Elizabeth A Grice

University of Pennsylvania, Philadelphia, Pennsylvania, United States

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Publications (26)273.34 Total impact

  • Brendan P Hodkinson, Elizabeth A Grice
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    ABSTRACT: Significance: The colonization of wounds by specific microbes or communities of microbes may delay healing and/or lead to infection-related complication. Studies of wound-associated microbial communities (microbiomes) to date have primarily relied upon culture-based methods, which are known to have extreme biases and are not reliable for the characterization of microbiomes. Biofilms are very resistant to culture and are therefore especially difficult to study with techniques that remain standard in clinical settings. Recent Advances: Culture-independent approaches employing next-generation DNA sequencing have provided researchers and clinicians a window into wound-associated microbiomes that could not be achieved before and has begun to transform our view of wound-associated biodiversity. Within the past decade, many platforms have arisen for performing this type of sequencing, with various types of applications for microbiome research being possible on each. Critical Issues: Wound care incorporating knowledge of microbiomes gained from next-generation sequencing could guide clinical management and treatments. The purpose of this review is to outline the current platforms, their applications, and the steps necessary to undertake microbiome studies using next-generation sequencing. Future Directions: As DNA sequencing technology progresses, platforms will continue to produce longer reads and more reads per run at lower costs. A major future challenge is to implement these technologies in clinical settings for more precise and rapid identification of wound bioburden.
    Advances in wound care. 01/2015; 4(1):50-58.
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    ABSTRACT: Significance: Open fractures are fractures in which the bone has violated the skin and soft tissue. Because of their severity, open fractures are associated with complications that can result in increased lengths of hospital stays, multiple operative interventions, and even amputation. One of the factors thought to influence the extent of these complications is exposure and contamination of the open fracture with environmental microorganisms, potentially those that are pathogenic in nature. Recent Advances: Current open fracture care aims to prevent infection by wound classification, prophylactic antibiotic administration, debridement and irrigation, and stable fracture fixation. Critical Issues: Despite these established treatment paradigms, infections and infection-related complications remain a significant clinical burden. To address this, improvements need to be made in our ability to detect bacterial infections, effectively remove wound contamination, eradicate infections, and treat and prevent biofilm formation associated with fracture fixation hardware. Future Directions: Current research is addressing these critical issues. While culture methods are of limited value, culture-independent molecular techniques are being developed to provide informative detection of bacterial contamination and infection. Other advanced contamination- and infection-detecting techniques are also being investigated. New hardware-coating methods are being developed to minimize the risk of biofilm formation in wounds, and immune stimulation techniques are being developed to prevent open fracture infections.
    Advances in wound care. 01/2015; 4(1):59-74.
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    ABSTRACT: Wound healing is a complex homeostatic response to injury that engages numerous cellular activities, processes, and cell-to-cell interactions. The complement system, an intricate network of proteins with important roles in immune surveillance and homeostasis, has been implicated in many physiological processes; however, its role in wound healing remains largely unexplored. In this study, we employ a murine model of excisional cutaneous wound healing and show that C3(-/-) mice exhibit accelerated early stages of wound healing. Reconstitution of C3(-/-) mice with serum from C3(+/+) mice or purified human C3 abrogated the accelerated wound-healing phenotype. Wound histology of C3(-/-) mice revealed a reduction in inflammatory infiltrate compared with C3(+/+) mice. C3 deficiency also resulted in increased accumulation of mast cells and advanced angiogenesis. We further show that mice deficient in the downstream complement effector C5 exhibit a similar wound-healing phenotype, which is recapitulated in C5aR1(-/-) mice, but not C3aR(-/-) or C5aR2(-/-) mice. Taken together, these data suggest that C5a signaling through C5aR may in part play a pivotal role in recruitment and activation of inflammatory cells to the wound environment, which in turn could delay the early stages of cutaneous wound healing. These findings also suggest a previously underappreciated role for complement in wound healing, and may have therapeutic implications for conditions of delayed wound healing. Copyright © 2014 by The American Association of Immunologists, Inc.
    Journal of immunology (Baltimore, Md. : 1950). 12/2014;
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    Keisha Findley, Elizabeth A Grice
    PLoS Pathogens 10/2014; 10(10):e1004436. · 8.14 Impact Factor
  • Ana M Misic, Sue E Gardner, Elizabeth A Grice
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    ABSTRACT: Significance: Bacterial burden is believed to play a significant role in impaired wound healing of chronic wounds and the development of infection-related complications. The standard of care in the clinic relies upon cultivation-dependent methods to identify microorganisms. These assays are biased toward microorganisms that thrive in isolation under laboratory conditions. Recent Advances: Significant advances in genomic technologies have enabled less-biased, culture-independent approaches to characterize microbial communities, or microbiomes. The aggregate sequencing and analysis of 16S ribosomal RNA genes has demonstrated that cultures under-represent true microbial diversity and load. Critical Issues: Despite recent advances that enable culture-independent analyses of microbiomes, those organisms that are important in impaired healing remain ambiguous. Inconsistent findings across various studies highlight the need to characterize microbiomes of chronic wounds with homogenous etiology to determine differences in microbiomes that may be driven by the wound environment and that may affect wound outcomes. Rigorous analyses of wound microbiomes in light of the three dimensions of bioburden (microbial diversity, microbial load, and pathogenic organisms), clinical metadata, and wound outcomes will be a significant step forward in our quest to understand the role of microorganisms in impaired healing. Future Directions: Longitudinal studies employing serial sampling are needed to appreciate the role of the dynamic microbial community in chronic wound healing. The value of clinical metadata needs to be examined as potential biomarkers of problematic microbiota and wound outcomes. Lastly, better characterization and understanding of wound microbiomes will open avenues for improved diagnostic and therapeutic tools for the nonhealing wound.
    Advances in wound care. 07/2014; 3(7):502-510.
  • Elizabeth A Grice
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    ABSTRACT: A vast diversity of microorganisms, including bacteria, fungi, viruses, and arthropods, colonize the human skin. Culture-independent genomic approaches for identifying and characterizing microbial communities have provided glimpses into the topographical, temporal, and interpersonal complexity that defines the skin microbiome. Identification of changes associated with cutaneous disease, including acne, atopic dermatitis, rosacea, and psoriasis, are being established. In this review, our current knowledge of the skin microbiome in health and disease is discussed, with particular attention to potential opportunities to leverage the skin microbiome as a diagnostic, prognostic, and/or therapeutic tool.
    Seminars in Cutaneous Medicine and Surgery 06/2014; 33(2):98-103. · 2.40 Impact Factor
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    ABSTRACT: Precise identification of bacteria associated with post-injury infection, co-morbidities, and outcomes could have a tremendous impact in the management and treatment of open fractures. We characterized microbiota colonizing open fractures using culture-independent, high-throughput DNA sequencing of bacterial 16S ribosomal RNA genes, and analyzed those communities with respect to injury mechanism, severity, anatomical site, and infectious complications. Thirty subjects presenting to the Hospital of the University of Pennsylvania for acute care of open fractures were enrolled in a prospective cohort study. Microbiota was collected from wound center and adjacent skin upon presentation to the emergency department, intraoperatively, and at two outpatient follow-up visits at approximately 25 and 50 days following initial presentation. Bacterial community composition and diversity colonizing open fracture wounds became increasingly similar to adjacent skin microbiota with healing. Mechanism of injury, severity, complication, and location were all associated with various aspects of microbiota diversity and composition. The results of this pilot study demonstrate the diversity and dynamism of the open fracture microbiota, and their relationship to clinical variables. Validation of these preliminary findings in larger cohorts may lead to the identification of microbiome-based biomarkers of complication risk and/or to aid in management and treatment of open fractures. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
    Journal of Orthopaedic Research 01/2014; · 2.88 Impact Factor
  • Geoffrey D Hannigan, Elizabeth A Grice
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    ABSTRACT: The skin is the primary physical barrier between the body and the external environment and is also a substrate for the colonization of numerous microbes. Previously, dermatological microbiology research was dominated by culture-based techniques, but significant advances in genomic technologies have enabled the development of less-biased, culture-independent approaches to characterize skin microbial communities. These molecular microbiology approaches illustrate the great diversity of microbiota colonizing the skin and highlight unique features such as site specificity, temporal dynamics, and interpersonal variation. Disruptions in skin commensal microbiota are associated with the progression of many dermatological diseases. A greater understanding of how skin microbes interact with each other and with their host, and how we can therapeutically manipulate those interactions, will provide powerful tools for treating and preventing dermatological disease.
    Cold Spring Harbor Perspectives in Medicine 12/2013; 3(12). · 7.56 Impact Factor
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    ABSTRACT: The skin is colonized by a plethora of microbes that include commensals and potential pathogens, but it is currently unknown how cutaneous host immune mechanisms influence the composition, diversity, and quantity of the skin microbiota. Here we reveal an interactive role for complement in cutaneous host-microbiome interactions. Inhibiting signaling of the complement component C5a receptor (C5aR) altered the composition and diversity of the skin microbiota as revealed by deep sequencing of the bacterial 16S rRNA gene. In parallel, we demonstrate that C5aR inhibition results in down-regulation of genes encoding cutaneous antimicrobial peptides, pattern recognition receptors, and proinflammatory mediators. Immunohistochemistry of inflammatory cell infiltrates in the skin showed reduced numbers of macrophages and lymphocytes with C5aR inhibition. Further, comparing cutaneous gene expression in germ-free mice vs. conventionally raised mice suggests that the commensal microbiota regulates expression of complement genes in the skin. These findings demonstrate a component of host immunity that impacts colonization of the skin by the commensal microbiota and vice versa, a critical step toward understanding host-microbe immune mutualism of the skin and its implications for health and disease. Additionally, we reveal a role for complement in homeostatic host-microbiome interactions of the skin.
    Proceedings of the National Academy of Sciences 08/2013; · 9.81 Impact Factor
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    ABSTRACT: Nonhealing diabetic foot ulcers (DFUs) are a common and costly complication of diabetes. Microbial burden, or "bioburden," is believed to underlie delayed healing, although little is known of those clinical factors that may influence microbial load, diversity, and/or pathogenicity. We profiled the microbiomes of neuropathic nonischemic DFUs without clinical evidence of infection in 52 individuals using high-throughput sequencing of the bacterial 16S ribosomal RNA gene. Comparatively, wound cultures, the standard diagnostic in the clinic, vastly underrepresent microbial load, microbial diversity, and the presence of potential pathogens. DFU microbiomes were heterogeneous, even in our tightly restricted study population, but partitioned into three clusters distinguished primarily by dominant bacteria and diversity. Ulcer depth was associated with ulcer cluster, positively correlated with abundance of anaerobic bacteria, and negatively correlated with abundance of Staphylococcus. Ulcer duration was positively correlated with bacterial diversity, species richness, and relative abundance of Proteobacteria, but was negatively correlated with relative abundance of Staphylococcus. Finally, poor glycemic control was associated with ulcer cluster, with poorest median glycemic control concentrating to Staphylococcus-rich and Streptococcus-rich ulcer clusters. Analyses of microbial community membership and structure may provide the most useful metrics in prospective studies to delineate problematic bioburden from benign colonization that can then be used to drive clinical treatment.
    Diabetes 11/2012; · 7.90 Impact Factor
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    Elizabeth A Grice, Julia A Segre
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    ABSTRACT: The human genome has been referred to as the blueprint of human biology. In this review we consider an essential but largely ignored overlay to that blueprint, the human microbiome, which is composed of those microbes that live in and on our bodies. The human microbiome is a source of genetic diversity, a modifier of disease, an essential component of immunity, and a functional entity that influences metabolism and modulates drug interactions. Characterization and analysis of the human microbiome have been greatly catalyzed by advances in genomic technologies. We discuss how these technologies have shaped this emerging field of study and advanced our understanding of the human microbiome. We also identify future challenges, many of which are common to human genetic studies, and predict that in the future, analyzing genetic variation and risk of human disease will sometimes necessitate the integration of human and microbial genomic data sets.
    Annual review of genomics and human genetics 06/2012; 13:151-70. · 11.57 Impact Factor
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    ABSTRACT: Atopic dermatitis (AD) has long been associated with Staphylococcus aureus skin colonization or infection and is typically managed with regimens that include antimicrobial therapies. However, the role of microbial communities in the pathogenesis of AD is incompletely characterized. To assess the relationship between skin microbiota and disease progression, 16S ribosomal RNA bacterial gene sequencing was performed on DNA obtained directly from serial skin sampling of children with AD. The composition of bacterial communities was analyzed during AD disease states to identify characteristics associated with AD flares and improvement post-treatment. We found that microbial community structures at sites of disease predilection were dramatically different in AD patients compared with controls. Microbial diversity during AD flares was dependent on the presence or absence of recent AD treatments, with even intermittent treatment linked to greater bacterial diversity than no recent treatment. Treatment-associated changes in skin bacterial diversity suggest that AD treatments diversify skin bacteria preceding improvements in disease activity. In AD, the proportion of Staphylococcus sequences, particularly S. aureus, was greater during disease flares than at baseline or post-treatment, and correlated with worsened disease severity. Representation of the skin commensal S. epidermidis also significantly increased during flares. Increases in Streptococcus, Propionibacterium, and Corynebacterium species were observed following therapy. These findings reveal linkages between microbial communities and inflammatory diseases such as AD, and demonstrate that as compared with culture-based studies, higher resolution examination of microbiota associated with human disease provides novel insights into global shifts of bacteria relevant to disease progression and treatment.
    Genome Research 03/2012; 22(5):850-9. · 13.85 Impact Factor
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    Elizabeth A Grice, Julia A Segre
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    ABSTRACT: Microbes colonizing and/or infecting chronic wounds undoubtedly play a major and interactive role in impaired healing, especially in amplifying and perpetuating the host innate immune response. The development of molecular techniques to identify and quantify microbial organisms has revolutionized our view of the microbial world. These less-biased, high throughput methods greatly enable investigations regarding host-microbe interactions in the chronic wound environment. This review focuses on the mounting evidence implicating microbes and excessive inflammation in chronic wounds, as well as the challenges associated with understanding how microbes modulate wound healing and the innate immune response.
    Advances in Experimental Medicine and Biology 01/2012; 946:55-68. · 2.01 Impact Factor
  • Elizabeth A Grice, Julia A Segre
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    ABSTRACT: The skin is the human body's largest organ, colonized by a diverse milieu of microorganisms, most of which are harmless or even beneficial to their host. Colonization is driven by the ecology of the skin surface, which is highly variable depending on topographical location, endogenous host factors and exogenous environmental factors. The cutaneous innate and adaptive immune responses can modulate the skin microbiota, but the microbiota also functions in educating the immune system. The development of molecular methods to identify microorganisms has led to an emerging view of the resident skin bacteria as highly diverse and variable. An enhanced understanding of the skin microbiome is necessary to gain insight into microbial involvement in human skin disorders and to enable novel promicrobial and antimicrobial therapeutic approaches for their treatment.
    Nature Reviews Microbiology 04/2011; 9(4):244-53. · 23.32 Impact Factor
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    ABSTRACT: Diabetics frequently suffer from chronic, nonhealing wounds. Although bacterial colonization and/or infection are generally acknowledged to negatively impact wound healing, the precise relationship between the microbial community and impaired wound healing remains unclear. Because the host cutaneous defense response is proposed to play a key role in modulating microbial colonization, we longitudinally examined the diabetic wound microbiome in tandem with host tissue gene expression. By sequencing 16S ribosomal RNA genes, we show that a longitudinal selective shift in wound microbiota coincides with impaired healing in diabetic mice (Lepr(db/db); db/db). We demonstrate a parallel shift in longitudinal gene expression that occurs in a cluster of genes related to the immune response. Further, we establish a correlation between relative abundance of Staphylococcus spp. and the expression of cutaneous defense response genes. Our data demonstrate that integrating two types of global datasets lends a better understanding to the dynamics governing host-microbe interactions.
    Proceedings of the National Academy of Sciences 08/2010; 107(33):14799-804. · 9.81 Impact Factor
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    ABSTRACT: The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET. In a study of 690 European- and 192 Chinese-descent probands and their parents or controls, we demonstrate the ubiquity of a >4-fold susceptibility from a C-->T allele (rs2435357: p = 3.9 x 10(-43) in European ancestry; p = 1.1 x 10(-21) in Chinese samples) that probably arose once within the intronic RET enhancer MCS+9.7. With in vitro assays, we now show that the T variant disrupts a SOX10 binding site within MCS+9.7 that compromises RET transactivation. The T allele, with a control frequency of 20%-30%/47% and case frequency of 54%-62%/88% in European/Chinese-ancestry individuals, is involved in all forms of HSCR. It is marginally associated with proband gender (p = 0.13) and significantly so with length of aganglionosis (p = 7.6 x 10(-5)) and familiality (p = 6.2 x 10(-4)). The enhancer variant is more frequent in the common forms of male, short-segment, and simplex families whereas multiple, rare, coding mutations are the norm in the less common and more severe forms of female, long-segment, and multiplex families. The T variant also increases penetrance in patients with rare RET coding mutations. Thus, both rare and common mutations, individually and together, make contributions to the risk of HSCR. The distribution of RET variants in diverse HSCR patients suggests a "cellular-recessive" genetic model where both RET alleles' function is compromised. The RET allelic series, and its genotype-phenotype correlations, shows that success in variant identification in complex disorders may strongly depend on which patients are studied.
    The American Journal of Human Genetics 07/2010; 87(1):60-74. · 11.20 Impact Factor
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    Genome Biology 01/2010; · 10.47 Impact Factor
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    ABSTRACT: Human skin is a large, heterogeneous organ that protects the body from pathogens while sustaining microorganisms that influence human health and disease. Our analysis of 16S ribosomal RNA gene sequences obtained from 20 distinct skin sites of healthy humans revealed that physiologically comparable sites harbor similar bacterial communities. The complexity and stability of the microbial community are dependent on the specific characteristics of the skin site. This topographical and temporal survey provides a baseline for studies that examine the role of bacterial communities in disease states and the microbial interdependencies required to maintain healthy skin.
    Science 06/2009; 324(5931):1190-2. · 31.48 Impact Factor
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    ABSTRACT: Suppressor of tumorigenicity 14 (St14) encodes matriptase, a serine protease, which regulates processing of profilaggrin to filaggin in vivo. Here, we report that transgenic mice with 1% of wild-type St14 levels (St14(hypo/-)) display aberrant processing of profilaggrin and model human ichthyotic skin phenotypes. Scaling of the skin appears at 1 week of age with underlying epidermal acanthosis and orthohyperkeratosis as well as a CD4+ T-cell dermal infiltrate. Upregulation of antimicrobial peptides occurs when challenged by exposure to the postnatal environment. Direct genomic sequencing of bacterial 16S rRNA genes to query microbial diversity identifies a significant shift in both phylogeny and community structure between St14(hypo/-) mice and control littermates. St14(hypo/-) mice have a selective shift in resident skin microbiota with a decrease of the dominant genus of skin bacteria, Pseudomonas and an accompanying increase of Corynebacterium and Streptococcus. St14(hypo/-) mice provide early evidence that the cutaneous microbiome can be specifically altered by genetic state, which may play an important role in modulating skin disease.
    Journal of Investigative Dermatology 05/2009; 129(10):2435-42. · 6.19 Impact Factor
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    ABSTRACT: The many layers and structures of the skin serve as elaborate hosts to microbes, including a diversity of commensal and pathogenic bacteria that contribute to both human health and disease. To determine the complexity and identity of the microbes inhabiting the skin, we sequenced bacterial 16S small-subunit ribosomal RNA genes isolated from the inner elbow of five healthy human subjects. This analysis revealed 113 operational taxonomic units (OTUs; "phylotypes") at the level of 97% similarity that belong to six bacterial divisions. To survey all depths of the skin, we sampled using three methods: swab, scrape, and punch biopsy. Proteobacteria dominated the skin microbiota at all depths of sampling. Interpersonal variation is approximately equal to intrapersonal variation when considering bacterial community membership and structure. Finally, we report strong similarities in the complexity and identity of mouse and human skin microbiota. This study of healthy human skin microbiota will serve to direct future research addressing the role of skin microbiota in health and disease, and metagenomic projects addressing the complex physiological interactions between the skin and the microbes that inhabit this environment.
    Genome Research 08/2008; 18(7):1043-50. · 13.85 Impact Factor

Publication Stats

2k Citations
273.34 Total Impact Points

Institutions

  • 2013–2014
    • University of Pennsylvania
      • Department of Dermatology
      Philadelphia, Pennsylvania, United States
    • Hospital of the University of Pennsylvania
      • Department of Pathology and Laboratory Medicine
      Philadelphia, PA, United States
  • 2012
    • University of Iowa
      • College of Nursing
      Iowa City, IA, United States
    • National Cancer Institute (USA)
      • Dermatology Branch
      Maryland, United States
  • 2008–2012
    • National Human Genome Research Institute
      Maryland, United States
  • 2005–2006
    • Johns Hopkins University
      • McKusick-Nathans Institute of Genetic Medicine
      Baltimore, MD, United States