Sarah Anzick - Academia.edu (original) (raw)

Papers by Sarah Anzick

PLOS Neglected Tropical Diseases, Dec 23, 2015

Background Infections with Taenia solium are the most common cause of adult acquired seizures wor... more Background Infections with Taenia solium are the most common cause of adult acquired seizures worldwide, and are the leading cause of epilepsy in developing countries. A better understanding of the genetic diversity of T. solium will improve parasite diagnostics and transmission pathways in endemic areas thereby facilitating the design of future control measures and interventions. Microsatellite markers are useful genome features, which enable strain typing and identification in complex pathogen genomes. Here we describe microsatellite identification and characterization in T. solium, providing information that will assist in global efforts to control this important pathogen. Methods For genome sequencing, T. solium cysts and proglottids were collected from Huancayo and Puno in Peru, respectively. Using next generation sequencing (NGS) and de novo assembly, we assembled two draft genomes and one hybrid genome. Microsatellite sequences were identified and 36 of them were selected for further analysis. Twenty T. solium isolates were collected from Tumbes in the northern region, and twenty from Puno in the southern region of Peru. The size-polymorphism of the selected microsatellites was determined with

Nature Communications, Jul 25, 2023

Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infectio... more Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19) and is influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the genetically diverse Collaborative Cross (CC) founder strains crossed to human ACE2 transgenic mice (K18-hACE2) that confers susceptibility to SARS-CoV-2. Infection of CC x K18-hACE2 resulted in a spectrum of survival, viral replication kinetics, and immune profiles. Importantly, in contrast to the K18-hACE2 model, early type I interferon (IFN-I) and regulated proinflammatory responses were required for control of SARS-CoV-2 replication in PWK x K18-hACE2 mice that were highly resistant to disease. Thus, virus dynamics and inflammation observed in COVID-19 can be modeled in diverse mouse strains that provide a genetically tractable platform for understanding anti-coronavirus immunity. The COVID-19 pandemic continues to pose a global threat to public health, due in part to the sequential evolution of new variants of concern (VOC) selected to evade immunity generated from previous infection or vaccination. The extreme variability in patient responses to infection, ranging from asymptomatic to life-threatening illness 1-3 , remains only partially understood. In addition, persistent post-COVID health problems can be severe and include a significant risk for future morbidity and mortality 4. The variability in disease presentation is dependent on genetic polymorphisms, age, sex, and the presence of underlying conditions 1,5,6 , underscoring the need for research models

Supplementary Figure 2. Discordances between automated and pathologists' scores: a) both patholog... more Supplementary Figure 2. Discordances between automated and pathologists' scores: a) both pathologists scored case as negative while Ariol scored the case as strong positive, secondary to detected staining of entrapped benign epithelium; b) average pathologists' score was 15% while Ariol scored this as 50%, probably due to a lower automated threshold for detecting light brown as positive stain; c) dark stain is recognized in vascular endothelial cells and entrapped clusters of epithelial cells within dense fibrous tissue, raising disagreements about the validity of the staining pattern, d) pathologists scored as negative, whereas Ariol scored as 90% of cells stained because the instrument misclassified benign stromal cells as tumor cells; e-f) pathologists interpreted as negative, Ariol scored as strong positive related to artifact; g-h) pathologists scored as negative, whereas Ariol scored as positive, probably reflecting machine misclassification of heavy counterstain (blue) as positive (brown). Note:Yellow dots denote nuclei which Ariol interpreted to be tumor nuclei showing positive staining and pink dots denote nuclei which Ariol interpreted to be tumor nuclei showing no positive staining.

Infection and Immunity, May 31, 2023

All members of the family Chlamydiaceae have lipopolysaccharides (LPS) that possess a shared carb... more All members of the family Chlamydiaceae have lipopolysaccharides (LPS) that possess a shared carbohydrate trisaccharide antigen, 3-deoxy- d -manno-oct-2-ulosonic acid (Kdo) that is functionally uncharacterized. A single gene, genus-specific epitope ( gseA ), is responsible for attaching the tri-Kdo to lipid IVA. To investigate the function of Kdo in chlamydial host cell interactions, we made a gseA -null strain (L2Δ gseA ) by using TargeTron mutagenesis.

Cancer Research, Apr 15, 2006

828 Small and large-scale chromosomal aberrations, including amplifications, deletions, and rearr... more 828 Small and large-scale chromosomal aberrations, including amplifications, deletions, and rearrangements, are commonly seen in solid tumors. In human colorectal cancer (CRC), amplification of chromosome regions 20q, 8q, 13q, 7p, 12p, and loss of 18q, 8p, 17p, 4p, and 15q are frequently observed. These regions harbor oncogenes, tumor suppressors, and DNA repair genes that are known to be involved in the etiology of the disease. A combined, high-resolution gene expression and DNA copy number approach has been applied to test the hypothesis that a more comprehensive measure of the genetic damage in CRC will reveal novel molecular targets. Here, microarrays consisting of ∼35,000 spotted oligonucleotides have been utilized to examine both gene expression and DNA copy number changes in primary colorectal tumors from patients with stage II-IV disease. A colorectal cancer tissue array containing approximately 100 CRC samples has been constructed for use in validation studies. To date, 50 primary CRC samples in which the site of metastasis and other clinical information is available have been profiled. For expression studies, an unsupervised, class-discovery algorithm was utilized to search for molecular signatures that are associated with the clinical data. A subset of samples characterized by genes involved in cell communication, signal transduction, and metabolism was identified; however, no correlation with the clinical data was found for this subset of tumors. Using class comparison and hierarchical clustering, a statistically significant set of genes discriminated between primary tumors located in the proximal (cecum, ascending colon, and transverse colon) colon from those isolated from the distal (descending, sigmoid, and rectal) colon, but no gene signatures were associated patient age, disease stage, or CEA levels. The same microarray platform was utilized for array comparative genomic hybridization (aCGH) studies. Analysis of the aCGH results revealed several chromosomal changes that have not been previously reported. A combined analysis of the aCGH and expression data, followed by validation on tumor tissue arrays, is being carried out to identify candidate genes associated with colorectal cancer.

Nature Medicine, Oct 1, 2004

Science immunology, May 13, 2022

Several infectious and autoimmune diseases are associated with an expansion of CD21−CD27−atypical... more Several infectious and autoimmune diseases are associated with an expansion of CD21−CD27−atypical B cells (atBCs) that up-regulate inhibitory receptors and exhibit altered B cell receptor (BCR) signaling. The function of atBCs remains unclear, and few studies have investigated the biology of pathogen-specific atBCs during acute infection. Here, we performed longitudinal flow cytometry analyses and RNA sequencing ofPlasmodium falciparum(Pf)–specific B cells isolated from study participants before and shortly after febrile malaria, with simultaneous analysis of influenza hemagglutinin (HA)–specific B cells as a comparator. At the healthy baseline before the malaria season, individuals had similar frequencies ofPf- and HA-specific atBCs that did not differ proportionally from atBCs within the total B cell population. BCR sequencing identified clonal relationships betweenPf-specific atBCs, activated B cells (actBCs), and classical memory B cells (MBCs) and revealed comparable degrees of somatic hypermutation. At the healthy baseline,Pf-specific atBCs were transcriptionally distinct fromPf-specific actBCs and classical MBCs. In response to acute febrile malaria,Pf-specific atBCs and actBCs up-regulated similar intracellular signaling cascades.Pf-specific atBCs showed activation of pathways involved in differentiation into antibody-secreting cells and up-regulation of molecules that mediate B-T cell interactions, suggesting that atBCs respond to T follicular helper (TFH) cells. In the presence of TFHcells and staphylococcal enterotoxin B, atBCs of malaria-exposed individuals differentiated into CD38+antibody-secreting cells in vitro, suggesting that atBCs may actively contribute to humoral immunity to infectious pathogens.

Nature Communications, May 18, 2023

One of the key events in viral encephalitis is the ability of virus to enter the central nervous ... more One of the key events in viral encephalitis is the ability of virus to enter the central nervous system (CNS). Several encephalitic viruses, including La Crosse Virus (LACV), primarily induce encephalitis in children, but not adults. This phenomenon is also observed in LACV mouse models, where the virus gains access to the CNS of weanling animals through vascular leakage of brain microvessels, likely through brain capillary endothelial cells (BCECs). To examine age and region-specific regulatory factors of vascular leakage, we used genome-wide transcriptomics and targeted siRNA screening to identify genes whose suppression affected viral pathogenesis in BCECs. Further analysis of two of these gene products, Connexin43 (Cx43/Gja1) and EphrinA2 (Efna2), showed a substantial effect on LACV pathogenesis. Induction of Cx43 by 4-phenylbutyric acid (4-PBA) inhibited neurological disease in weanling mice, while Efna2 deficiency increased disease in adult mice. Thus, we show that Efna2 and Cx43 expressed by BCECs are key mediators of LACV-induced neuroinvasion and neurological disease. La Crosse Virus (LACV), a negative-sense RNA virus belonging to the bunyaviridae family 1 , is one of the leading causes of arboviral encephalitis in children 2. In adults, LACV infection generally causes a very mild, febrile syndrome 3. The higher incidence of neurological disease in children compared to adults suggests age-related differences that may be responsible for the ability of the virus to gain access to the central nervous system (CNS) and/or cause damage within the CNS. Understanding these differences could provide avenues for prevention or treatment of LACV encephalitis. The blood-brain barrier (BBB) is a selectively permeable barrier that plays an important role in inhibiting the access of pathogens to the CNS. The blood-brain barrier (BBB) is comprised mainly of brain capillary endothelial cells (BCECs) with neighboring astrocytes, basement membrane and pericytes, which interact with surrounding neurons and microglia to form the neurovascular unit 4. The selective permeability across the BCECs is defined by several transporter and carrier proteins along with the tight junction (TJ), adherens junction (AJ) and gap junction (GJ) (collectively cell junction (CJ)) proteins) 5,6. The integrity of the BBB is strengthened during development 7,8. It reaches its peak in adulthood and then gradually weakens with age due to reduced CJ protein expression and functional impairment of transporters 9,10. The pathology observed from LACV encephalitis indicates substantial breakdown of the BBB. Immunohistochemistry (IHC) analysis of LACV patient brain biopsies shows perivascular mononuclear cuffing with focal aggregates of immune cells 11 , and further studies have

Journal of Clinical Oncology, Jun 1, 2005

3678 Background: Metastatic disease is the hallmark of human malignancy that continues to challen... more 3678 Background: Metastatic disease is the hallmark of human malignancy that continues to challenge even the most recent advances in cancer treatment. In colorectal cancer, the major site of metastatic spread is the liver, but other sites include lung, and peritoneum, among others. In addition to elucidating mechanisms of tumor spread, predicting the pattern of metastatic spread could allow a more focused surveillance and adjuvant therapy. The aim of this study was to study the pattern of metastatic spread in colorectal cancer using gene expression micorarrays. Methods: Using microarrays consisting of ∼35,000 spotted oligonucleotides, we profiled 40 primary colorectal cancer samples from patients with resected primary tumors who developed metastatic disease. Patients were grouped into three patterns of isolated or dominant metastatic spread: liver, lung, and peritoneum/mesentery. Class comparison analysis and hierarchical clustering was performed on the array data. Results: An evident distinction could be...

Nature Medicine, Mar 14, 2004

Genomic amplification at 20q11-13 is a common event in human cancers. We isolated a germline tran... more Genomic amplification at 20q11-13 is a common event in human cancers. We isolated a germline translocation breakpoint at 20q11 from a bladder cancer patient. We identified CDC91L1, the gene encoding CDC91L1 (also called phosphatidylinositol glycan class U (PIG-U), a transamidase complex unit in the glycosylphosphatidylinositol (GPI) anchoring pathway), as the only gene whose expression was affected by the translocation. CDC91L1 was amplified and overexpressed in about one-third of bladder cancer cell lines and primary tumors, as well as in oncogenic uroepithelial cells transformed with human papillomavirus (HPV) E7. Forced overexpression of CDC91L1 malignantly transformed NIH3T3 cells in vitro and in vivo. Overexpression of CDC91L1 also resulted in upregulation of the urokinase receptor (uPAR), a GPI-anchored protein, and in turn increased STAT-3 phosphorylation in bladder cancer cells. Our findings suggest that CDC91L1 is an oncogene in bladder cancer, and implicate the GPI anchoring system as a potential oncogenic pathway and therapeutic target in human cancers.

Social Science Research Network, 2020

Long-term SARS-CoV-2 shedding was observed from the upper respiratory tract of an immunocompromis... more Long-term SARS-CoV-2 shedding was observed from the upper respiratory tract of an immunocompromised patient with chronic lymphocytic leukemia and acquired hypogammaglobulinemia. Shedding of SARS-CoV-2 genomic and subgenomic RNA was observed up to 105 days, and infectious virus up to 70 days past the initial diagnosis. The infection was not cleared after a first treatment with convalescent plasma, suggesting limited impact on SARS-CoV-2 in the upper respiratory tract. SARS-CoV-2 RNA was no longer detected several weeks after a second transfusion of convalescent plasma. There was marked within-host genomic evolution of SARS-CoV-2, with continuous turnover of dominant viral variants. However, replication kinetics in VeroE6 cells and primary human alveolar epithelial tissues were not affected. Our data indicate that certain immunocompromised patients may shed infectious virus for longer durations than previously recognized. Detection of of subgenomic RNA is recommended in persistently SARS-CoV-2 positive individuals as a proxy for shedding of infectious virus. Funding: This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID). T.A.B. is supported by the Medical Research Council UK (MR/S007555/1). The Wellcome Centre for Human Genetics is supported by Wellcome Centre grant 203141/Z/16Z. Conflict of Interest: The authors declare no competing interests.

Journal of Clinical Investigation, Nov 15, 2022

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic ... more Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and TNF-α production, which enhanced fungal killing in an interdependent manner. Deficiency of either Dectin-1 or CARD9 was associated with more severe fungal disease, recapitulating the human observation. Because these data implicated impaired Dectin-1 responses in susceptibility to phaeohyphomycosis, we evaluated 17 additional unrelated patients with severe forms of the infection. We found that 12 out of 17 carried deleterious CLEC7A mutations associated with an altered Dectin-1 extracellular C-terminal domain and impaired Dectin-1-dependent cytokine production. Thus, we show that Dectin-1 and CARD9 promote protective TNF-α-and IL-1β-mediated macrophage defense against C. cassiicola. More broadly, we demonstrate that human Dectin-1 deficiency may contribute to susceptibility to severe phaeohyphomycosis by certain dematiaceous fungi.

The journal of sexual medicine, 2014

INTRODUCTION Aging-related erectile dysfunction (A-ED) is a neurovascular and refractory disorder... more INTRODUCTION Aging-related erectile dysfunction (A-ED) is a neurovascular and refractory disorder with complicated pathophysiological mechanisms and a high prevalence. MicroRNAs (miRNAs), which modulate a variety of cell functions, may be involved in the pathophysiological processes of this disorder. AIM To investigate the miRNA profile in the corpus cavernosum (CC) of aging rats with ED, and to analyze the target genes and signaling pathways regulated by the dysregulated miRNAs. METHODS According to the apomorphine test, the experimental animals were divided into three groups: aging rats with ED (group AE), aging rats with normal erectile function (group AN), and young rats as normal controls (group YN). After the erectile functional test, CCs from each group were then collected for histological and molecular measurements. MAIN OUTCOME MEASURES Intracavernous pressure response to electric stimulation of the cavernous nerve was used to evaluate erectile function. Histological change...

Frontiers in Immunology, 2021

Low nadir CD4 T-cell counts in HIV+ patients are associated with high morbidity and mortality and... more Low nadir CD4 T-cell counts in HIV+ patients are associated with high morbidity and mortality and lasting immune dysfunction, even after antiretroviral therapy (ART). The early events of immune recovery of T cells and B cells in severely lymphopenic HIV+ patients have not been fully characterized. In a cohort of lymphopenic (CD4 T-cell count < 100/µL) HIV+ patients, we studied mononuclear cells isolated from peripheral blood (PB) and lymph nodes (LN) pre-ART (n = 40) and 6-8 weeks post-ART (n = 30) with evaluation of cellular immunophenotypes; histology on LN sections; functionality of circulating T follicular helper (cTfh) cells; transcriptional and B-cell receptor profile on unfractionated LN and PB samples; and plasma biomarker measurements. A group of 19 healthy controls (HC, n = 19) was used as a comparator. T-cell and B-cell lymphopenia was present in PB pre-ART in HIV+ patients. CD4:CD8 and CD4 T- and B-cell PB subsets partly normalized compared to HC post-ART as viral loa...

ABSTRACTInflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) ... more ABSTRACTInflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19) and is influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the genetically diverse Collaborative Cross (CC) founder strains crossed to human ACE2 transgenic mice (K18-hACE2) that confers susceptibility to SARS-CoV-2. Infection of CC x K18- hACE2 resulted in a spectrum of survival, viral replication kinetics, and immune profiles. Importantly, in contrast to the K18-hACE2 model, early type I interferon (IFN-I) and regulated proinflammatory responses were required for control of SARS-CoV-2 replication in PWK x K18-hACE2 mice that were highly resistant to disease. Thus, virus dynamics and inflammation observed in COVID-19 can be modeled in diverse mouse strains that provide a ge...

Cell, 2020

Elongator protein 3 (ELP3) acetylates histones in the nucleus but also plays a role in the cytopl... more Elongator protein 3 (ELP3) acetylates histones in the nucleus but also plays a role in the cytoplasm. Here, we report that in Drosophila neurons, ELP3 is necessary and sufficient to acetylate the ELKS family member Bruchpilot, an integral component of the presynaptic density where neurotransmitters are released. We find that in elp3 mutants, presynaptic densities assemble normally, but they show morphological defects such that their cytoplasmic extensions cover a larger area, resulting in increased vesicle tethering as well as a more proficient neurotransmitter release. We propose a model where ELP3dependent acetylation of Bruchpilot at synapses regulates the structure of individual presynaptic densities and neurotransmitter release efficiency. Neuron ELP3 Acetylates BRP