Most downloaded biology preprints, since beginning of last month
in category pathology
684 results found. For more information, click each entry to expand.
3,339 downloads medRxiv pathology
Scott Wesley Long, Randall J. Olsen, Paul A. Christensen, David W. Bernard, James J Davis, Maulik Shukla, Marcus Nguyen, Matthew Ojeda Saavedra, Prasanti Yerramilli, Layne Pruitt, Sishir Subedi, Hung-Che Kuo, Heather Hendrickson, Ghazaleh Eskandari, Hoang A.T. Nguyen, James Hunter Long, Muthiah Kumaraswami, Jule Goike, Daniel Boutz, Jimmy Gollihar, Jason S. McLellan, Chia-Wei Chou, Kamyab Javanmardi, Ilya J. Finkelstein, James Musser
We sequenced the genomes of 5,085 SARS-CoV-2 strains causing two COVID-19 disease waves in metropolitan Houston, Texas, an ethnically diverse region with seven million residents. The genomes were from viruses recovered in the earliest recognized phase of the pandemic in Houston, and an ongoing massive second wave of infections. The virus was originally introduced into Houston many times independently. Virtually all strains in the second wave have a Gly614 amino acid replacement in the spike protein, a polymorphism that has been linked to increased transmission and infectivity. Patients infected with the Gly614 variant strains had significantly higher virus loads in the nasopharynx on initial diagnosis. We found little evidence of a significant relationship between virus genotypes and altered virulence, stressing the linkage between disease severity, underlying medical conditions, and host genetics. Some regions of the spike protein - the primary target of global vaccine efforts - are replete with amino acid replacements, perhaps indicating the action of selection. We exploited the genomic data to generate defined single amino acid replacements in the receptor binding domain of spike protein that, importantly, produced decreased recognition by the neutralizing monoclonal antibody CR30022. Our study is the first analysis of the molecular architecture of SARS-CoV-2 in two infection waves in a major metropolitan region. The findings will help us to understand the origin, composition, and trajectory of future infection waves, and the potential effect of the host immune response and therapeutic maneuvers on SARS-CoV-2 evolution.
1,027 downloads medRxiv pathology
SARS-CoV-2 has rapidly spread across the United States, causing extensive morbidity and mortality, though the histopathologic basis of severe disease cases has yet to be studied in detail. Over the past century, autopsy has contributed significantly to our understanding of numerous disease processes, but for several reasons, autopsy reports following deaths related to SARS- CoV-2 have thus far been limited across the globe. We report on the relevant cardiopulmonary findings in the first series of autopsies in the United States, with the cause of death being due to SARS-CoV-2 infection. These cases identify key pathologic states potentially contributing to severe disease and decompensation in these patients.
971 downloads medRxiv pathology
Objectives: We compared the Abbott ID NOW COVID-19 point-of-care test (POCT) with polymerase chain reaction (PCR)-based methods to assess the claimed sensitivity and specificity of POCT and to optimize test utilization in our regional health care system. Methods: Assuming PCR to be the gold standard, we used a convenience sampling of mostly symptomatic COVID-19 suspect hospital patients who had already been tested for internal validation and guideline development purposes by both PCR and POCT to calculate the sensitivity and specificity of POCT with Clopper-Pearson 95% confidence intervals (CI). Results: During the study period, 113 paired patient samples met eligibility criteria. The sensitivity of POCT in this population was calculated to be 94.1% [CI 71.31-99.85%] and the specificity was 99.0% [CI 94.33-99.97%]. Conclusions: Based on the lower sensitivity of POCT and the estimated prevalence of COVID-19 in our symptomatic and asymptomatic hospital patients, we recommend a two-pronged testing approach in which COVID-19 suspect patients are tested by the more sensitive PCR, while asymptomatic patients with a low pre-test probability of infection are tested with POCT supplemented by PCR confirmation of positive results. Furthermore, isolation decisions should not be based on POCT results alone.
771 downloads medRxiv pathology
The COVID-19 pandemic caused by the SARS-CoV-2 Coronavirus has stretched national testing capacities to breaking points in almost all countries of the world. The need to rapidly screen vast numbers of a countrys population in order to control the spread of the infection is paramount. However, the logistical requirement for reagent supply (and associated cost) of RT-PCR based testing (the current front-line test) have been hugely problematic. Mass spectrometry-based methods using swab and gargle samples have been reported with promise, but have not approached the task from a systematic analysis of the entire diagnostic process. Here, the pipeline from sample processing, the biological characteristics of the pathogen in human biofluid, the downstream bio- and physical-chemistry and the all-important data processing with clinical interpretation and reporting, are carefully compiled into a single high throughput and reproducible rapid process. Utilizing MALDI-ToF mass spectrometric detection to viral envelope glycoproteins in a systems biology - multidisciplinary team approach, we have achieved a multifaceted clinical MALDI ToF MS screening test, primarily (but not limited to) SARS-CoV-2, with direct applicable to other future epidemics/pandemics that may arise. The clinical information generated not only includes SARS-CoV-2 Coronavirus detection (Spike protein fragments S1, S2b, S2a peaks), but other respiratory viral infections detected as well as an assessment of generalised oral upper respiratory immune response (elevated total Ig light chain peak) and a measure of the viral immune response (elevated intensity of IgA heavy chain peak). The advantages of the method include; 1) ease of sampling, 2) speed of analysis, and much reduced cost of testing. These features reveal the diagnostic utility of MALDI-ToF mass spectrometry as a powerful and economically attractive global solution.
754 downloads bioRxiv pathology
Andrew C. Nelson, Benjamin Auch, Matthew Schomaker, Daryl M. Gohl, Patrick Grady, Darrell Johnson, Robyn Kincaid, Kylene E Karnuth, Jerry Daniel, Jessica K Fiege, Elizabeth J Fay, Tyler Bold, Ryan A Langlois, Kenneth B. Beckman, Sophia Yohe
The COVID-19 global pandemic is an unprecedented health emergency. Insufficient access to testing has hampered effective public health interventions and patient care management in a number of countries. Furthermore, the availability of regulatory-cleared reagents has challenged widespread implementation of testing. We rapidly developed a qRT-PCR SARS-CoV-2 detection assay using a 384-well format and tested its analytic performance across multiple nucleic acid extraction kits. Our data shows robust analytic accuracy on residual clinical biospecimens. Limit of detection sensitivity and specificity was confirmed with currently available commercial reagents. Our methods and results provide valuable information for other high-complexity laboratories seeking to develop effective, local, laboratory-developed procedures with high-throughput capability to detect SARS-CoV-2.
707 downloads medRxiv pathology
Clare Bryce, Zachary Grimes, Elisabet Pujadas, Sadhna Ahuja, Mary Beth Beasley, Randy Albrecht, Tahyna Hernandez, Aryeh Stock, Zhen Zhao, Mohamed Al Rasheed, Joyce Chen, Li Li, Diane Wang, Adriana Corben, Kenneth Haines, William Westra, Melissa Umphlett, Ronald E Gordon, Jason Reidy, Bruce Petersen, Fadi Salem, MariaIsabel Fiel, Siraj M El Jamal, Nadejda M. Tsankova, Jane Houldsworth, Zarmeen Mussa, Wen-Chun Liu, Brandon Veremis, Emilia Sordillo, Melissa Gitman, Michael Nowak, Rachel Brody, Noam Harpaz, Miriam Merad, Sacha Gnjatic, Ryan Donnelly, Patricia Seigler, Calvin Keys, Jennifer Cameron, Isaiah Moultrie, Kae-Lynn Washington, Jacquelyn Treatman, Robert Sebra, Jeffrey Jhang, Adolfo Firpo, John Lednicky, Alberto Paniz-Mondolfi, Carlos Cordon-Cardo, Mary Fowkes
BACKGROUND Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe, disproportionately affecting New York City. A comprehensive, integrative autopsy series that advances the mechanistic discussion surrounding this disease process is still lacking. METHODS Autopsies were performed at the Mount Sinai Hospital on 67 COVID-19 positive patients and data from the clinical records were obtained from the Mount Sinai Data Warehouse. The experimental design included a comprehensive microscopic examination carried out by a team of expert pathologists, along with transmission electron microscopy, immunohistochemistry, RNA in situ hybridization, as well as immunology and serology assays. RESULTS Laboratory results of our COVID-19 cohort show elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8 and TNF. Autopsies revealed large pulmonary emboli in four cases. We report microthrombi in multiple organ systems including the brain, as well as conspicuous hemophagocytosis and a secondary hemophagocytic lymphohistiocytosis-like syndrome in many of our patients. We provide electron microscopic, immunofluorescent and immunohistochemical evidence of the presence of the virus and the ACE2 receptor in our samples. CONCLUSIONS We report a comprehensive autopsy series of 67 COVID-19 positive patients revealing that this disease, so far conceptualized as a primarily respiratory viral illness, also causes endothelial dysfunction, a hypercoagulable state, and an imbalance of both the innate and adaptive immune responses. Novel findings reported here include an endothelial phenotype of ACE2 in selected organs, which correlates with clotting abnormalities and thrombotic microangiopathy, addressing the prominent coagulopathy and neuropsychiatric symptoms. Another original observation is that of macrophage activation syndrome, with hemophagocytosis and a hemophagocytic lymphohistiocytosis-like disorder, underlying the microangiopathy and excessive cytokine release. We discuss the involvement of critical regulatory pathways.
677 downloads medRxiv pathology
The coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread to more than 100 countries posing as a serious threat to the public health on a global scale. Patients with comorbidity such as hypertension suffer more severe infection with elevated case fatality rate. Development of effective anti-viral drug is in urgent need to treat COVID-19 patients. Here we report that calcium channel blockers (CCBs), a type of anti-hypertension drugs that are widely used in the clinics, can significantly inhibit the post-entry replication events of SARS-CoV-2 in vitro. Comparison with two other major types of anti-hypertension drugs, the angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), showed that only CCBs display significant anti-SARS-CoV-2 efficacy. Combined treatment with chloroquine and CCBs significantly enhanced the anti-SARS-CoV-2 efficacy. Retrospective clinical investigation of COVID-19 patients revealed that the CCB amlodipine besylate administration was associated with reduced case fatality rate of patients with hypertension. Results from this study suggest that CCB administration for COVID-19 patients with hypertension as the comorbidity might improve the disease outcome.
603 downloads bioRxiv pathology
Purpose: Conjunctival signs and symptoms are observed in a subset of patients with COVID-19, and SARS-CoV-2 has been detected in tears, raising concerns regarding the eye both as a portal of entry and carrier of the virus. The purpose of this study was to determine whether ocular surface cells possess the key factors required for cellular susceptibility to SARS-CoV-2 entry/infection. Methods: We analyzed human post-mortem eyes as well as surgical specimens for the expression of ACE2 (the receptor for SARS-CoV-2) and TMPRSS2, a cell surface-associated protease that facilitates viral entry following binding of the viral spike protein to ACE2. Results: Across all eye specimens, immunohistochemical analysis revealed expression of ACE2 in the conjunctiva, limbus, and cornea, with especially prominent staining in the superficial conjunctival and corneal epithelial surface. Surgical conjunctival specimens also showed expression of ACE2 in the conjunctival epithelium, especially prominent in the superficial epithelium, as well as the substantia propria. All eye and conjunctival specimens also expressed TMPRSS2. Finally, western blot analysis of protein lysates from human corneal epithelium obtained during refractive surgery confirmed expression of ACE2 and TMPRSS2. Conclusions: Together, these results indicate that ocular surface cells including conjunctiva are susceptible to infection by SARS-CoV-2, and could therefore serve as a portal of entry as well as a reservoir for person-to-person transmission of this virus. This highlights the importance of safety practices including face masks and ocular contact precautions in preventing the spread of COVID-19 disease. ### Competing Interest Statement The authors have declared no competing interest.
481 downloads bioRxiv pathology
Non-alcoholic steatohepatitis (NASH) is a fatty liver disease characterized by accumulation of fat in hepatocytes with concurrent inflammation and is associated with morbidity, cirrhosis and liver failure. After extraction of a liver core biopsy, tissue sections are stained with hematoxylin and eosin (H&E) to grade NASH activity, and stained with trichrome to stage fibrosis. Methods to computationally transform one stain into another on digital whole slide images (WSI) can lessen the need for additional physical staining besides H&E, reducing personnel, equipment, and time costs. Generative adversarial networks (GAN) have shown promise for virtual staining of tissue. We conducted a large-scale validation study of the viability of GANs for H&E to trichrome conversion on WSI (n=574). Pathologists were largely unable to distinguish real images from virtual/synthetic images given a set of twelve Turing Tests. We report high correlation between staging of real and virtual stains (r=0.86; 95% CI: 0.84-0.88). Stages assigned to both virtual and real stains correlated similarly with a number of clinical biomarkers and progression to End Stage Liver Disease (Hazard Ratio HR = 2.06, CI 95% 1.36-3.12, P < 0.001 for real stains; HR = 2.02, CI 95% 1.40-2.92, p < 0.001 for virtual stains). Our results demonstrate that virtual trichrome technologies may offer a software solution that can be employed in the clinical setting as a diagnostic decision aid. ### Competing Interest Statement The authors have declared no competing interest.
451 downloads bioRxiv pathology
Christopher R. Merritt, Giang T Ong, Sarah Church, Kristi Barker, Gary Geiss, Margaret Hoang, Jaemyeong Jung, Yan Liang, Jill McKay-Fleisch, Karen Nguyen, Kristina Sorg, Isaac Sprague, Charles Warren, Sarah Warren, Zoey Zhou, Daniel R. Zollinger, Dwayne L. Dunaway, Gordon B. Mills, Joseph M. Beechem
We have developed Digital Spatial Profiling (DSP), a non-destructive method for high-plex spatial profiling of proteins and RNA, using oligonucleotide detection technologies with unlimited multiplexing capability. The key breakthroughs underlying DSP are threefold: (1) multiplexed readout of proteins/RNA using oligo-tags; (2) oligo-tags attached to affinity reagents (antibodies/RNA probes) through a photocleavable (PC) linker; (3) photocleaving light projected onto the tissue sample to release PC-oligos in any spatial pattern. Here we show precise analyte reproducibility, validation, and cellular resolution using DSP. We also demonstrate biological proof-of-concept using lymphoid, colorectal tumor, and autoimmune tissue as models to profile immune cell populations, stroma, and cancer cells to identify factors specific for the diseased microenvironment. DSP utilizes the unlimited multiplexing capability of modern genomic approaches, while simultaneously providing spatial context of protein and RNA to examine biological questions based on analyte location and distribution.
438 downloads medRxiv pathology
BackgroundThe current COVID-19 pandemic is considered one of the most serious public health crisis over the last few decades. Although the disease can result in diverse, multiorgan pathology, there have been very few studies addressing the postmortem pathological findings of the cases. Active autopsy amid this pandemic could be an essential tool for diagnosis, surveillance, and research. ObjectiveTo provide a total picture of the SARS-CoV-2 histopathological features of different body organs in postmortem autopsies through a systematic search of the published literature. MethodsA systematic search of electronic databases (PubMed, ScienceDirect, Google scholar, Medrxiv & Biorxiv) was carried out from December 2019 to August, 15th 2020, for journal articles of different study designs reporting postmortem pathological findings in COVID-19 cases. PRISMA guidelines were used for reporting the review. ResultsA total of 50 articles reporting 430 cases were included in our analysis. Postmortem pathological findings were reported for different body organs, pulmonary system (42 articles), cardiovascular system (23 articles), hepatobiliary system (22 articles), kidney (16 articles), spleen, and lymph nodes (12 articles), and central nervous system (7 articles). In lung samples, diffuse alveolar damage (DAD) was the most commonly reported findings in 239 cases (84.4%). Myocardial hypertrophy (87 cases by 51.2%), arteriosclerosis (121 cases by 62%), and steatosis (118 cases by 59.3%) were the most commonly reported pathological findings in the heart, kidney, and hepatobiliary system respectively. ConclusionAutopsy examination as an investigation tool could help in a better understanding of SARS-CoV-2 pathophysiology, diagnosis, management, and subsequently improving patient care.
399 downloads bioRxiv pathology
Fan Wu, Su Zhao, Bin Yu, Yan-Mei Chen, Wen Wang, Yi Hu, Zhi-Gang Song, Zhao-Wu Tao, Jun-Hua Tian, Yuan-Yuan Pei, Ming-Li Yuan, Yu-Ling Zhang, Fa-Hui Dai, Yi Liu, Qi-Min Wang, Jiao-Jiao Zheng, Lin Xu, Edward C Holmes, Yong-Zhen Zhang
Emerging and re-emerging infectious diseases, such as SARS, MERS, Zika and highly pathogenic influenza present a major threat to public health–. Despite intense research effort, how, when and where novel diseases appear are still the source of considerable uncertainly. A severe respiratory disease was recently reported in the city of Wuhan, Hubei province, China. At the time of writing, at least 62 suspected cases have been reported since the first patient was hospitalized on December 12nd 2019. Epidemiological investigation by the local Center for Disease Control and Prevention (CDC) suggested that the outbreak was associated with a sea food market in Wuhan. We studied seven patients who were workers at the market, and collected bronchoalveolar lavage fluid (BALF) from one patient who exhibited a severe respiratory syndrome including fever, dizziness and cough, and who was admitted to Wuhan Central Hospital on December 26th 2019. Next generation metagenomic RNA sequencing identified a novel RNA virus from the family Coronaviridae designed WH-Human-1 coronavirus (WHCV). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that WHCV was most closely related (89.1% nucleotide similarity similarity) to a group of Severe Acute Respiratory Syndrome (SARS)-like coronaviruses (genus Betacoronavirus , subgenus Sarbecovirus ) previously sampled from bats in China and that have a history of genomic recombination. This outbreak highlights the ongoing capacity of viral spill-over from animals to cause severe disease in humans. : #ref-1 : #ref-3 : #ref-4
383 downloads bioRxiv pathology
Liqun He, Maarja Andaloussi Mäe, Lars Muhl, Ying Sun, Riikka Pietilä, Khayrun Nahar, Elisa Vázquez Liébanas, Malin Jonsson Fagerlund, Anders Oldner, Jianping Liu, Guillem Genové, Lei Zhang, Yuan Xie, Stefanos Leptidis, Giuseppe Mocci, Simon Stritt, Ahmed Osman, Andrey Anisimov, Karthik Amudhala Hemanthakumar, Markus Räsänen, Olivier Mirabeau, Emil Hansson, Johan Björkegren, Michael Vanlandewijck, Klas Blomgren, Taija Mäkinen, Xiao-Rong Peng, Thomas D. Arnold, Kari Alitalo, Lars I Eriksson, Urban Lendahl, Christer Betsholtz
Accumulating clinical observations implicate vascular inflammation as an underlying cause of coagulopathy in severely ill COVID-19 patients and it was recently suggested that SARS-CoV-2 virus particles infect endothelial cells. Here, we show that endothelial cells do not express angiotensin-converting enzyme-2 (ACE2), the SARS-CoV-2 receptor. Instead, pericytes and microvascular smooth muscle cells express ACE2 in an organotypic manner. Pericyte deficiency leads to increased endothelial expression and release of Von Willebrand factor and intravascular platelet and fibrin aggregation, suggesting that pericytes limit endothelial pro-thrombotic responses. That pericytes and not endothelial cells express ACE2 may provide important clues to the pathology of COVID-19, as pericytes are normally shielded behind an endothelial barrier and may get infected only when this barrier is compromised by COVID-19 risk factors. ### Competing Interest Statement C.B. is a consultant for AstraZeneca BioPharmaceuticals R&D. X.-R. P. is an employee of AstraZeneca BioPharmaceuticals R&D.
379 downloads medRxiv pathology
Di Wu, Ting Shu, Xiaobo Yang, Jian-Xin Song, Mingliang Zhang, Chengye Yao, Liu Wen, Muhan Huang, Yuan Yu, Qingyu Yang, Tingju Zhu, Jiqian Xu, Jingfang Mu, Yaxin Wang, Hong Wang, Tang Tang, Yujie Ren, Yongran Wu, Shu-Hai Lin, Yang Qiu, Ding-Yu Zhang, You Shang, Xi Zhou
The pandemic of the coronavirus disease 2019 (COVID-19) has become a global public health crisis. COVID-19 is marked by its rapid progression from mild to severe conditions, particularly in the absence of adequate medical care. However, the physiological changes associated with COVID-19 are barely understood. In this study, we performed untargeted metabolomic and lipidomic analyses of plasma from a cohort of COVID-19 patients who had experienced different symptoms. We found the metabolite and lipid alterations exhibit apparent correlation with the course of disease in these COVID-19 patients, indicating that the development of COVID-19 affected patient metabolism. Moreover, many of the metabolite and lipid alterations, particularly ones associated with hepatic functions, have been found to align with the progress and severity of COVID-19. This work provides valuable knowledge about blood biomarkers associated with COVID-19 and potential therapeutic targets, and presents important resource for further studies of COVID-19 pathogenesis.
374 downloads medRxiv pathology
Ronny Nienhold, Yari Ciani, Viktor H Koelzer, Alexandar Tzankov, Jasmin D Haslbauer, Thomas Menter, Nathalie Schwab, Maurice Henkel, Angela Frank, Veronika Zsikla, Niels Willi, Werner Kempf, Thomas Hoyler, Mattia Barbareschi, Holger Moch, Markus Tolnay, Gieri Cathomas, Francesca Demichelis, Tobias Junt, Kirsten D Mertz
Coronavirus Disease 19 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has grown to a worldwide pandemic with substantial mortality. Immune mediated damage has been proposed as a pathogenic factor, but immune responses in lungs of COVID-19 patients remain poorly characterized. Therefore we conducted transcriptomic, histologic and cellular profiling of post mortem COVID-19 (n=34 tissues from 16 patients) and normal lung tissues (n=9 tissues from 6 patients). Two distinct immunopathological reaction patterns of lethal COVID-19 were identified. One pattern showed high local expression of interferon stimulated genes (ISGhigh) and cytokines, high viral loads and limited pulmonary damage, the other pattern showed severely damaged lungs, low ISGs (ISGlow), low viral loads and abundant infiltrating activated CD8+ T cells and macrophages. ISGhigh patients died significantly earlier after hospitalization than ISGlow patients. Our study may point to distinct stages of progression of COVID-19 lung disease and highlights the need for peripheral blood biomarkers that inform about patient lung status and guide treatment.
369 downloads bioRxiv pathology
Marian Kalocsay, Zoltan Maliga, Ajit J. Nirmal, Robyn J. Eisert, Gary A. Bradshaw, Isaac H Solomon, Yu-An Chen, Roxanne J. Pelletier, Connor A Jacobson, Julian Mintseris, Robert F. Padera, Amanda J. Martinot, Dan H. Barouch, Sandro Santagata, Peter K. Sorger
Normal tissue physiology and repair depends on communication with the immune system. Understanding this communication at the molecular level in intact tissue requires new methods. The consequences of SARS-CoV-2 infection, which can result in acute respiratory distress, thrombosis and death, has been studied primarily in accessible liquid specimens such as blood, sputum and bronchoalveolar lavage, all of which are peripheral to the primary site of infection in the lung. Here, we describe the combined use of multiplexed deep proteomics with multiplexed imaging to profile infection and its sequelae directly in fixed lung tissue specimens obtained from necropsy of infected animals and autopsy of human decedents. We characterize multiple steps in disease response from cytokine accumulation and protein phosphorylation to activation of receptors, changes in signaling pathways, and crosslinking of fibrin to form clots. Our data reveal significant differences between naturally resolving SARS-CoV-2 infection in rhesus macaques and lethal COVID-19 in humans. The approach we describe is broadly applicable to other tissues and diseases. ### Competing Interest Statement PKS is a member of the SAB or BOD member of Applied Biomath, RareCyte Inc., and Glencoe Software; PKS is also a member of the NanoString SAB. SS is a consultant for RareCyte Inc. The other authors declare no outside interests.
359 downloads bioRxiv pathology
Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/2019-nCoV) has spread quickly worldwide, with more than 29 million cases and 920,000 deaths. Interestingly, coronaviruses were found to subvert and hijack the autophagic process to allow their viral replication. One of the spotlights had been focused on the autophagy inhibitors as a target mechanism effective in the inhibition of SARS-CoV-2 infection. Consequently, chloroquine (CQ) and hydroxychloroquine (HCQ), a derivative of CQ, was suggested as the first potentially be therapeutic strategies as they are known to be autophagy inhibitors. Then, they were used as therapeutics in SARS-CoV-2 infection along with remdesivir, for which the FDA approved emergency use authorization. Here, we investigated the antiviral activity and associated mechanism of GNS561, a small basic lipophilic molecule inhibitor of late-stage autophagy, against SARS-CoV-2. Our data indicated that GNS561 showed the highest antiviral effect for two SARS-CoV-2 strains compared to CQ and remdesivir. Focusing on the autophagy mechanism, we showed that GNS561, located in LAMP2-positive lysosomes, together with SARS-CoV-2, blocked autophagy by increasing the size of LC3-II spots and the accumulation of autophagic vacuoles in the cytoplasm with the presence of multilamellar bodies characteristic of a complexed autophagy. Finally, our study revealed that the combination of GNS561 and remdesivir was associated with a strong synergistic antiviral effect against SARS-CoV-2. Overall, our study highlights GNS561 as a powerful drug in SARS-CoV-2 infection and supports that the hypothesis that autophagy inhibitors could be an alternative strategy for SARS-CoV-2 infection. ### Competing Interest Statement P.H., E.B. and S.M. are Genoscience Pharma Employees.
276 downloads medRxiv pathology
Sefer Elezkurtaj, Selina Greuel, Jana Ihlow, Edward Michaelis, Philip Bischoff, Catarina Alisa Kunze, Bruno Valentin Sinn, Manuela Gerhold, Kathrin Hauptmann, Barbara Ingold-Heppner, Florian Miller, Hermann Herbst, Victor Max Corman, Hubert Martin, Frank L. Heppner, David Horst
Infection by the new corona virus strain SARS-CoV-2 and its related syndrome COVID-19 has caused several hundreds of thousands of deaths worldwide. Patients of higher age and with preexisting chronic health conditions are at an increased risk of fatal disease outcome. However, detailed information on causes of death and the contribution of comorbidities to death yet is missing. Here, we report autopsy findings on causes of death and comorbidities of 26 decedents that had clinically presented with severe COVID-19. We found that septic shock and multi organ failure was the most common immediate cause of death, often due to suppurative pulmonary infection. Respiratory failure due to diffuse alveolar damage presented as the most immediate cause of death in fewer cases. Several comorbidities, such as hypertension, ischemic heart disease, and obesity were present in the vast majority of patients. Our findings reveal that causes of death were directly related to COVID-19 in the majority of decedents, while they appear not to be an immediate result of preexisting health conditions and comorbidities. We therefore suggest that the majority of patients had died of COVID-19 with only contributory implications of preexisting health conditions to the mechanism of death.
265 downloads bioRxiv pathology
Currently, the world is suffering from the pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. So far, 30 million people have been infected with SARS-CoV-2, and nearly 1 million people have died because of COVID-19 worldwide, causing serious health, economical, and sociological problems. However, the mechanism of the effect of SARS-CoV-2 on human host cells has not been defined. The present study reports that the SARS-CoV-2 spike protein alone without the rest of the viral components is sufficient to elicit cell signaling in lung vascular cells. The treatment of human pulmonary artery smooth muscle cells or human pulmonary artery endothelial cells with recombinant SARS-CoV-2 spike protein S1 subunit (Val16 - Gln690) at 10 ng/ml (0.13 nM) caused an activation of MEK phosphorylation. The activation kinetics was transient with a peak at 10 min. The recombinant protein that contains only the ACE2 receptor-binding domain of SARS-CoV-2 spike protein S1 subunit (Arg319 - Phe541), on the other hand, did not cause this activation. Consistent with the activation of cell growth signaling in lung vascular cells by SARS-CoV-2 spike protein, pulmonary vascular walls were found to be thickened in COVID-19 patients. Thus, SARS-CoV-2 spike protein-mediated cell growth signaling may participate in adverse cardiovascular/pulmonary outcomes, and this mechanism may provide new therapeutic targets to combat COVID-19. ### Competing Interest Statement The authors have declared no competing interest.
262 downloads bioRxiv pathology
Serology testing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is increasingly being used during the current pandemic of Coronavirus Disease 2019 (COVID-19). The clinical and epidemiologic utilities of antibody-based SARS-CoV-2 testing are under debate. Characterizing these assays helps to understand the disease and provide scientific basis to decide how to best use these assays. The study assessed one chemiluminescent assay (Abbott COVID-2 IgG) and two lateral flow assays (STANDARD Q [SQ] IgM/IgG Duo and Wondfo Total Antibody Test). Validation included 113 blood samples from 71 PCR-confirmed COVID-19 patients and 1182 samples from negative controls and interferences/cross-reactions, including 1063 pre-pandemic samples. IgM antibodies against SARS-CoV-2 were detected as early as post-symptom onset days 3-4. IgG antibodies were first detected post-onset days 5-6 by SQ assays. The detection rates increased gradually, and SQ IgG, Abbott IgG and Wondfo Total detected antibodies from all the PCR-confirmed patients 14 days after symptom onset. Overall agreements between SQ IgM/IgG and Wondfo Total reached 88.5% and 94.6% between SQ IgG and Abbott IgG (Kappa = 0.75, 0.89). No cross-reaction with other endemic coronavirus infections were identified. Viral hepatitis and autoimmune samples were the main cross-reactions observed. However, the interferences/cross-reactions were low. The specificities were 100% for SQ IgG and Wondfo Total and 99.62% for Abbott IgG and 98.87% for SQ IgM. These findings demonstrate high sensitivity and specificity of appropriately validated antibody-based SARS-CoV-2 assays with implications for clinical use and epidemiological seroprevalence studies.
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
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