Digital Commons Network^™

Staphylococcus Aureus Injection Drug Use-Associated Bloodstream Infections Are Propagated By Community Outbreaks Of Diverse Lineages, Laura R Marks, Juan J Calix, John A Wildenthal, Meghan A Wallace, Sanjam S Sawhney, Eric M Ransom, Michael J Durkin, Jeffrey P Henderson, Carey-Ann D Burnham, Gautam Dantas

Open Access Publications

Background: The ongoing injection drug use (IDU) crisis in the United States has been complicated by an emerging epidemic of

Methods: We performed a case-control study comparing

Results: Here we show that patients with IDU-BSI experience longer durations of bacteremia and have lower medical therapy completion rates. In phylogenetic analyses, 45/154 and 1/91 contemporaneous IDU-BSI and non-IDU BSI staphylococcal isolates, respectively, group into multiple, unique clonal clusters, revealing that pathogen community transmission distinctively spurs IDU-BSI. Lastly, multiple

Conclusions: We identify clonal expansion of multiple

A Class Ii Mhc-Targeted Vaccine Elicits Immunity Against Sars-Cov-2 And Its Variants, Novalia Pishesha, Paul W Rothlauf, Mariel J Liebeskind, Maria A Vakaki, Louis-Marie Bloyet, Marjorie Cornejo Pontelli, Ma Xenia G Ilagan, William J Buchser, Sean P J Whelan, Et Al

Open Access Publications

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 100 million infections and millions of deaths. Effective vaccines remain the best hope of curtailing SARS-CoV-2 transmission, morbidity, and mortality. The vaccines in current use require cold storage and sophisticated manufacturing capacity, which complicates their distribution, especially in less developed countries. We report the development of a candidate SARS-CoV-2 vaccine that is purely protein based and directly targets antigen-presenting cells. It consists of the SARS-CoV-2 Spike receptor-binding domain (Spike

Cd36 Maintains The Gastric Mucosa And Associates With Gastric Disease, Miriam Jacome-Sosa, Zhi-Feng Miao, Vivek S Peche, Edward F Morris, Ramkumar Narendran, Kathryn M Pietka, Dmitri Samovski, Hei-Yong G Lo, Terri Pietka, Latisha Love-Gregory, Nada A Abumrad, Et Al

Open Access Publications

The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd36

Cytokine Exposure Mediates Transcriptional Activation Of The Orphan Nuclear Receptor Nur77 In Hematopoietic Cells, Orsola Di Martino, Haixia Niu, Gayla Hadwiger, Margaret A Ferris, John S Welch

Open Access Publications

The orphan nuclear receptor Nur77 is an immediate-early response gene that based on tissue and cell context is implicated in a plethora of cellular processes, including proliferation, differentiation, apoptosis, metabolism, and inflammation. Nur77 has a ligand-binding pocket that is obstructed by hydrophobic side groups. Naturally occurring, cell-endogenous ligands have not been identified, and Nur77 transcriptional activity is thought to be regulated through posttranslational modification and modulation of protein levels. To determine whether Nur77 is transcriptionally active in hematopoietic cells in vivo, we used an upstream activating sequence (UAS)-GFP transgenic reporter. We found that Nur77 is transcriptionally inactive in vivo in …

U2af1 Is A Haplo-Essential Gene Required For Hematopoietic Cancer Cell Survival In Mice, Brian A Wadugu, Sridhar Nonavinkere Srivatsan, Amanda Heard, Michael O Alberti, Matthew Ndonwi, Jie Liu, Sarah Grieb, Joseph Bradley, Jin Shao, Tanzir Ahmed, Cara L Shirai, Ajay Khanna, Christopher A Miller, Matthew J Walter, Et Al

Open Access Publications

Somatic mutations in the spliceosome gene U2AF1 are common in patients with myelodysplastic syndromes. U2AF1 mutations that code for the most common amino acid substitutions are always heterozygous, and the retained WT allele is expressed, suggesting that mutant hematopoietic cells may require the residual WT allele to be viable. We show that hematopoiesis and RNA splicing in U2af1 heterozygous knockout mice were similar to those in control mice, but that deletion of the WT allele in U2AF1(S34F) heterozygous mutant-expressing hematopoietic cells (i.e., hemizygous mutant) was lethal. These results confirm that U2AF1 mutant hematopoietic cells are dependent on the expression of …

8-Azaadenosine And 8-Chloroadenosine Are Not Selective Inhibitors Of Adar, Kyle A Cottrell, Luisangely Soto Torres, Michael G Dizon, Jason D Weber

Open Access Publications

The RNA editing enzyme ADAR, is an attractive therapeutic target for multiple cancers. Through its deaminase activity, ADAR edits adenosine to inosine in dsRNAs. Loss of ADAR in some cancer cell lines causes activation of the type I interferon pathway and the PKR translational repressor, leading to inhibition of proliferation and stimulation of cell death. As such, inhibition of ADAR function is a viable therapeutic strategy for many cancers. However, there are no FDA approved inhibitors of ADAR. Two small molecules have been previously shown to inhibit ADAR or reduce its expression: 8-azaadenosine and 8-chloroadenosine. Here we show that neither …

Long-Term Prognosis And Educational Determinants Of Brain Network Decline In Older Adult Individuals, Micaela Y Chan, Liang Han, Claudia A Carreno, Ziwei Zhang, Rebekah M Rodriguez, Megan Larose, Jason Hassenstab, Gagan S Wig

Open Access Publications

Older adults with lower education are at greater risk for dementia. It is unclear which brain changes lead to these outcomes. Longitudinal imaging-based measures of brain structure and function were examined in adult individuals (baseline age, 45-86 years; two to five visits per participant over 1-9 years). College degree completion differentiates individual-based and neighborhood-based measures of socioeconomic status and disadvantage. Older adults (~65 years and over) without a college degree exhibit a pattern of declining large-scale functional brain network organization (resting-state system segregation) that is less evident in their college-educated peers. Declining brain system segregation predicts impending changes in dementia …

Tai Chi For Cancer Survivors: A Systematic Review Toward Consensus-Based Guidelines, Lin Yang, Kerri Winters-Stone, Benny Rana, Chao Cao, Linda E Carlson, Kerry S Courneya, Christine M Friedenreich, Kathryn H Schmitz

Open Access Publications

To manage acute, long-term, and late effects of cancer, current guidelines recommend moderate-to-vigorous intensity aerobic and resistance exercise. Unfortunately, not all cancer survivors are able or willing to perform higher intensity exercise during difficult cancer treatments or because of other existing health conditions. Tai Chi is an equipment-free, multicomponent mind-body exercise performed at light-to-moderate intensity that may provide a more feasible alternative to traditional exercise programs for some cancer survivors. This systematic review evaluated the therapeutic efficacy of Tai Chi across the cancer care continuum. We searched MEDLINE/PubMed, Embase, SCOPUS, and CINAHL databases for interventional studies from inception to 18 …

Novel Radiographic Presentation Of Primary Syphilis Of The Tonsil, Garrett Camps, Cole Pavelchek, Rami Eldaya, Matthew Parsons

Open Access Publications

A 61-year-old HIV+ male presented to an infectious disease clinic with a complaint of sore throat. A painless ulcerated mass was discovered on the right tonsil resulting in further evaluation with a CT scan of the neck. Imaging confirmed the presence of a mass centered on the palatine tonsil and associated lymphadenopathy. A presumptive diagnosis of HPV-related squamous cell carcinoma was made due to patient risk factors. However, multiple biopsies found no evidence of carcinoma, but instead revealed the presence of spirochetes that stained positive for

Diagnostics To Support Elimination Of Lymphatic Filariasis-Development Of Two Target Product Profiles, Kimberly Y. Won, Gary J. Weil, Et Al

Open Access Publications

As lymphatic filariasis (LF) programs move closer to established targets for validation elimination of LF as a public health problem, diagnostic tools capable of supporting the needs of the programs are critical for success. Known limitations of existing diagnostic tools make it challenging to have confidence that program endpoints have been achieved. In 2019, the World Health Organization (WHO) established a Diagnostic Technical Advisory Group (DTAG) for Neglected Tropical Diseases tasked with prioritizing diagnostic needs including defining use-cases and target product profiles (TPPs) for needed tools. Subsequently, disease-specific DTAG subgroups, including one focused on LF, were established to develop TPPs …

Cardiac Myosin Contraction And Mechanotransduction In Health And Disease, Samantha K Barrick, Michael J Greenberg

Open Access Publications

Cardiac myosin is the molecular motor that powers heart contraction by converting chemical energy from ATP hydrolysis into mechanical force. The power output of the heart is tightly regulated to meet the physiological needs of the body. Recent multiscale studies spanning from molecules to tissues have revealed complex regulatory mechanisms that fine-tune cardiac contraction, in which myosin not only generates power output but also plays an active role in its regulation. Thus, myosin is both shaped by and actively involved in shaping its mechanical environment. Moreover, these studies have shown that cardiac myosin-generated tension affects physiological processes beyond muscle contraction. …

First Clinical Experience Of Correcting Phantom-Based Image Distortion Related To Gantry Position On A 0.35t Mr-Linac, Benjamin C Lewis, Jaeik Shin, Benjamin Quinn, Enzo Barberi, Domenic Sievert, Jin Sung Kim, Taeho Kim

Open Access Publications

MR-guided radiotherapy requires strong imaging spatial integrity to deliver high quality plans and provide accurate dose calculation. The MRI system, however, can be compromised by the integrated linear accelerator (Linac), resulting in inaccurate imaging isocenter position and geometric distortion. Dependence on gantry position further complicates the correction of distortions. This work presents a new clinical application of a commercial phantom and software system that quantifies isocenter alignment and geometric distortion, as well as providing a deformation vector field (DVF). A large distortion phantom and a smaller grid phantom were imaged at multiple gantry angles from 0 to 330° on a …

Development Of A Resource Guide To Help Patients Receive Appropriate Care, Erin D Solomon, Heidi Walsh, Meredith Parsons, Tristan Mcintosh, Jessica Mozersky, James M Dubois

Open Access Publications

After 10 years researching physician wrongdoing (i.e., sexual violations, improper prescribing, and unnecessary procedures), we developed a resource guide to help patients receive appropriate care and respond to inappropriate care. We gathered evaluative patient feedback, engaged physicians, and disseminated the guide. It is available at beforeyourvisit.org.

Factors Associated With The Mechanism Of Acl Tears In The National Football League: A Video-Based Analysis, Robert Brophy, Edward Wojtys, Christina Mack, Kalyani Hawaldar, Mackenzie Herzog, Brett D Owens

Open Access Publications

Background: The factors associated with anterior cruciate ligament (ACL) injury mechanism in professional American football players are not well-understood.

Hypothesis: It was hypothesized that football-related and player-specific factors, such as position and body mass index (BMI), are associated with ACL injury mechanism in these athletes.

Study Design: Descriptive epidemiology study.

Methods: Videos of ACL tears occurring in National Football League (NFL) games over 6 consecutive seasons from 2014 to 2019 were reviewed by 2 orthopaedic surgeons who specialize in sports medicine. For each injury, the role of contact (

Results: Of the 140 ACL tears, a minority occurred via direct …

Cardiac Stereotactic Ablative Radiotherapy For Control Of Refractory Ventricular Tachycardia: Initial Uk Multicentre Experience, Justin Lee, Clifford Robinson, Phillip Cuculich, Geoffrey Hugo, Et Al

Open Access Publications

BACKGROUND: Options for patients with ventricular tachycardia (VT) refractory to antiarrhythmic drugs and/or catheter ablation remain limited. Stereotactic radiotherapy has been described as a novel treatment option.

METHODS: Seven patients with recurrent refractory VT, deemed high risk for either first time or redo invasive catheter ablation, were treated across three UK centres with non-invasive cardiac stereotactic ablative radiotherapy (SABR). Prior catheter ablation data and non-invasive mapping were combined with cross-sectional imaging to generate radiotherapy plans with aim to deliver a single 25 Gy treatment. Shared planning and treatment guidelines and prospective peer review were used.

RESULTS: Acute suppression of VT …

Incisional Lumbodorsal Hernias Following Retroperitoneal Robotic Partial Nephrectomies For Small Renal Masses At A High-Volume Tertiary Referral Center, Alexander K. Chow, Brandon Malik Wahba, Tarik Phillips, Kenneth G. Sands, Joel Vetter, Ramakrishna Venkatesh, Eric H. Kim, Sam B. Bhayani, Robert S. Figenshau

Open Access Publications

No abstract provided.

Biofilm Formation And Virulence Of Shigella Flexneri Are Modulated By Ph Of Gastrointestinal Tract, I-Ling Chiang, Yi Wang, Satoru Fujii, Brian D Muegge, Qiuhe Lu, Phillip I Tarr, Thaddeus S Stappenbeck

Open Access Publications

No abstract provided.

Mast Cell Activation Symptoms Are Prevalent In Long-Covid, Leonard B Weinstock, Jill B Brook, Arthur S Walters, Ashleigh Goris, Lawrence B Afrin, Gerhard J Molderings

Open Access Publications

OBJECTIVES: Hyper-inflammation caused by COVID-19 may be mediated by mast cell activation (MCA) which has also been hypothesized to cause Long-COVID (LC) symptoms. We determined prevalence/severity of MCA symptoms in LC.

METHODS: Adults in LC-focused Facebook support groups were recruited for online assessment of symptoms before and after COVID-19. Questions included presence and severity of known MCA and LC symptoms and validated assessments of fatigue and quality of life. General population controls and mast cell activation syndrome (MCAS) patients were recruited for comparison if they were ≥18 years of age and never had overt COVID-19 symptoms.

RESULTS: There were 136 …

In Silico Epitope Prediction Analyses Highlight The Potential For Distracting Antigen Immunodominance With Allogeneic Cancer Vaccines, C Alston James, Peter Ronning, Darren Cullinan, Kelsy C Cotto, Erica K Barnell, Katie M Campbell, Zachary L Skidmore, Dominic E Sanford, S Peter Goedegebuure, William E Gillanders, Obi L Griffith, William G Hawkins, Malachi Griffith

Open Access Publications

Allogeneic cancer vaccines are designed to induce antitumor immune responses with the goal of impacting tumor growth. Typical allogeneic cancer vaccines are produced by expansion of established cancer cell lines, transfection with vectors encoding immunostimulatory cytokines, and lethal irradiation. More than 100 clinical trials have investigated the clinical benefit of allogeneic cancer vaccines in various cancer types. Results show limited therapeutic benefit in clinical trials and currently there are no FDA approved allogeneic cancer vaccines. We used recently developed bioinformatics tools including the pVAC-seq suite of software tools to analyze DNA/RNA sequencing data from the TCGA to examine the repertoire …

Validation Of Ad8-Philippines (Ad8-P): A Brief Informant-Based Questionnaire For Dementia Screening In The Philippines, Jacqueline C Dominguez, John C Morris, Et Al

Open Access Publications

Aim: This study was aimed at validating the Filipino version of AD8 (AD8-P).

Methods: Community-dwelling Filipino older persons aged ≥60 years, together with their informants, participated in this study. Psychologists independently interviewed the informants with AD8-P and administered the Filipino-validated Mini-Mental State Examination (MMSE-P) and Montreal Cognitive Assessment (MoCA-P) to the older persons. Neurologists and geriatrician conducted physical and neurological examination and Clinical Dementia Rating™ (CDR™) to determine cognitive diagnosis and were blinded with the results of AD8-P. Dementia was diagnosed based on DSM-IV-TR criteria. AD8-P discriminatory ability to screen for dementia was evaluated according to DSM-IV-TR diagnostic criteria for …

Patients With Definite And Inconclusive Evidence Of Reflux According To Lyon Consensus Display Similar Motility And Esophagogastric Junction Characteristics, Mentore Ribolsi, Edoardo Savarino, Benjamin Rogers, Arvind Rengarajan, Marco Della Coletta, Matteo Ghisa, Michele Cicala, C Prakash Gyawali

Open Access Publications

Background/Aims: The role of esophageal high-resolution manometry (HRM) within Lyon consensus phenotypes, especially patients with inconclusive gastroesophageal reflux disease (GERD) evidence, has not been fully investigated. In this multicenter, observational study we aim to compare HRM parameters in patients with GERD stratified according to the Lyon consensus.

Methods: Clinical and endoscopic data, HRM and multichannel intraluminal impedance-pH (MII-pH) studies performed off proton pump inhibitor therapy in patients with esophageal GERD symptoms were reviewed. Lyon consensus criteria identified pathological GERD, reflux hypersensitivity, functional heartburn, and inconclusive GERD. Patients, with inconclusive GERD were further subdivided into 2 groups based on total reflux …

Motor Improvements Enabled By Spinal Cord Stimulation Combined With Physical Training After Spinal Cord Injury: Review Of Experimental Evidence In Animals And Humans, Ismael Seáñez, Marco Capogrosso

Open Access Publications

Electrical spinal cord stimulation (SCS) has been gaining momentum as a potential therapy for motor paralysis in consequence of spinal cord injury (SCI). Specifically, recent studies combining SCS with activity-based training have reported unprecedented improvements in motor function in people with chronic SCI that persist even without stimulation. In this work, we first provide an overview of the critical scientific advancements that have led to the current uses of SCS in neurorehabilitation: e.g. the understanding that SCS activates dormant spinal circuits below the lesion by recruiting large-to-medium diameter sensory afferents within the posterior roots. We discuss how this led to …

The Application Of Exercise Training For Diabetic Peripheral Neuropathy, Clifton J. Holmes, Mary K. Hastings

Open Access Publications

Diabetic peripheral neuropathy (DPN) is the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes. It is associated with pain, paresthesia, sensory loss, muscle atrophy with fat infiltration, and muscular dysfunction typically starting distally in the feet and progressing proximally. Muscle deterioration within the leg and foot can lead to muscle dysfunction, reduced mobility, and increases the risk of disability, ulceration, and amputation. Exercise training is an established method for increasing the different components of physical fitness, including enhancing body composition and improving neuromuscular strength. A number of experimental studies …

High Seropositivity Rate Of Neutralizing Antibodies To Astrovirus Va1 In Human Populations, Andrew B Janowski, Macee C Owen, Holly Dudley, Tomás López, Rafaela Espinosa, Memory Elvin-Lewis, Alejandro Colichon, Carlos F Arias, Peter D Burbelo, David Wang

Open Access Publications

Astroviruses are common pathogens of the human gastrointestinal tract, but they have been recently identified from cases of fatal meningoencephalitis. Astrovirus VA1 is the most frequently detected astrovirus genotype from cases of human encephalitis, but the prevalence of neutralizing antibodies to VA1 in human sera is unknown. We developed a focus reduction neutralization assay (FRNT) for VA1 and measured the seroprevalence of neutralizing antibodies from two cohorts of adult and pediatric serum samples: (i) an age-stratified cohort from St. Louis, MO, collected from 2007 to 2008 and (ii) a cohort from the Peruvian Amazonian River Basin collected in the late …

Structural Mechanism Of Sars-Cov-2 Neutralization By Two Murine Antibodies Targeting The Rbd, John M Errico, Haiyan Zhao, Rita E Chen, Zhuoming Liu, James Brett Case, Meisheng Ma, Aaron J Schmitz, Michael J Rau, James A J Fitzpatrick, Pei-Yong Shi, Michael S Diamond, Sean P J Whelan, Ali H Ellebedy, Daved H Fremont

Open Access Publications

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has necessitated the rapid development of antibody-based therapies and vaccines as countermeasures. Here, we use cryoelectron microscopy (cryo-EM) to characterize two protective anti-SARS-CoV-2 murine monoclonal antibodies (mAbs) in complex with the spike protein, revealing similarities between epitopes targeted by human and murine B cells. The more neutralizing mAb, 2B04, binds the receptor-binding motif (RBM) of the receptor-binding domain (RBD) and competes with angiotensin-converting enzyme 2 (ACE2). By contrast, 2H04 binds adjacent to the RBM and does not compete for ACE2 binding. Naturally occurring sequence variants of SARS-CoV-2 and corresponding neutralization escape …

A Novel Class Of Tmprss2 Inhibitors Potently Block Sars-Cov-2 And Mers-Cov Viral Entry And Protect Human Epithelial Lung Cells, Matthew Mahoney, Vishnu C Damalanka, Michael A Tartell, Anne E Mayer Bridwell, Jorine Voss, Partha Karmakar, Paul W Rothlauf, Cassandra E Thompson, Christina L Stallings, Sean P J Whelan, James W Janetka, Et Al

Open Access Publications

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have significantly improved activity over the existing known inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC

American Society Of Hematology Living Guidelines On The Use Of Anticoagulation For Thromboprophylaxis In Patients With Covid-19: May 2021 Update On The Use Of Intermediate-Intensity Anticoagulation In Critically Ill Patients, Adam Cuker, Kristen M Sanfilippo, Et Al

Open Access Publications

BACKGROUND: COVID-19-related critical illness is associated with an increased risk of venous thromboembolism (VTE).

OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19-related critical illness who do not have confirmed or suspected VTE.

METHODS: ASH formed a multidisciplinary guideline panel that included 3 patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process …

Comparative Genomics Of Mycobacterium Avium Complex Reveals Signatures Of Environment-Specific Adaptation And Community Acquisition, Eric C Keen, Joohee Choi, Meghan A Wallace, Michelle Azar, Carlos R Mejia-Chew, Shail B Mehta, Thomas C Bailey, Lindsay J Caverly, Carey-Ann D Burnham, Gautam Dantas

Open Access Publications

Nontuberculous mycobacteria, including those in the Mycobacterium avium complex (MAC), constitute an increasingly urgent threat to global public health. Ubiquitous in soil and water worldwide, MAC members cause a diverse array of infections in humans and animals that are often multidrug resistant, intractable, and deadly. MAC lung disease is of particular concern and is now more prevalent than tuberculosis in many countries, including the United States. Although the clinical importance of these microorganisms continues to expand, our understanding of their genomic diversity is limited, hampering basic and translational studies alike. Here, we leveraged a unique collection of genomes to characterize …

Neutralizing Monoclonal Antibodies That Target The Spike Receptor Binding Domain Confer Fc Receptor-Independent Protection Against Sars-Cov-2 Infection In Syrian Hamsters, Wen Su, Sin Fun Sia, Aaron J Schmitz, Traci L Bricker, Tyler N Starr, Allison J Greaney, Jackson S Turner, Bassem M Mohammed, Zhuoming Liu, Ka Tim Choy, Tamarand L Darling, Astha Joshi, Ka Man Cheng, Alvina Y L Wong, Houda H Harastani, John M Nicholls, Sean P J Whelan, Jesse D Bloom, Hui-Ling Yen, Ali H Ellebedy, Adrianus C M Boon

Open Access Publications

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main target for neutralizing antibodies. These antibodies can be elicited through immunization or passively transferred as therapeutics in the form of convalescent-phase sera or monoclonal antibodies (MAbs). Potently neutralizing antibodies are expected to confer protection; however, it is unclear whether weakly neutralizing antibodies contribute to protection. Also, their mechanism of action

Human Monoclonal Antibodies Against Ns1 Protein Protect Against Lethal West Nile Virus Infection, Alex W Wessel, Michael P Doyle, Taylor B Engdahl, Jessica Rodriguez, James E Crowe, Michael S Diamond

Open Access Publications

Envelope protein-targeted vaccines for flaviviruses are limited by concerns of antibody-dependent enhancement (ADE) of infections. Nonstructural protein 1 (NS1) provides an alternative vaccine target that avoids this risk since this protein is absent from the virion. Beyond its intracellular role in virus replication, extracellular forms of NS1 function in immune modulation and are recognized by host-derived antibodies. The rational design of NS1-based vaccines requires an extensive understanding of the antigenic sites on NS1, especially those targeted by protective antibodies. Here, we isolated human monoclonal antibodies (MAbs) from individuals previously naturally infected with WNV, mapped their epitopes using structure-guided mutagenesis, and …