aeruginosa EC1, isolated previously from a chronic rhinosinusitis patient. Microbiota profiling (16S rRNA sequencing), histologic, and immunologic analyses [interferon-gamma (IFN-γ) and eotaxin-1 (CCL11) gene expression] were performed at 1, 7, and 10 days postinfection (D1PI, D7PI, and D10PI) in antimicrobial-treated and untreated animals.

Results: At D1PI, P. aeruginosa EC1 dominated the upper airway microbiome and was associated with a significant increase in sinus mucosa goblet cell hyperplasia, mucin hypersecretion (p < 0.001), and IFN-γ expression in antibiotic-treated and untreated animals, although the magnitude of pathogen enrichment was lower in the latter group. Mucin hypersecretion and IFN-γ expression subsided by 7D7PI in both groups of mice, coincident with a depletion of the infectious strain. However, other members of the Pseudomonadaceae family remained significantly enriched (p < 0.05, q < 0.05) in the microbiome at D7PI and D10PI and this perturbation was associated with induction of eotaxin-1 at these later time-points.

Conclusion: Murine intranasal P. aeruginosa EC1 infection causes a pervasive shift in the sinus microbiome that persists despite histologic resolution and is associated with a reproducible immunologic shift from an initial IFN-γ response to a temporal induction of eotaxin-1.
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http://dx.doi.org/10.1002/alr.21819DOI Listing
December 2016

Evaluation of Malassezia and Common Fungal Pathogens in Subtypes of Chronic Rhinosinusitis.

Int Forum Allergy Rhinol 2016 09 6;6(9):950-5. Epub 2016 May 6.

Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA.

Background: Fungal hypersensitivity and fungal microbiome dysbiosis are possible etiologies of chronic rhinosinusitis. The sinus fungal microbiome is not well characterized; novel sinus-associated fungi, including Malassezia, have only recently been described. The goals for this study were to verify Malassezia as a dominant component of the sinus microbiome, to speciate sinus Malassezia, and to compare select fungal species in chronic rhinosinusitis (CRS) subtypes with known fungal association to chronic rhinosinusitis with polyps (CRSwNP) and healthy controls.

Methods: Twenty-eight patients were enrolled and categorized as CRSwNP (n = 15), fungus ball (n = 3), allergic fungal rhinosinusitis (AFRS, n = 3), or healthy control (n = 7). Brush samples were taken from ethmoid or maxillary sinus mucosa and tested for DNA from 7 index fungi using quantitative polymerase chain reaction. Index fungal species were chosen based on existing data of the sinus fungal microbiome.

Results: Malassezia species were detected in 68% of patients, without variation among clinical phenotypes (p > 0.99). Malassezia restricta was more commonly detected than Malassezia globosa (p = 0.029). Presence of one Malassezia species predicted the presence of the other (p = 0.035). Aspergillus was identified in 2 of 3 of fungus ball patients (both A. fumigatus) and 2 of 3 AFRS patients (1 A. fumigatus and 1 A. flavus). Aspergillus was absent in control and CRSwNP patients (p < 0.001).

Conclusion: This study confirmed and speciated Malassezia in healthy and diseased sinuses. Presence of Malassezia species in all groups suggests a commensal role for the fungus. Future work will determine whether Malassezia influences CRS pathogenesis. Aspergillus species were identified in fungal CRS subtypes despite negative surgical cultures, highlighting the importance of culture-independent technology.
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http://dx.doi.org/10.1002/alr.21777DOI Listing
September 2016

Sub-inhibitory fosmidomycin exposures elicits oxidative stress in Salmonella enterica serovar Typhimurium LT2.

PLoS One 2014 21;9(4):e95271. Epub 2014 Apr 21.

Department of Chemistry, Northern Arizona University, Flagstaff, Arizona, United States of America.

Fosmidomycin is a time-dependent nanomolar inhibitor of methylerythritol phosphate (MEP) synthase, which is the enzyme that catalyzes the first committed step in the MEP pathway to isoprenoids. Importantly, fosmidomycin is one of only a few MEP pathway-specific inhibitors that exhibits antimicrobial activity. Most inhibitors identified to date only exhibit activity against isolated pathway enzymes. The MEP pathway is the sole route to isoprenoids in many bacteria, yet has no human homologs. The development of inhibitors of this pathway holds promise as novel antimicrobial agents. Similarly, analyses of the bacterial response toward MEP pathway inhibitors provides valuable information toward the understanding of how emergent resistance may ultimately develop to this class of antibiotics. We have examined the transcriptional response of Salmonella enterica serovar typhimurium LT2 to sub-inhibitory concentrations of fosmidomycin via cDNA microarray and RT-PCR. Within the regulated genes identified by microarray were a number of genes encoding enzymes associated with the mediation of reactive oxygen species (ROS). Regulation of a panel of genes implicated in the response of cells to oxidative stress (including genes for catalases, superoxide dismutases, and alkylhydrogen peroxide reductases) was investigated and mild upregulation in some members was observed as a function of fosmidomycin exposure over time. The extent of regulation of these genes was similar to that observed for comparable exposures to kanamycin, but differed significantly from tetracycline. Furthermore, S. typhimurium exposed to sub-inhibitory concentrations of fosmidomycin displayed an increased sensitivity to exogenous H2O2 relative to either untreated controls or kanamycin-treated cells. Our results suggest that endogenous oxidative stress is one consequence of exposures to fosmidomycin, likely through the temporal depletion of intracellular isoprenoids themselves, rather than other mechanisms that have been proposed to facilitate ROS accumulation in bacteria (e.g. cell death processes or the ability of the antibiotic to redox cycle).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095271PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994034PMC
January 2015

Probiotic strategies for treatment of respiratory diseases.

Trends Microbiol 2013 Sep 23;21(9):485-92. Epub 2013 May 23.

Division of Gastroenterology, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.

Recent advances in next-generation sequencing and phylogenetic microarray technologies have identified diverse, niche-specific microbial communities that comprise the human superorganism. Mucosal microbiome perturbation is a prominent feature of an increasing number of chronic inflammatory disorders, including respiratory diseases, and efforts are now focused on identifying novel microbe-based strategies to treat or manage these conditions. Considering the evidence for niche-specificity and the diversity of function that human microbial communities afford, the range of therapeutic species used to date in probiotic supplements is strikingly narrow and is limited to species typically of gastrointestinal origin. Although the field is still relatively nascent, the potential for identifying novel microbe-based therapeutics in the human microbiome is great. This article focuses primarily on the respiratory tract, its associated microbiome, potential interactions with the gastrointestinal microbiota, and the possibilities for microbiome-manipulation strategies in the treatment and prevention of respiratory disease.
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http://dx.doi.org/10.1016/j.tim.2013.04.008DOI Listing
September 2013

Regulation of virulence gene expression resulting from Streptococcus pneumoniae and nontypeable Haemophilus influenzae interactions in chronic disease.

PLoS One 2011 5;6(12):e28523. Epub 2011 Dec 5.

Department of Biological Sciences, Northern Arizona University, Flagstaff, Arizona, United States of America.

Chronic rhinosinusitis (CRS) is a common inflammatory disease of the sinonasal cavity mediated, in part, by polymicrobial communities of bacteria. Recent molecular studies have confirmed the importance of Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi) in CRS. Here, we hypothesize that interaction between S. pneumoniae and NTHi mixed-species communities cause a change in bacterial virulence gene expression. We examined CRS as a model human disease to validate these polymicrobial interactions. Clinical strains of S. pneumoniae and NTHi were grown in mono- and co-culture in a standard biofilm assay. Reverse transcriptase real-time PCR (RTqPCR) was used to measure gene expression of key virulence factors. To validate these results, we investigated the presence of the bacterial RNA transcripts in excised human tissue from patients with CRS. Consequences of physical or chemical interactions between microbes were also investigated. Transcription of NTHi type IV pili was only expressed in co-culture in vitro, and expression could be detected ex vivo in diseased tissue. S. pneumoniae pyruvate oxidase was up-regulated in co-culture, while pneumolysin and pneumococcal adherence factor A were down-regulated. These results were confirmed in excised human CRS tissue. Gene expression was differentially regulated by physical contact and secreted factors. Overall, these data suggest that interactions between H. influenzae and S. pneumoniae involve physical and chemical mechanisms that influence virulence gene expression of mixed-species biofilm communities present in chronically diseased human tissue. These results extend previous studies of population-level virulence and provide novel insight into the importance of S. pneumoniae and NTHi in CRS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028523PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230614PMC
July 2012

In vitro antimicrobial studies of silver carbene complexes: activity of free and nanoparticle carbene formulations against clinical isolates of pathogenic bacteria.

J Antimicrob Chemother 2012 Jan 3;67(1):138-48. Epub 2011 Oct 3.

Department of Biological Sciences, Northern Arizona University, PO Box 5640, Building 21, Flagstaff, AZ 86011, USA.

Objectives: Silver carbenes may represent novel, broad-spectrum antimicrobial agents that have low toxicity while providing varying chemistry for targeted applications. Here, the bactericidal activity of four silver carbene complexes (SCCs) with different formulations, including nanoparticles (NPs) and micelles, was tested against a panel of clinical strains of bacteria and fungi that are the causative agents of many skin and soft tissue, respiratory, wound, blood, and nosocomial infections.

Methods: MIC, MBC and multidose experiments were conducted against a broad range of bacteria and fungi. Time-release and cytotoxicity studies of the compounds were also carried out. Free SCCs and SCC NPs were tested against a panel of medically important pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Acinetobacter baumannii (MRAB), Pseudomonas aeruginosa, Burkholderia cepacia and Klebsiella pneumoniae.

Results: All four SCCs demonstrated strong efficacy in concentration ranges of 0.5-90 mg/L. Clinical bacterial isolates with high inherent resistance to purified compounds were more effectively treated either with an NP formulation of these compounds or by repeated dosing. Overall, the compounds were active against highly resistant bacterial strains, such as MRSA and MRAB, and were active against the biodefence pathogens Bacillus anthracis and Yersinia pestis. All of the medically important bacterial strains tested play a role in many different infectious diseases.

Conclusions: The four SCCs described here, including their development as NP therapies, show great promise for treating a wide variety of bacterial and fungal pathogens that are not easily killed by routine antimicrobial agents.
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http://dx.doi.org/10.1093/jac/dkr408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236053PMC
January 2012

Tobacco smoke mediated induction of sinonasal microbial biofilms.

PLoS One 2011 Jan 6;6(1):e15700. Epub 2011 Jan 6.

Department of Otorhinolaryngology, Head and Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Cigarette smokers and those exposed to second hand smoke are more susceptible to life threatening infection than non-smokers. While much is known about the devastating effect tobacco exposure has on the human body, less is known about the effect of tobacco smoke on the commensal and commonly found pathogenic bacteria of the human respiratory tract, or human respiratory tract microbiome. Chronic rhinosinusitis (CRS) is a common medical complaint, affecting 16% of the US population with an estimated aggregated cost of $6 billion annually. Epidemiologic studies demonstrate a correlation between tobacco smoke exposure and rhinosinusitis. Although a common cause of CRS has not been defined, bacterial presence within the nasal and paranasal sinuses is assumed to be contributory. Here we demonstrate that repetitive tobacco smoke exposure induces biofilm formation in a diverse set of bacteria isolated from the sinonasal cavities of patients with CRS. Additionally, bacteria isolated from patients with tobacco smoke exposure demonstrate robust in vitro biofilm formation when challenged with tobacco smoke compared to those isolated from smoke naïve patients. Lastly, bacteria from smoke exposed patients can revert to a non-biofilm phenotype when grown in the absence of tobacco smoke. These observations support the hypothesis that tobacco exposure induces sinonasal biofilm formation, thereby contributing to the conversion of a transient and medically treatable infection to a persistent and therapeutically recalcitrant condition.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0015700PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017060PMC
January 2011

Flagellum-mediated biofilm defense mechanisms of Pseudomonas aeruginosa against host-derived lactoferrin.

Infect Immun 2009 Oct 3;77(10):4559-66. Epub 2009 Aug 3.

Department of Biological Sciences, Northern Arizona University, Flagstaff, Arizona 86001, USA.

Chronic infection with the gram-negative organism Pseudomonas aeruginosa is a leading cause of morbidity and mortality in human patients, despite high doses of antibiotics used to treat the various diseases this organism causes. These infections are chronic because P. aeruginosa readily forms biofilms, which are inherently resistant to antibiotics as well as the host's immune system. Our laboratory has been investigating specific mutations in P. aeruginosa that regulate biofilm bacterial susceptibility to the host. To continue our investigation of the role of genetics in bacterial biofilm host resistance, we examined P. aeruginosa biofilms that lack the flgK gene. This mutant lacks flagella, which results in defects in early biofilm development (up to 36 h). For these experiments, the flgK-disrupted strain and the parental strain (PA14) were used in a modified version of the 96-well plate microtiter assay. Biofilms were challenged with freshly isolated human leukocytes for 4 to 6 h and viable bacteria enumerated by CFU. Subsequent to the challenge, both mononuclear cells (monocytes and lymphocytes) and neutrophils, along with tumor necrosis factor alpha (TNF-alpha), were required for optimal killing of the flgK biofilm bacteria. We identified a cytokine cross talk network between mononuclear cells and neutrophils that was essential to the production of lactoferrin and bacterial killing. Our data suggest that TNF-alpha is secreted from mononuclear cells, causing neutrophil activation, resulting in the secretion of bactericidal concentrations of lactoferrin. These results extend previous studies of the importance of lactoferrin in the innate immune defense against bacterial biofilms.
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http://dx.doi.org/10.1128/IAI.00075-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747969PMC
October 2009