Imaging Techniques: Essential Tools for the Study of SARS-CoV-2 Infection

The world has seen the emergence of a new virus in 2019, SARS-CoV-2, causing the COVID-19 pandemic and millions of deaths worldwide. Microscopy can be much more informative than conventional detection methods such as RT-PCR. This review aims to present the up-to-date microscopy observations in patients, the in vitro studies of the virus and viral proteins and their interaction with their host, discuss the microscopy techniques for detection and study of SARS-CoV-2, and summarize the reagents used for SARS-CoV-2 detection. From basic fluorescence microscopy to high resolution techniques and combined technologies, this article shows the power and the potential of microscopy techniques, especially in the field of virology.

[1]  Wei Huang,et al.  Advances in Pathogenesis, Progression, Potential Targets and Targeted Therapeutic Strategies in SARS-CoV-2-Induced COVID-19 , 2022, Frontiers in Immunology.

[2]  E. Masliah,et al.  Does SARS-CoV-2 affect neurodegenerative disorders? TLR2, a potential receptor for SARS-CoV-2 in the CNS , 2022, Experimental & Molecular Medicine.

[3]  M. Tarnopolsky,et al.  COVID‐19‐Associated Critical Illness Myopathy with Direct Viral Effects , 2022, Annals of neurology.

[4]  B. Stripp,et al.  Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis , 2022, European Respiratory Journal.

[5]  Jun Yu,et al.  SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1 , 2022, Cell Death & Differentiation.

[6]  C. Kaminski,et al.  SARS-CoV-2 nucleocapsid protein adheres to replication organelles before viral assembly at the Golgi/ERGIC and lysosome-mediated egress , 2022, Science advances.

[7]  Xiao Li,et al.  SARS-CoV-2 Causes Mitochondrial Dysfunction and Mitophagy Impairment , 2022, Frontiers in Microbiology.

[8]  K. To,et al.  In-House Immunofluorescence Assay for Detection of SARS-CoV-2 Antigens in Cells from Nasopharyngeal Swabs as a Diagnostic Method for COVID-19 , 2021, Diagnostics.

[9]  M. Rico,et al.  Multiplex Gene Tagging with CRISPR-Cas9 for Live-Cell Microscopy and Application to Study the Role of SARS-CoV-2 Proteins in Autophagy, Mitochondrial Dynamics, and Cell Growth , 2021, The CRISPR journal.

[10]  A. Diaspro,et al.  A spatial multi-scale fluorescence microscopy toolbox discloses entry checkpoints of SARS-CoV-2 variants in Vero E6 cells , 2021, Computational and Structural Biotechnology Journal.

[11]  R. Bartenschlager,et al.  Contribution of autophagy machinery factors to HCV and SARS-CoV-2 replication organelle formation , 2021, Cell Reports.

[12]  D. Klionsky,et al.  The role of autophagy in the pathogenesis of SARS-CoV-2 infection in different cell types , 2021, Autophagy.

[13]  D. Bliss,et al.  A high content microscopy-based platform for detecting antibodies to the nucleocapsid, spike and membrane proteins of SARS-CoV-2 , 2021, medRxiv.

[14]  J. De la Cruz-Enríquez,et al.  SARS-CoV-2 induces mitochondrial dysfunction and cell death by oxidative stress/inflammation in leukocytes of COVID-19 patients , 2021, Free radical research.

[15]  A. Khmaladze,et al.  Mitochondrial Dynamics in SARS-COV2 Spike Protein Treated Human Microglia: Implications for Neuro-COVID , 2021, Journal of Neuroimmune Pharmacology.

[16]  Hong Zhang,et al.  ORF3a of SARS-CoV-2 promotes lysosomal exocytosis-mediated viral egress , 2021, Developmental Cell.

[17]  S. Yamanaka,et al.  Dual inhibition of TMPRSS2 and Cathepsin Bprevents SARS-CoV-2 infection in iPS cells , 2021, Molecular Therapy - Nucleic Acids.

[18]  A. Erman,et al.  Just Seeing Is Not Enough for Believing: Immunolabelling as Indisputable Proof of SARS-CoV-2 Virions in Infected Tissue , 2021, Viruses.

[19]  Yuchen R. He,et al.  Label-free SARS-CoV-2 detection and classification using phase imaging with computational specificity , 2021, Light, science & applications.

[20]  Matthew J. O’Meara,et al.  Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19 , 2021, Proceedings of the National Academy of Sciences.

[21]  D. Roberts,et al.  A standardized definition of placental infection by SARS-CoV-2, a consensus statement from the National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development SARS-CoV-2 Placental Infection Workshop , 2021, American Journal of Obstetrics and Gynecology.

[22]  D. Roberts,et al.  SPECIAL REPORT: A standardized definition of placental infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a consensus statement from the National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIH/NICHD) SARS-CoV-2 placen , 2021, American Journal of Obstetrics and Gynecology.

[23]  C. Hourioux,et al.  Secretory Vesicles Are the Principal Means of SARS-CoV-2 Egress , 2021, Cells.

[24]  V. Falcón,et al.  SARS-CoV-2: preliminary study of infected human nasopharyngeal tissue by high resolution microscopy , 2021, Virology journal.

[25]  V. Raj,et al.  SARS-CoV-2 Cellular Entry Is Independent of the ACE2 Cytoplasmic Domain Signaling , 2021, Cells.

[26]  M. Soto,et al.  The kidnapping of mitochondrial function associated with the SARS-CoV-2 infection. , 2021, Histology and histopathology.

[27]  Eyal Sela,et al.  Unified platform for genetic and serological detection of COVID-19 with single-molecule technology , 2021, medRxiv.

[28]  J. Liu,et al.  The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-Ι , 2021, Proceedings of the National Academy of Sciences.

[29]  G. Nolan,et al.  SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment , 2021, Cell Metabolism.

[30]  Timothy A. Blenkinsop,et al.  SARS-CoV-2 infects human adult donor eyes and hESC-derived ocular epithelium , 2021, Cell Stem Cell.

[31]  Jiang Ren,et al.  The intersection of COVID-19 and cancer: signaling pathways and treatment implications , 2021, Molecular cancer.

[32]  Xu Tan,et al.  Current Strategies of Antiviral Drug Discovery for COVID-19 , 2021, Frontiers in Molecular Biosciences.

[33]  H. Erfle,et al.  Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation , 2021, Nature Communications.

[34]  Yong Lin,et al.  The SARS-CoV-2 protein ORF3a inhibits fusion of autophagosomes with lysosomes , 2021, Cell Discovery.

[35]  Yuzhang Wu,et al.  Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 infection , 2021, Nature Communications.

[36]  R. Sebra,et al.  Tissue-based SARS-CoV-2 detection in fatal COVID-19 infections: Sustained direct viral-induced damage is not necessary to drive disease progression , 2021, Human Pathology.

[37]  B. La Scola,et al.  Microscopic Observation of SARS-Like Particles in RT-qPCR SARS-CoV-2 Positive Sewage Samples , 2021, Pathogens.

[38]  Jincun Zhao,et al.  RNA-induced liquid phase separation of SARS-CoV-2 nucleocapsid protein facilitates NF-κB hyper-activation and inflammation , 2021, Signal Transduction and Targeted Therapy.

[39]  M. Guzmán,et al.  SARS-CoV-2: enhancement and segmentation of high-resolution microscopy images—Part I , 2021, Signal, Image and Video Processing.

[40]  M. Gale,et al.  SARS-CoV-2 ORF6 Disrupts Bidirectional Nucleocytoplasmic Transport through Interactions with Rae1 and Nup98 , 2021, mBio.

[41]  L. Bao,et al.  Distinct uptake, amplification, and release of SARS-CoV-2 by M1 and M2 alveolar macrophages , 2021, Cell discovery.

[42]  R. Holmdahl,et al.  Dependence of SARS-CoV-2 infection on cholesterol-rich lipid raft and endosomal acidification , 2021, Computational and Structural Biotechnology Journal.

[43]  K. Nagashima,et al.  FIB-SEM as a Volume Electron Microscopy Approach to Study Cellular Architectures in SARS-CoV-2 and Other Viral Infections: A Practical Primer for a Virologist , 2021, Viruses.

[44]  N. Gassler,et al.  Early postmortem mapping of SARS-CoV-2 RNA in patients with COVID-19 and the correlation with tissue damage , 2021, eLife.

[45]  P. Boor,et al.  Detection methods for SARS-CoV-2 in tissue , 2021, Der Pathologe.

[46]  Daniel S. Chertow,et al.  SARS-CoV-2 infection of the oral cavity and saliva , 2021, Nature Medicine.

[47]  J. Min,et al.  SARS-CoV-2 cell tropism and multiorgan infection , 2021, Cell discovery.

[48]  M. Gabbrielli,et al.  How long can SARS-CoV-2 persist in human corpses? , 2021, International Journal of Infectious Diseases.

[49]  S. Finke,et al.  Light Sheet Microscopy-Assisted 3D Analysis of SARS-CoV-2 Infection in the Respiratory Tract of the Ferret Model , 2021, Viruses.

[50]  G. Ippolito,et al.  Evidences for lipid involvement in SARS-CoV-2 cytopathogenesis , 2021, Cell Death & Disease.

[51]  L. Pena,et al.  In Vitro and In Vivo Models for Studying SARS-CoV-2, the Etiological Agent Responsible for COVID-19 Pandemic , 2021, Viruses.

[52]  S. Ciesek,et al.  A SARS-CoV-2 cytopathicity dataset generated by high-content screening of a large drug repurposing collection , 2021, Scientific data.

[53]  M. Diamond,et al.  SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis , 2021, JACC: Basic to Translational Science.

[54]  Sara E. Miller,et al.  Difficulties in Differentiating Coronaviruses from Subcellular Structures in Human Tissues by Electron Microscopy , 2021, Emerging infectious diseases.

[55]  V. Arumugaswami,et al.  Deleterious Effects of SARS-CoV-2 Infection on Human Pancreatic Cells , 2021, Frontiers in Cellular and Infection Microbiology.

[56]  L. Saba,et al.  Liver infection and COVID-19: the electron microscopy proof and revision of the literature. , 2021, European review for medical and pharmacological sciences.

[57]  A. Stenzinger,et al.  SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas , 2021, Nature Metabolism.

[58]  J. Minna,et al.  Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression , 2021, Science Advances.

[59]  M. Guzmán,et al.  SARS-CoV-2: preliminary study of infected human nasopharyngeal tissue by high resolution microscopy , 2021, Virology Journal.

[60]  J. Diedrich,et al.  The SARS-CoV-2 nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein , 2021, Nature Communications.

[61]  A. Tzankov,et al.  Ocular Pathology and Occasionally Detectable Intraocular Severe Acute Respiratory Syndrome Coronavirus-2 RNA in Five Fatal Coronavirus Disease-19 Cases , 2021, Ophthalmic Research.

[62]  L. Pantanowitz,et al.  Postmortem Findings Associated With SARS-CoV-2 , 2021, The American journal of surgical pathology.

[63]  H. Rothan,et al.  Cell-Based High-Throughput Screening Protocol for Discovering Antiviral Inhibitors Against SARS-COV-2 Main Protease (3CLpro) , 2021, Molecular Biotechnology.

[64]  M. Segondy,et al.  SARS-Cov-2 fulminant myocarditis: an autopsy and histopathological case study , 2021, International Journal of Legal Medicine.

[65]  P. McPherson,et al.  SARS-CoV-2 infects cells after viral entry via clathrin-mediated endocytosis , 2021, Journal of Biological Chemistry.

[66]  M. Soto,et al.  The kidnapping of mitochondrial function associated to the SARS-CoV-2 infection , 2020 .

[67]  S. Kamphuis,et al.  Severe Acute Respiratory Syndrome Coronavirus 2 Placental Infection and Inflammation Leading to Fetal Distress and Neonatal Multi-Organ Failure in an Asymptomatic Woman , 2020, Journal of the Pediatric Infectious Diseases Society.

[68]  David S Priemer,et al.  Muscle Biopsy Findings in a Case of SARS-CoV-2-Associated Muscle Injury , 2020, Journal of neuropathology and experimental neurology.

[69]  Hai Yu,et al.  Virus‐Free and Live‐Cell Visualizing SARS‐CoV‐2 Cell Entry for Studies of Neutralizing Antibodies and Compound Inhibitors , 2020, Small methods.

[70]  Y. Bi,et al.  ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation , 2020, Developmental Cell.

[71]  Paul J. Ackerman,et al.  SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation , 2020, bioRxiv.

[72]  M. Hazawa,et al.  Overexpression of SARS-CoV-2 protein ORF6 dislocates RAE1 and NUP98 from the nuclear pore complex , 2020, Biochemical and Biophysical Research Communications.

[73]  Xinwen Chen,et al.  Host metabolism dysregulation and cell tropism identification in human airway and alveolar organoids upon SARS-CoV-2 infection , 2020, Protein & Cell.

[74]  A. Chinnaiyan,et al.  Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2 , 2020, Proceedings of the National Academy of Sciences.

[75]  J. Bloom,et al.  Metabolic reprogramming and epigenetic changes of vital organs in SARS-CoV-2–induced systemic toxicity , 2020, JCI insight.

[76]  F. Weber,et al.  Imaging of SARS-CoV-2 infected Vero E6 cells by helium ion microscopy , 2020, Beilstein journal of nanotechnology.

[77]  I. Brown,et al.  Development of immunohistochemistry and in situ hybridisation for the detection of SARS-CoV and SARS-CoV-2 in formalin-fixed paraffin-embedded specimens , 2020, Scientific Reports.

[78]  M. Edirisinghe,et al.  Rapid and label-free detection of COVID-19 using coherent anti-Stokes Raman scattering microscopy , 2020, MRS communications.

[79]  C. Conrad,et al.  Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19 , 2020, Nature Neuroscience.

[80]  M. Porcionatto,et al.  3D culture models to study SARS-CoV-2 infectivity and antiviral candidates: From spheroids to bioprinting , 2020, Biomedical Journal.

[81]  Nicolas L. Fawzi,et al.  SARS‐CoV‐2 nucleocapsid protein phase‐separates with RNA and with human hnRNPs , 2020, The EMBO journal.

[82]  R. Bartenschlager,et al.  Integrative Imaging Reveals SARS-CoV-2-Induced Reshaping of Subcellular Morphologies , 2020, Cell Host & Microbe.

[83]  M. Atkinson,et al.  Expression of SARS-CoV-2 Entry Factors in the Pancreas of Normal Organ Donors and Individuals with COVID-19 , 2020, Cell Metabolism.

[84]  Zhìhóng Hú,et al.  Infection of human sweat glands by SARS-CoV-2 , 2020, Cell discovery.

[85]  P. Majmudar,et al.  Prevalence of SARS-CoV-2 in human post-mortem ocular tissues , 2020, The Ocular Surface.

[86]  C. Alpers,et al.  Characterizing Viral Infection by Electron Microscopy , 2020, The American Journal of Pathology.

[87]  D. Pajkrt,et al.  A Perspective on Organoids for Virology Research , 2020, Viruses.

[88]  Jianxing He,et al.  Histopathologic Findings in the Explant Lungs of a Patient With COVID-19 Treated With Bilateral Orthotopic Lung Transplant. , 2020, Transplantation.

[89]  Jared L. Johnson,et al.  Identification of SARS-CoV-2 Inhibitors using Lung and Colonic Organoids , 2020, Nature.

[90]  S. Chanda,et al.  SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling , 2020, Proceedings of the National Academy of Sciences.

[91]  R. Hilgenfeld,et al.  SARS-CoV-2 Mpro inhibitors and activity-based probes for patient-sample imaging , 2020, Nature Chemical Biology.

[92]  C. Scagnolari,et al.  Naringenin is a powerful inhibitor of SARS-CoV-2 infection in vitro , 2020, Pharmacological Research.

[93]  A. Helenius,et al.  Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity , 2020, Science.

[94]  A. Vaughan,et al.  Virus Detection and Identification in Minutes Using Single-Particle Imaging and Deep Learning , 2020, medRxiv.

[95]  P. Majmudar,et al.  Prevalence of SARS-CoV-2 in human post-mortem ocular tissues , 2020, medRxiv.

[96]  L. Vandekerckhove,et al.  On the whereabouts of SARS-CoV-2 in the human body: A systematic review , 2020, PLoS pathogens.

[97]  Alistair S Brown,et al.  High-Throughput Screening for Inhibitors of the SARS-CoV-2 Protease Using a FRET-Biosensor , 2020, Molecules.

[98]  A. Tzankov,et al.  Hunting coronavirus by transmission electron microscopy – a guide to SARS‐CoV‐2‐associated ultrastructural pathology in COVID‐19 tissues , 2020, Histopathology.

[99]  Vineet D. Menachery,et al.  Evasion of Type I Interferon by SARS-CoV-2 , 2020, Cell Reports.

[100]  P. Saldiva,et al.  SARS-CoV-2–triggered neutrophil extracellular traps mediate COVID-19 pathology , 2020, The Journal of experimental medicine.

[101]  M. Hollinshead,et al.  Ultrastructure of cell trafficking pathways and coronavirus: how to recognise the wolf amongst the sheep , 2020, The Journal of pathology.

[102]  J. Bräsen,et al.  Direct evidence of SARS-CoV-2 in gut endothelium , 2020, Intensive Care Medicine.

[103]  Catherine Z. Chen,et al.  Identification of SARS-CoV-2 3CL Protease Inhibitors by a Quantitative High-Throughput Screening , 2020, ACS pharmacology & translational science.

[104]  R. Bartenschlager,et al.  A Versatile Reporter System To Monitor Virus-Infected Cells and Its Application to Dengue Virus and SARS-CoV-2 , 2020, Journal of Virology.

[105]  Jihye Yun,et al.  Infection of Brain Organoids and 2D Cortical Neurons with SARS-CoV-2 Pseudovirus , 2020, Viruses.

[106]  Niloofar Khoshdel-Rad,et al.  Engineering a Model to Study Viral Infections: Bioprinting, Microfluidics, and Organoids to Defeat Coronavirus Disease 2019 (COVID-19) , 2020, International journal of bioprinting.

[107]  Xin Hu,et al.  Quantum Dot-Conjugated SARS-CoV-2 Spike Pseudo-Virions Enable Tracking of Angiotensin Converting Enzyme 2 Binding and Endocytosis , 2020, ACS nano.

[108]  X. Mao,et al.  iPSCs-Derived Platform: A Feasible Tool for Probing the Neurotropism of SARS-CoV-2 , 2020, ACS chemical neuroscience.

[109]  Jianxing He,et al.  Histopatological Findings in the Explant Lungs of a Patient With COVID-19 Treated With Bilateral Orthotopic Lung Transplant. , 2020, Transplantation.

[110]  M. Laue,et al.  Morphometry of SARS-CoV and SARS-CoV-2 particles in ultrathin plastic sections of infected Vero cell cultures , 2020, Scientific Reports.

[111]  M. Trauner,et al.  Post-mortem viral dynamics and tropism in COVID-19 patients in correlation with organ damage , 2020, Virchows Archiv.

[112]  M. Rivera,et al.  Comparison of RNA In Situ Hybridization and Immunohistochemistry Techniques for the Detection and Localization of SARS-CoV-2 in Human Tissues , 2020, The American journal of surgical pathology.

[113]  A. Tzankov,et al.  3D virtual pathohistology of lung tissue from Covid-19 patients based on phase contrast X-ray tomography , 2020, eLife.

[114]  D. Raoult,et al.  The Strengths of Scanning Electron Microscopy in Deciphering SARS-CoV-2 Infectious Cycle , 2020, Frontiers in Microbiology.

[115]  A. Tzankov,et al.  Author response: 3D virtual pathohistology of lung tissue from Covid-19 patients based on phase contrast X-ray tomography , 2020 .

[116]  A. Herman,et al.  Chilblains and COVID‐19: why SARS‐CoV‐2 endothelial infection is questioned , 2020, The British journal of dermatology.

[117]  B. Gerber,et al.  SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule , 2020, Kidney International.

[118]  J. Richt,et al.  Detection of SARS-CoV-2 by RNAscope®in situ hybridization and immunohistochemistry techniques , 2020, Archives of Virology.

[119]  J. Chan,et al.  SARS-CoV-2 infects human neural progenitor cells and brain organoids , 2020, Cell Research.

[120]  V. D’Agati,et al.  Postmortem Kidney Pathology Findings in Patients with COVID-19. , 2020, Journal of the American Society of Nephrology : JASN.

[121]  Ze-Guang Han,et al.  SARS-CoV-2 Orf9b suppresses type I interferon responses by targeting TOM70 , 2020, Cellular & Molecular Immunology.

[122]  P. Kirchhof,et al.  Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases. , 2020, JAMA cardiology.

[123]  D. A. Stein,et al.  TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells , 2020, Life Science Alliance.

[124]  Agati,et al.  Kidney Biopsy Findings in Patients with COVID-19. , 2020, Journal of the American Society of Nephrology : JASN.

[125]  J. Lacy,et al.  Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series , 2020, The Lancet.

[126]  Timothy A. Blenkinsop,et al.  SARS-CoV-2 Infection of Ocular Cells from Human Adult Donor Eyes and hESC-Derived Eye Organoids. , 2020, SSRN.

[127]  Doyoun Kim,et al.  Therapeutic Strategies Against COVID-19 and Structural Characterization of SARS-CoV-2: A Review , 2020, Frontiers in Microbiology.

[128]  M. Baldewijns,et al.  Vertical transmission of SARS-CoV-2 infection and preterm birth , 2020, European Journal of Clinical Microbiology & Infectious Diseases.

[129]  S. Mukhopadhyay,et al.  Detection of SARS-CoV-2 in formalin-fixed paraffin-embedded tissue sections using commercially available reagents , 2020, Laboratory Investigation.

[130]  J. Knoblich,et al.  Human organoids: model systems for human biology and medicine , 2020, Nature Reviews Molecular Cell Biology.

[131]  Francesco Castelli,et al.  Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics , 2020, The Lancet Infectious Diseases.

[132]  Rachel S. G. Sealfon,et al.  Genomic RNA Elements Drive Phase Separation of the SARS-CoV-2 Nucleocapsid , 2020, Molecular Cell.

[133]  N. Gassler,et al.  Early postmortem mapping of SARS-CoV-2 RNA in patients with COVID-19 and correlation to tissue damage , 2020, bioRxiv.

[134]  N. Gokden,et al.  Appearances Can Be Deceiving - Viral-like Inclusions in COVID-19 Negative Renal Biopsies by Electron Microscopy. , 2020, Kidney360.

[135]  Beata Turoňová,et al.  In situ structural analysis of SARS-CoV-2 spike reveals flexibility mediated by three hinges , 2020, Science.

[136]  S. Farhadian,et al.  SARS-CoV-2 infection of the placenta. , 2020, The Journal of clinical investigation.

[137]  Andrew R. Leach,et al.  The Global Phosphorylation Landscape of SARS-CoV-2 Infection , 2020, Cell.

[138]  Felicitas Escher,et al.  Evidence of SARS-CoV-2 mRNA in endomyocardial biopsies of patients with clinically suspected myocarditis tested negative for COVID-19 in nasopharyngeal swab , 2020, Cardiovascular research.

[139]  Zhènglì Shí,et al.  Alveolar macrophage dysfunction and cytokine storm in the pathogenesis of two severe COVID-19 patients , 2020, EBioMedicine.

[140]  I. Solomon,et al.  In situ detection of SARS-CoV-2 in lungs and airways of patients with COVID-19 , 2020, Modern Pathology.

[141]  M. Zweckstetter,et al.  Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates , 2020, Nature Communications.

[142]  Duc-Huy T. Nguyen,et al.  A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids , 2020, Cell Stem Cell.

[143]  F. Hamprecht,et al.  Microscopy‐based assay for semi‐quantitative detection of SARS‐CoV‐2 specific antibodies in human sera , 2020, bioRxiv.

[144]  C. Hamm,et al.  Detection of viral SARS‐CoV‐2 genomes and histopathological changes in endomyocardial biopsies , 2020, ESC heart failure.

[145]  M. Bárcena,et al.  Double-Membrane Vesicles as Platforms for Viral Replication , 2020, Trends in Microbiology.

[146]  A. Tanuri,et al.  Ultrastructural analysis of SARS-CoV-2 interactions with the host cell via high resolution scanning electron microscopy , 2020, Scientific Reports.

[147]  Sreekala S. Nampoothiri,et al.  The hypothalamus as a hub for putative SARS-CoV-2 brain infection , 2020 .

[148]  Andrea Gianatti,et al.  Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study , 2020, The Lancet Infectious Diseases.

[149]  J. Vincent,et al.  Unspecific post-mortem findings despite multiorgan viral spread in COVID-19 patients , 2020, Critical Care.

[150]  Manuela Teresa Raimondi,et al.  Bioengineering tools to speed up the discovery and preclinical testing of vaccines for SARS-CoV-2 and therapeutic agents for COVID-19 , 2020, Theranostics.

[151]  Lisa E. Gralinski,et al.  SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract , 2020, Cell.

[152]  P. Libby,et al.  Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients , 2020, Pharmacology & Therapeutics.

[153]  Hannah Gilmore,et al.  Molecular Detection of SARS-CoV-2 Infection in FFPE Samples and Histopathologic Findings in Fatal SARS-CoV-2 Cases , 2020, American journal of clinical pathology.

[154]  Maha Alafeef,et al.  Selective Naked-Eye Detection of SARS-CoV-2 Mediated by N Gene Targeted Antisense Oligonucleotide Capped Plasmonic Nanoparticles , 2020, ACS nano.

[155]  T. Uyeki,et al.  Pathology and Pathogenesis of SARS-CoV-2 Associated with Fatal Coronavirus Disease, United States , 2020, Emerging infectious diseases.

[156]  A. Benachi,et al.  Transplacental transmission of SARS-CoV-2 infection , 2020, Nature Communications.

[157]  Victor G. Puelles,et al.  Multiorgan and Renal Tropism of SARS-CoV-2 , 2020, The New England journal of medicine.

[158]  A. Vintzileos,et al.  Visualization of severe acute respiratory syndrome coronavirus 2 invading the human placenta using electron microscopy , 2020, American Journal of Obstetrics and Gynecology.

[159]  Fang Lin,et al.  SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19 , 2020, Journal of Hepatology.

[160]  E. Farkash,et al.  Ultrastructural Evidence for Direct Renal Infection with SARS-CoV-2. , 2020, Journal of the American Society of Nephrology : JASN.

[161]  F. Scholkmann,et al.  Electron microscopy of SARS-CoV-2: a challenging task – Authors' reply , 2020, The Lancet.

[162]  A. Tagliabracci,et al.  SARS-CoV-2 identification in lungs, heart and kidney specimens by transmission and scanning electron microscopy. , 2020, European review for medical and pharmacological sciences.

[163]  Sara E. Miller,et al.  Electron microscopy of SARS-CoV-2: a challenging task , 2020, The Lancet.

[164]  Lo'ai Alanagreh,et al.  The Human Coronavirus Disease COVID-19: Its Origin, Characteristics, and Insights into Potential Drugs and Its Mechanisms , 2020, Pathogens.

[165]  X. Bian,et al.  Pathological evidence for residual SARS-CoV-2 in pulmonary tissues of a ready-for-discharge patient , 2020, Cell Research.

[166]  J. Sejvar,et al.  Neurological associations of COVID-19 , 2020, The Lancet Neurology.

[167]  M. Diamond,et al.  TMPRSS2 and TMPRSS4 mediate SARS-CoV-2 infection of human small intestinal enterocytes , 2020, bioRxiv.

[168]  M. Fowkes,et al.  Central nervous system involvement by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) , 2020, Journal of medical virology.

[169]  Y. Liu,et al.  Detection of the SARS-CoV-2 Nucleocaspid Protein (NP) Using Immunohistochemistry , 2020, BIO-PROTOCOL.

[170]  N. Low,et al.  False-negative results of initial RT-PCR assays for COVID-19: A systematic review , 2020, medRxiv.

[171]  C. Wenk,et al.  Multiscale 3-dimensional pathology findings of COVID-19 diseased lung using high-resolution cleared tissue microscopy , 2020, bioRxiv.

[172]  Cheng Wan,et al.  Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China , 2020, Kidney International.

[173]  D. Raoult,et al.  Ultrarapid diagnosis, microscope imaging, genome sequencing, and culture isolation of SARS-CoV-2 , 2020, European Journal of Clinical Microbiology & Infectious Diseases.

[174]  K. Yuen,et al.  Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2 , 2020, Cell.

[175]  Yuzhang Wu,et al.  The Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Directly Decimates Human Spleens and Lymph Nodes , 2020, medRxiv.

[176]  Abraham J. Koster,et al.  A unifying structural and functional model of the coronavirus replication organelle: Tracking down RNA synthesis , 2020, bioRxiv.

[177]  M. Scully,et al.  Laser spectroscopic technique for direct identification of a single virus I: FASTER CARS , 2020, Proceedings of the National Academy of Sciences.

[178]  Zhicong Yang,et al.  The SARS-CoV-2 outbreak: What we know , 2020, International Journal of Infectious Diseases.

[179]  Amicia D Elliott Confocal Microscopy: Principles and Modern Practices , 2019, Current protocols in cytometry.

[180]  Haibo Xu,et al.  Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer , 2020, Journal of Thoracic Oncology.

[181]  H. Shan,et al.  Evidence for Gastrointestinal Infection of SARS-CoV-2 , 2020, Gastroenterology.

[182]  Weijia Wen,et al.  Organ-on-a-chip: recent breakthroughs and future prospects , 2020, BioMedical Engineering OnLine.

[183]  P. Niu,et al.  Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China , 2020, Cell Host & Microbe.

[184]  Gengfu Xiao,et al.  Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro , 2020, Cell Research.

[185]  K. To,et al.  SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists , 2020, Emerging microbes & infections.

[186]  Leszek Kaczmarek,et al.  Advances in Ex Situ Tissue Optical Clearing , 2019, Laser & Photonics Reviews.

[187]  Dries Braeken,et al.  Brain-on-a-chip Devices for Drug Screening and Disease Modeling Applications. , 2019, Current pharmaceutical design.

[188]  A. Nag,et al.  SARS coronavirus protein nsp1 disrupts localization of Nup93 from the nuclear pore complex. , 2019, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[189]  Wenling Wang,et al.  High-Throughput Screening and Identification of Potent Broad-Spectrum Inhibitors of Coronaviruses , 2019, Journal of Virology.

[190]  T. Kornberg,et al.  Designing a Green Fluorogenic Protease Reporter by Flipping a Beta Strand of GFP for Imaging Apoptosis in Animals. , 2019, Journal of the American Chemical Society.

[191]  Sungsu Park,et al.  A Microfluidic Spheroid Culture Device with a Concentration Gradient Generator for High-Throughput Screening of Drug Efficacy , 2018, Molecules.

[192]  Christoph Fahrenson,et al.  Optimization of cell-laden bioinks for 3D bioprinting and efficient infection with influenza A virus , 2018, Scientific Reports.

[193]  Lawrence D. True,et al.  Light-sheet microscopy for slide-free non-destructive pathology of large clinical specimens , 2017, Nature Biomedical Engineering.

[194]  S. Tasoglu,et al.  A Bioprinted Liver-on-a-Chip for Drug Screening Applications. , 2016, Trends in biotechnology.

[195]  Barbara Rothen-Rutishauser,et al.  Engineering an in vitro air-blood barrier by 3D bioprinting , 2015, Scientific Reports.

[196]  Alexandra Bokinsky,et al.  Dual-view plane illumination microscopy for rapid and spatially isotropic imaging , 2014, Nature Protocols.

[197]  S. Subramaniam,et al.  Three-Dimensional Imaging of Viral Infections. , 2014, Annual review of virology.

[198]  Yanan Du,et al.  Micro-scaffold array chip for upgrading cell-based high-throughput drug testing to 3D using benchtop equipment. , 2014, Lab on a chip.

[199]  Justin Senseney,et al.  Spatially isotropic four-dimensional imaging with dual-view plane illumination microscopy , 2013, Nature Biotechnology.

[200]  M. Raimondi,et al.  A miniaturized, optically accessible bioreactor for systematic 3D tissue engineering research , 2012, Biomedical microdevices.

[201]  R. Osellame,et al.  Two-Photon Laser Polymerization: From Fundamentals to Biomedical Application in Tissue Engineering and Regenerative Medicine , 2012, Journal of applied biomaterials & functional materials.

[202]  Norbert Bannert,et al.  Evaluation of tip-enhanced Raman spectroscopy for characterizing different virus strains. , 2011, The Analyst.

[203]  D. Ingber,et al.  Reconstituting Organ-Level Lung Functions on a Chip , 2010, Science.

[204]  Wolfgang Link,et al.  High content screening: seeing is believing. , 2010, Trends in biotechnology.

[205]  D. Ingber,et al.  A human breathing lung‐on‐a‐chip , 2010, Annals of the American Thoracic Society.

[206]  W. Link,et al.  A novel imaging‐based high‐throughput screening approach to anti‐angiogenic drug discovery , 2009, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[207]  Ji-Xin Cheng,et al.  Coherent Anti-Stokes Raman Scattering Microscopy , 2007, 2008 Conference on Lasers and Electro-Optics and 2008 Conference on Quantum Electronics and Laser Science.

[208]  Bo Zhang,et al.  Multiple organ infection and the pathogenesis of SARS , 2005, The Journal of experimental medicine.

[209]  James P. Freyer,et al.  The Use of 3-D Cultures for High-Throughput Screening: The Multicellular Spheroid Model , 2004, Journal of biomolecular screening.

[210]  H. Gelderblom,et al.  Electron microscopy for rapid diagnosis of infectious agents in emergent situations. , 2003, Emerging infectious diseases.

[211]  H. Gelderblom,et al.  Electron Microscopy for Rapid Diagnosis of Emerging Infectious Agents , 2003, Emerging Infectious Diseases.

[212]  N. Clark,et al.  Direct Evidence , 1934 .

[213]  I. Batlutskaya,et al.  Low homology between 2019-nCoV Orf8 protein and its SARS-CoV counterparts questions their identical function , 2021, BIO Web of Conferences.

[214]  Alfonso J. Rodriguez-Morales,et al.  SARS-CoV-2, SARS-CoV, and MERS-COV: A comparative overview , 2020 .

[215]  Tanaka The role of , 2000, Journal of insect physiology.

[216]  M. Tortorello,et al.  Microscopy Techniques , 2022 .