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Introduction
We address fundamental questions in two related fields: viral pathogenesis and immunology. We apply this towards disease models (e.g. skin disease).
1) We use mouse genetics to identify host requirements for persistent viral infection. Once identified, these host factors represent ideal targets to better understand and thus treat persistent viral infections.
2) We are preparing to do human translational work using discarded patient skin.
Publications
Publications (61)
Keratinocyte carcinomas (KC), including basal and squamous cell carcinomas, are the most common human cancers worldwide. While 75% of all KC (4 million annual cases in the US) are treated with conventional excision, this surgical modality has much lower cure rates than Mohs micrographic surgery, likely due to the bread-loaf histopathological assess...
Background:
Perioperative patient anxiety in Mohs micrographic surgery (MMS) is associated with increased postoperative pain and decreased satisfaction.
Objective:
To determine whether a 3-dimensionally printed MMS model with standardized education (SE) improves perioperative patient understanding and anxiety.
Methods:
An unblinded, randomized...
In an effort to increase the efficiency and cure rate of nonmelanoma skin cancer (NMSC) excisions, we have developed a point-of-care method of imaging and evaluation of skin cancer margins. We evaluate the skin surgical specimens using a smart, near-infrared probe (6qcNIR) that fluoresces in the presence of cathepsin proteases overexpressed in NMSC...
CD160 is highly expressed by NK cells and is associated with cytolytic effector activity. Herpes virus entry mediator (HVEM) activates NK cells for cytokine production and cytolytic function via CD160. Fc-fusions are a well-established class of therapeutics, where the Fc domain provides additional biological and pharmacological properties to the fu...
Elimination of the latent HIV reservoir remains the biggest hurdle to achieve HIV cure. In order to specifically eliminate HIV infected cells they must be distinguishable from uninfected cells. CD2 was recently identified as a potential marker enriched in the HIV-1 reservoir on CD4+ T cells, the largest, longest-lived and best-characterized constit...
There is competing evidence that plasmacytoid dendritic cells (pDC), the most potent source of IFN-I, may initiate psoriasis. We targeted pDC function using the slc15a4feeble loss-of-function mouse whose pDC are unresponsive to TLR agonists. slc15a4feeble treated with the topical TLR7-agonist imiquimod (IMQ) demonstrated decreased epidermal thicken...
Background
During chronic hepatitis C virus (HCV) infection, Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) levels mark active liver inflammation and tissue damage, while albumin reflects synthetic liver function and nutritional status. Transient Elastography (TE) is a clinical measure of liver stiffness that facilitates evalua...
Previously, we determined that genetic and environmental factors contributed equally towards rosacea in twins. To assess an environmental factor, we characterized the malar cheek bacterial microbiome from twins discordant for rosacea. We found no significant difference in facial microbiome alpha and beta diversity between related twins discordant f...
Background:
Chronic hepatitis C virus (HCV) and HIV infections are associated with impaired responses to neo-antigens contained in hepatitis A virus (HAV)/hepatitis B virus (HBV) vaccines, yet responsible mechanisms are unclear.
Methods:
ACTG 5232 and CFAR0910 were clinical trials where pre-vaccine levels of plasma IP10, IL-6, sCD163 and sCD14 w...
Background:
There is a continued need for strategies to prevent influenza. While cetylpyridinium chloride (CPC), a broad-spectrum antimicrobial agent, has an extensive antimicrobial spectrum, its ability to affect respiratory viruses has not been studied in detail.
Objectives:
Here, we evaluate the ability of CPC to disrupt influenza viruses in...
We previously observed that aquaporin-3 and aquaporin-10 are upregulated in the epidermis of hand dermatitis patients [1]. To address the functional relevance of this upregulation, we overexpressed AQP3/AQP10 in mice using the human K1 promoter. Combining imiquimod with detergent-containing water challenge, a common trigger in hand and other dermat...
Background:
Mohs micrographic surgery examines all margins of the resected sample and has a 99% cure rate. However, many nonmelanoma skin cancers (NMSCs) are not readily amenable to Mohs micrographic surgery. This defines an unmet clinical need to assess the completeness of non-Mohs micrographic surgery resections during surgery to prevent re-exci...
Background
Immune activation predicts morbidity during HCV and HIV infection, though mechanisms underlying immune activation are unclear. Plasma autotaxin and its enzymatic product, lysophosphatidic-acid (LPA), are elevated during HCV infection, and LPA activates immunocytes, but whether this contributes to immune activation is unknown.
Methods
We...
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. Despite significant improvement in the treatment of T-ALL, approximately 20% of children and most adults undergo relapse. Previous findings demonstrated that loss of T-cell quiescence due to a mutation in the Slfn2 gene (elektra) leads to acquisition of an aberra...
Current anti-retroviral treatment (ART) for HIV is effective in maintaining HIV at undetectable levels. However, cessation of ART results in immediate and brisk rebound of viremia to high levels. This rebound is driven by an HIV reservoir mainly enriched in memory CD4(+) T cells. In order to provide any form of functional HIV Cure, elimination of t...
As CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) play crucial immunomodulatory roles during infections, one key question is how these cells are controlled during antimicrobial immune responses. Mechanisms controlling their homeostasis are central to ensure efficient protection against pathogens, as well as to control infection-associated immunop...
Chronic viral infections (e.g., HIV, HBV, HCV) represent a significant source of morbidity and mortality with over 500 million people infected worldwide. Dendritic cells (DCs) and macrophages are key cell types for productive viral replication and persistent systemic infection. We demonstrate that the plant virus cowpea mosaic virus (CPMV) displays...
Endoplasmic reticulum (ER)-resident proteins are continually retrieved from the Golgi and returned to the ER by Lys-Asp-Glu-Leu (KDEL) receptors, which bind to an eponymous tetrapeptide motif at their substrate's C terminus. Mice and humans possess three paralogous KDEL receptors, but little is known about their functional redundancy, or if their m...
To our knowledge, this is the first study on rosacea to formally define genetic and environmental contributions.
To study a cohort of identical and fraternal twins to determine whether genetic factors contribute to rosacea development and, if genetic factors are present, quantitatively estimate the genetic contribution, as well as to identify envir...
Here, we examine the mechanism by which plasmacytoid dendritic cells (pDCs) and type I interferons promote humoral autoimmunity. In an amyloid-induced experimental autoimmune model, neutrophil depletion enhanced anti-nuclear antibody development, which correlated with heightened IFN-γ production by natural killer (NK) cells. IFN-α/β produced by pDC...
Pompholyx remains a chronic skin affliction without a compelling pathophysiological explanation. The disease is characterized by the sudden onset of vesicles exclusively in the palms and soles which generally resolves. However, the disease may progress and the vesicles may expand and fuse; with chronicity there is deep fissuring. Multiple therapeut...
: Langerhans cell histiocytosis (LCH) carries a prognosis, which ranges from benign to potentially fatal. There is currently little framework to decipher metrics, which predict the benign versus aggressive nature of LCH. We wanted to determine whether molluscum contagiosum virus (MCV) DNA could be isolated from a cutaneous lesion, demonstrating Lan...
Lymphocytic choriomeningitis virus (LCMV) is a common infection of rodents first identified over eighty years ago in St. Louis, MO, U.S.A. It is best known for its application in immunological studies. The history of LCMV closely correlates with the development of modern immunology. With the use of LCMV as a model pathogen several key concepts have...
Background:
We present a compendium of N-ethyl-N-nitrosourea (ENU)-induced mouse mutations, identified in our laboratory over a period of 10 years either on the basis of phenotype or whole genome and/or whole exome sequencing, and archived in the Mutagenetix database. Our purpose is threefold: 1) to formally describe many point mutations, includin...
Slc15a4 is not required to control acute viral infection. Serum and organs were collected at the indicated times post LCMV Armstrong infection and infectious virus was titered. WT and feeble mice infected i.v. with 2×106 pfu of the acute LCMV Armstrong strain. Animals were then sacrificed and the indicated tissue was isolated for viral titers at 5...
Intact intrinsic function of homozygous Slc15a4feeble/feeble NK cells. Percentage of CFSE-labeled Tap1−/− cells remaining in the blood of Tap1−/−, C57BL/6J, and feeble mice 24 h after injection of a 1∶1 mixture of CFSE-labeled Tap1−/− and WT splenocytes was measured by flow cytometry. 1 of 2 independent experiments is shown with the same results. T...
Slc15a4 is not required for antigen specific T cell responses against an acute LCMV Armstrong infection in vivo. 8 days after LCMV Cl13 infection, splenocytes from WT and feeble mice were cultured ex vivo with the indicated peptides or without peptide for 5 hours and then stained with antibodies to quantitate T cell antigen specific production of I...
feeble CD8 T cells and antigen presenting cells do not display defects ex vivo. Spleens were harvested from naïve adult OT-I and OT-I; feeble mice. Whole splenocytes were then cultured for 3 days with CFSE over a range of specific peptide concentrations as indicated. Antigen induced cell proliferation was enumerated by flow cytometry. One of 2 repr...
Immune cell recruitment and activation early during splenic infection. Splenocytes were harvested from WT and feeble mice 0, 1, 3 and 5 days post infection (A–D, respectively) with LCMV Clone 13. Cells were counted and stained with antibodies to surface markers to distinguish B cell, T cell, dendritic cell (DC) and macrophage cell numbers. Cells we...
Author Summary
The immune system consists of two arms aimed at fighting infection. Innate immunity represents the first barrier of defense to swiftly react – within minutes – following intrusion by a pathogen. Adaptive immunity is activated a few days later. Cross-talk between these two systems is critical but the means of communication are not yet...
The site 1 protease, encoded by Mbtps1, mediates the initial cleavage of site 2 protease substrates, including sterol regulatory element binding proteins and CREB/ATF transcription factors. We demonstrate that a hypomorphic mutation of Mbtps1 called woodrat (wrt) caused hypocholesterolemia, as well as progressive hypopigmentation of the coat, that...
Herpesviruses are thought to be highly genetically stable, and their use as vaccine vectors has been proposed. However, studies
of the human gammaherpesvirus, Epstein-Barr virus, have found viral isolates containing mutations in HLA class I-restricted
epitopes. Using murine gammaherpesvirus 68 expressing ovalbumin (OVA), we examined the stability o...
Hemophagocytic lymphohistiocytosis (HLH) is a rare inflammatory disorder with a poor prognosis for affected individuals. To find a means of suppressing the clinical phenotype, we investigated the cellular and molecular mechanisms leading to HLH in Unc13d(jinx/jinx) mice, in which cytolytic function of NK and CD8(+) T cells is impaired. Unc13d(jinx/...
The recombinant engineering of trisegmented lymphocytic choriomeningitis virus (LCMV) to express two genes of interest was
recently reported. We used this technology to efficiently express green fluorescent protein (GFP) and the immunoregulatory
gene product interleukin-10 (IL-10) in vitro, assess IL-10 function in vivo during viral meningitis, and...
The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV), which naturally persists in rodents, represents a model for HIV, HBV, and HCV. Cleavage of the viral glycoprotein precursor by membrane-bound transcription factor peptidase, site 1 (Mbtps1 or site-1 protease), is crucial for the life cycle of arenaviruses and therefore represents...
A previously unappreciated signal necessary for dendritic cell (DC)-mediated activation of natural killer (NK) cells during viral infection was revealed by a recessive N-ethyl-N-nitrosourea-induced mutation called warmflash (wmfl). Wmfl homozygotes displayed increased susceptibility to mouse cytomegalovirus (MCMV) infection. In response to MCMV inf...
Here we describe a previously unknown form of inherited immunodeficiency revealed by an N-ethyl-N-nitrosourea-induced mutation called elektra. Mice homozygous for this mutation showed enhanced susceptibility to bacterial and viral infection and diminished numbers of T cells and inflammatory monocytes that failed to proliferate after infection and d...
Work-up Quick ReferenceThe Dermatologic Differential AlgorithmAlopecia Work-UpAphthosis Classification and WorkupAmyloidosesXanthomasHyperlipoproteinemias: Fredrickson ClassificationHistiocytosisLupus ErythematosusAntinuclear AntibodiesAutoantibodies in Connective Tissue DiseasesVasculitisCryoglobulinemiaCTCL ClassificationCutaneous B-cell Lymphoma...
Surgical Margins GuidelinesGuideline for Prophylactic AntibioticsGuideline for Prophylactic AntiviralsAnestheticsSurgical AnatomyCutaneous ReconstructionRepair Options: StairsSuturesElectrosurgeryWound HealingAntiseptic ScrubsLasersPhotodynamic TherapyUV SpectrumUV Protection MeasurementsUV Associations/SpecificitiesGlogau Wrinkle ScaleFitzpatrick...
The colour illustrations for Chapter is 2 included, as follows:
Medication Quick ReferenceSystemic MedicationsGeneral ReferenceCorticosteroidAcne - TopicalAcne - SystemicAlopeciaAnalgesicsAnesthetics - TopicalAntibioticsAntifungalsAntiparasiticsAntiviralsAntihistaminesAntipruriticBleaching Agents/Depigmenting AgentsTopical ChemotherapyCTCLPsoriasisSeborrheic DermatitisHypertrichosisHyperhidrosisWound CareVitami...
Establishment of latent infection and reactivation from latency are critical aspects of herpesvirus infection and pathogenesis.
Interfering with either of these steps in the herpesvirus life cycle may offer a novel strategy for controlling herpesvirus
infection and associated disease pathogenesis. Prior studies show that mice deficient in gamma int...
A 53-year-old black man presented with a 1-month history of large annular pruritic plaques on his trunk and extremities. The plaques had raised, violaceous borders and dusky, depressed centers, through which superficial dermal blood vessels could be readily visualized. Some of the plaques were confluent and rather extensive (Figure 1). The patient’...
Macrophages (M phi) are activated by IFN gamma and are important cellular targets for infection by human and murine cytomegalovirus (MCMV), making it advantageous for CMVs to block IFN gamma-induced M phi differentiation. We found that MCMV infection inhibited IFN gamma regulation of many genes in M phi. MCMV infection blocked IFN gamma responses a...
Despite robust host immune responses the betaherpesvirus murine cytomegalovirus (MCMV) is able to establish lifelong infection.
This capacity is due at least in part to the virus utilizing multiple immune evasion mechanisms to blunt host responses. Macrophages
are an important cell for MCMV infection, dissemination, and latency despite expression i...
Despite robust host immune responses the betaherpesvirus murine cytomegalovirus (MCMV) is able to establish lifelong infection. This capacity is due at least in part to the virus utilizing multiple immune evasion mechanisms to blunt host responses. Macrophages are an important cell for MCMV infection, dissemination, and latency despite expression i...
Interferon (IFN)-gamma and macrophages (Mphi) play key roles in acute, persistent, and latent murine cytomegalovirus (MCMV) infection. IFN-gamma mechanisms were compared in embryonic fibroblasts (MEFs) and bone marrow Mphi (BMMphi). IFN-gamma inhibited MCMV replication in a signal transducer and activator of transcription (STAT)-1alpha-dependent ma...
In Escherichia coli, the Cpx two-component regulatory system activates expression of protein folding and degrading factors in response to misfolded proteins in the bacterial envelope (inner membrane, periplasm, and outer membrane). It is comprised of the histidine kinase CpxA and the response regulator CpxR. This response plays a role in protection...
Gene silencing is required to stably maintain distinct patterns of gene expression during eukaryotic development and has been correlated with the induction of chromatin domains that restrict gene activity. We describe the isolation of human (EZH2) and mouse (Ezh1) homologues of the Drosophila Polycomb-group (Pc-G) gene Enhancer of zeste [E(z)], a c...
Gene silencing is required to stably maintain distinct patterns of gene expression during eukaryotic development and has been correlated with the induction of chromatin domains that restrict gene activity. We describe the isolation of human (EZH2) and mouse (Ezh1) homologues of the Drosophila Polycomb-group (Pc-G) gene Enhancer of zeste [E(z)], a c...
Thesis (Ph. D.)--Washington University, 2004. Program in Immunology. Includes bibliographical references.
Projects
Project (1)
