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2.
Sci Rep ; 11(1): 21259, 2021 10 28.
Article in English | MEDLINE | ID: covidwho-1493217

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently a serious public health concern worldwide. Notably, co-infection with other pathogens may worsen the severity of COVID-19 symptoms and increase fatality. Here, we show that co-infection with influenza A virus (IAV) causes more severe body weight loss and more severe and prolonged pneumonia in SARS-CoV-2-infected hamsters. Each virus can efficiently spread in the lungs without interference by the other. However, in immunohistochemical analyses, SARS-CoV-2 and IAV were not detected at the same sites in the respiratory organs of co-infected hamsters, suggesting that either the two viruses may have different cell tropisms in vivo or each virus may inhibit the infection and/or growth of the other within a cell or adjacent areas in the organs. Furthermore, a significant increase in IL-6 was detected in the sera of hamsters co-infected with SARS-CoV-2 and IAV at 7 and 10 days post-infection, suggesting that IL-6 may be involved in the increased severity of pneumonia. Our results strongly suggest that IAV co-infection with SARS-CoV-2 can have serious health risks and increased caution should be applied in such cases.


Subject(s)
COVID-19/complications , Orthomyxoviridae Infections/complications , Pneumonia, Viral/complications , SARS-CoV-2 , Animals , COVID-19/pathology , COVID-19/virology , Coinfection/pathology , Disease Models, Animal , Female , Humans , Interleukin-6/blood , Lung/diagnostic imaging , Lung/pathology , Mesocricetus , Orthomyxoviridae/pathogenicity , Orthomyxoviridae Infections/pathology , Orthomyxoviridae Infections/virology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Severity of Illness Index , Virus Replication
5.
PLoS One ; 15(9): e0238412, 2020.
Article in English | MEDLINE | ID: covidwho-1388884

ABSTRACT

We investigate phase transitions associated with three control methods for epidemics on small world networks. Motivated by the behavior of SARS-CoV-2, we construct a theoretical SIR model of a virus that exhibits presymptomatic, asymptomatic, and symptomatic stages in two possible pathways. Using agent-based simulations on small world networks, we observe phase transitions for epidemic spread related to: 1) Global social distancing with a fixed probability of adherence. 2) Individually initiated social isolation when a threshold number of contacts are infected. 3) Viral shedding rate. The primary driver of total number of infections is the viral shedding rate, with probability of social distancing being the next critical factor. Individually initiated social isolation was effective when initiated in response to a single infected contact. For each of these control measures, the total number of infections exhibits a sharp phase transition as the strength of the measure is varied.


Subject(s)
Coronavirus Infections/transmission , Models, Theoretical , Pneumonia, Viral/transmission , Asymptomatic Diseases , Betacoronavirus/isolation & purification , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Epidemics , Humans , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Virus Shedding
6.
JCI Insight ; 5(19)2020 10 02.
Article in English | MEDLINE | ID: covidwho-1388620

ABSTRACT

The emergence of SARS-CoV-2 has created an international health crisis, and small animal models mirroring SARS-CoV-2 human disease are essential for medical countermeasure (MCM) development. Mice are refractory to SARS-CoV-2 infection owing to low-affinity binding to the murine angiotensin-converting enzyme 2 (ACE2) protein. Here, we evaluated the pathogenesis of SARS-CoV-2 in male and female mice expressing the human ACE2 gene under the control of the keratin 18 promoter (K18). In contrast to nontransgenic mice, intranasal exposure of K18-hACE2 animals to 2 different doses of SARS-CoV-2 resulted in acute disease, including weight loss, lung injury, brain infection, and lethality. Vasculitis was the most prominent finding in the lungs of infected mice. Transcriptomic analysis from lungs of infected animals showed increases in transcripts involved in lung injury and inflammatory cytokines. In the low-dose challenge groups, there was a survival advantage in the female mice, with 60% surviving infection, whereas all male mice succumbed to disease. Male mice that succumbed to disease had higher levels of inflammatory transcripts compared with female mice. To our knowledge, this is the first highly lethal murine infection model for SARS-CoV-2 and should be valuable for the study of SARS-CoV-2 pathogenesis and for the assessment of MCMs.


Subject(s)
Cause of Death , Coronavirus Infections/pathology , Disease Progression , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/pathology , Severe Acute Respiratory Syndrome/pathology , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Coronavirus Infections/physiopathology , Disease Models, Animal , Female , Humans , Lung/pathology , Male , Mice , Mice, Transgenic , Pandemics , Pneumonia, Viral/physiopathology , Severe Acute Respiratory Syndrome/physiopathology , Severity of Illness Index , Survival Rate , Virus Replication/genetics
11.
Vascul Pharmacol ; 130: 106680, 2020 07.
Article in English | MEDLINE | ID: covidwho-1386723

ABSTRACT

Angiotensin-converting enzyme (ACE) and its homologue, ACE2, have been mostly associated with hypertensive disorder. However, recent pandemia of SARS-CoV-2 has put these proteins at the center of attention, as this virus has been shown to exploit ACE2 protein to enter cells. Clear difference in the response of affected patients to this virus has urged researchers to find the molecular basis and pathophysiology of the cell response to this virus. Different levels of expression and function of ACE proteins, underlying disorders, consumption of certain medications and the existence of certain genomic variants within ACE genes are possible explanations for the observed difference in the response of individuals to the SARS-CoV-2 infection. In the current review, we discuss the putative mechanisms for this observation.


Subject(s)
Coronavirus Infections/enzymology , Peptidyl-Dipeptidase A/biosynthesis , Pneumonia, Viral/enzymology , COVID-19 , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Humans , Pandemics , Peptidyl-Dipeptidase A/blood , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Pneumonia, Viral/pathology
13.
Clin Immunol ; 215: 108426, 2020 06.
Article in English | MEDLINE | ID: covidwho-1385285
14.
Cell ; 181(5): 969-977, 2020 05 28.
Article in English | MEDLINE | ID: covidwho-1385208

ABSTRACT

SARS-CoV-2 infection is mild in the majority of individuals but progresses into severe pneumonia in a small proportion of patients. The increased susceptibility to severe disease in the elderly and individuals with co-morbidities argues for an initial defect in anti-viral host defense mechanisms. Long-term boosting of innate immune responses, also termed "trained immunity," by certain live vaccines (BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells. We propose that induction of trained immunity by whole-microorganism vaccines may represent an important tool for reducing susceptibility to and severity of SARS-CoV-2.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/immunology , Immunity, Innate , Immunomodulation , Pneumonia, Viral/immunology , SARS Virus/physiology , Animals , BCG Vaccine/immunology , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , Coronavirus Infections/transmission , Humans , Immunity, Innate/drug effects , Lung/immunology , Lung/pathology , Lymphopenia/pathology , Middle East Respiratory Syndrome Coronavirus/physiology , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/physiopathology , Pneumonia, Viral/transmission , SARS-CoV-2 , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/pathology , Virus Replication
15.
Molecules ; 25(21)2020 Nov 02.
Article in English | MEDLINE | ID: covidwho-1389462

ABSTRACT

Zebrafish has been a reliable model system for studying human viral pathologies. SARS-CoV-2 viral infection has become a global chaos, affecting millions of people. There is an urgent need to contain the pandemic and develop reliable therapies. We report the use of a humanized zebrafish model, xeno-transplanted with human lung epithelial cells, A549, for studying the protective effects of a tri-herbal medicine Coronil. At human relevant doses of 12 and 58 µg/kg, Coronil inhibited SARS-CoV-2 spike protein, induced humanized zebrafish mortality, and rescued from behavioral fever. Morphological and cellular abnormalities along with granulocyte and macrophage accumulation in the swim bladder were restored to normal. Skin hemorrhage, renal cell degeneration, and necrosis were also significantly attenuated by Coronil treatment. Ultra-high-performance liquid chromatography (UHPLC) analysis identified ursolic acid, betulinic acid, withanone, withaferine A, withanoside IV-V, cordifolioside A, magnoflorine, rosmarinic acid, and palmatine as phyto-metabolites present in Coronil. In A549 cells, Coronil attenuated the IL-1ß induced IL-6 and TNF-α cytokine secretions, and decreased TNF-α induced NF-κB/AP-1 transcriptional activity. Taken together, we show the disease modifying immunomodulatory properties of Coronil, at human equivalent doses, in rescuing the pathological features induced by the SARS-CoV-2 spike protein, suggesting its potential use in SARS-CoV-2 infectivity.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Plant Extracts/therapeutic use , Pneumonia, Viral/drug therapy , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Air Sacs/drug effects , Air Sacs/virology , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , COVID-19 , Chromatography, High Pressure Liquid/methods , Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , Disease Models, Animal , Fever/drug therapy , Fever/etiology , Hemorrhage/prevention & control , Humans , Interleukin-6/metabolism , Kidney/drug effects , Necrosis/pathology , Necrosis/prevention & control , Pandemics , Phytotherapy , Pneumonia, Viral/pathology , Pneumonia, Viral/physiopathology , Respiratory Mucosa/transplantation , Transcriptional Activation/drug effects , Tumor Necrosis Factor-alpha/metabolism , Zebrafish
16.
Int J Mol Sci ; 21(13)2020 Jul 07.
Article in English | MEDLINE | ID: covidwho-1389380

ABSTRACT

The SARS-CoV-2 virus is a recently-emerged zoonotic pathogen already well adapted to transmission and replication in humans. Although the mutation rate is limited, recently introduced mutations in SARS-CoV-2 have the potential to alter viral fitness. In addition to amino acid changes, mutations could affect RNA secondary structure critical to viral life cycle, or interfere with sequences targeted by host miRNAs. We have analysed subsets of genomes from SARS-CoV-2 isolates from around the globe and show that several mutations introduce changes in Watson-Crick pairing, with resultant changes in predicted secondary structure. Filtering to targets matching miRNAs expressed in SARS-CoV-2-permissive host cells, we identified ten separate target sequences in the SARS-CoV-2 genome; three of these targets have been lost through conserved mutations. A genomic site targeted by the highly abundant miR-197-5p, overexpressed in patients with cardiovascular disease, is lost by a conserved mutation. Our results are compatible with a model that SARS-CoV-2 replication within the human host is constrained by host miRNA defences. The impact of these and further mutations on secondary structures, miRNA targets or potential splice sites offers a new context in which to view future SARS-CoV-2 evolution, and a potential platform for engineering conditional attenuation to vaccine development, as well as providing a better understanding of viral tropism and pathogenesis.


Subject(s)
Betacoronavirus/genetics , Genome, Viral , MicroRNAs/metabolism , RNA, Viral/chemistry , 3' Untranslated Regions , Base Sequence , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/virology , Databases, Genetic , Humans , MicroRNAs/chemistry , MicroRNAs/genetics , Mutation , Nucleic Acid Conformation , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , RNA Splice Sites , RNA Splicing , SARS-CoV-2 , Sequence Alignment , Viral Nonstructural Proteins/genetics , Viral Proteins/chemistry , Viral Proteins/genetics , Viral Proteins/metabolism
17.
Lancet Infect Dis ; 20(10): 1135-1140, 2020 10.
Article in English | MEDLINE | ID: covidwho-1377877

ABSTRACT

BACKGROUND: COVID-19 is characterised by respiratory symptoms, which deteriorate into respiratory failure in a substantial proportion of cases, requiring intensive care in up to a third of patients admitted to hospital. Analysis of the pathological features in the lung tissues of patients who have died with COVID-19 could help us to understand the disease pathogenesis and clinical outcomes. METHODS: We systematically analysed lung tissue samples from 38 patients who died from COVID-19 in two hospitals in northern Italy between Feb 29 and March 24, 2020. The most representative areas identified at macroscopic examination were selected, and tissue blocks (median seven, range five to nine) were taken from each lung and fixed in 10% buffered formalin for at least 48 h. Tissues were assessed with use of haematoxylin and eosin staining, immunohistochemical staining for inflammatory infiltrate and cellular components (including staining with antibodies against CD68, CD3, CD45, CD61, TTF1, p40, and Ki-67), and electron microscopy to identify virion localisation. FINDINGS: All cases showed features of the exudative and proliferative phases of diffuse alveolar damage, which included capillary congestion (in all cases), necrosis of pneumocytes (in all cases), hyaline membranes (in 33 cases), interstitial and intra-alveolar oedema (in 37 cases), type 2 pneumocyte hyperplasia (in all cases), squamous metaplasia with atypia (in 21 cases), and platelet-fibrin thrombi (in 33 cases). The inflammatory infiltrate, observed in all cases, was largely composed of macrophages in the alveolar lumina (in 24 cases) and lymphocytes in the interstitium (in 31 cases). Electron microscopy revealed that viral particles were predominantly located in the pneumocytes. INTERPRETATION: The predominant pattern of lung lesions in patients with COVID-19 patients is diffuse alveolar damage, as described in patients infected with severe acute respiratory syndrome and Middle East respiratory syndrome coronaviruses. Hyaline membrane formation and pneumocyte atypical hyperplasia are frequent. Importantly, the presence of platelet-fibrin thrombi in small arterial vessels is consistent with coagulopathy, which appears to be common in patients with COVID-19 and should be one of the main targets of therapy. FUNDING: None.


Subject(s)
Coronavirus Infections/pathology , Lung/pathology , Pneumonia, Viral/pathology , Adult , Aged , Aged, 80 and over , Autopsy , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Female , Humans , Hyaline Membrane Disease , Inflammation , Italy/epidemiology , Lung/blood supply , Lung/ultrastructure , Lung/virology , Male , Middle Aged , Neutrophil Infiltration , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Pulmonary Alveoli/blood supply , Pulmonary Alveoli/pathology , Pulmonary Alveoli/ultrastructure , Pulmonary Alveoli/virology , Pulmonary Artery/pathology , SARS-CoV-2 , Thrombosis
19.
FASEB J ; 35(9): e21801, 2021 09.
Article in English | MEDLINE | ID: covidwho-1345745

ABSTRACT

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a crucial role in mediating viral entry into host cells. However, whether it contributes to pulmonary hyperinflammation in patients with coronavirus disease 2019 is not well known. In this study, we developed a spike protein-pseudotyped (Spp) lentivirus with the proper tropism of the SARS-CoV-2 spike protein on the surface and determined the distribution of the Spp lentivirus in wild-type C57BL/6J male mice that received an intravenous injection of the virus. Lentiviruses with vesicular stomatitis virus glycoprotein (VSV-G) or with a deletion of the receptor-binding domain (RBD) in the spike protein [Spp (∆RBD)] were used as controls. Two hours postinfection (hpi), there were 27-75 times more viral burden from Spp lentivirus in the lungs than in other organs; there were also about 3-5 times more viral burden from Spp lentivirus than from VSV-G lentivirus in the lungs, liver, kidney, and spleen. Deletion of RBD diminished viral loads in the lungs but not in the heart. Acute pneumonia was observed in animals 24 hpi. Spp lentivirus was mainly found in SPC+ and LDLR+ pneumocytes and macrophages in the lungs. IL6, IL10, CD80, and PPAR-γ were quickly upregulated in response to infection in the lungs as well as in macrophage-like RAW264.7 cells. Furthermore, forced expression of the spike protein in RAW264.7 cells significantly increased the mRNA levels of the same panel of inflammatory factors. Our results demonstrated that the spike protein of SARS-CoV-2 confers the main point of viral entry into the lungs and can induce cellular pathology. Our data also indicate that an alternative ACE2-independent viral entry pathway may be recruited in the heart and aorta.


Subject(s)
Macrophages/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Spike Glycoprotein, Coronavirus/immunology , Acute Disease , Alveolar Epithelial Cells/virology , Animals , B7-1 Antigen , Cell Line , Inflammation Mediators , Interleukin-10 , Interleukin-6 , Lentivirus/genetics , Lentivirus/isolation & purification , Lentivirus/metabolism , Lung/immunology , Lung/pathology , Lung/virology , Macrophages/virology , Male , Membrane Glycoproteins , Mice , Mice, Inbred C57BL , PPAR gamma , RAW 264.7 Cells , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Viral Envelope Proteins
20.
Cancer Cytopathol ; 129(8): 632-641, 2021 08.
Article in English | MEDLINE | ID: covidwho-1342873

ABSTRACT

BACKGROUND: Bronchoalveolar lavage (BAL) in patients with severe coronavirus disease 2019 (COVID-19) may provide additional and complementary findings for the management of these patients admitted to intensive care units (ICUs). This study addresses the cytological features of the infection and highlights the more influential inflammatory components. The correlation between pathological variables and clinical data is also analyzed. METHODS: The authors performed a retrospective analysis of the cytopathological features of BAL in 20 COVID-19 patients and 20 members of a matched cohort from a critical ICU who had acute respiratory distress syndrome caused by other pulmonary conditions. RESULTS: A comparison of the controls (n = 20) and the COVID-19 patients (n = 20) revealed that the latter had a higher neutrophil count (median, 63.8% of the cell count) with lower percentages of macrophages and lymphocytes. An increase in the expression of CD68-positive, monocytic multinucleated giant cells (MGCs) was reported; megakaryocytes were not detected on CD61 staining. Perls staining showed isolated elements. In situ RNA analysis demonstrated scattered chromogenic signals in type II pneumocytes. An ultrastructural analysis confirmed the presence of intracytoplasmic vacuoles containing rounded structures measuring 140 nm in diameter (putative viral particles). In COVID-19 patients, the clinicopathological correlation revealed a positive correlation between lactate dehydrogenase values and MGCs (r = 0.54). CONCLUSIONS: The analysis of BAL samples might be implemented as a routine practice for the evaluation of COVID-19 patients in ICUs in the appropriate clinical scenario. Additional studies using a larger sample size of patients who developed COVID-19 during the second wave of the epidemic in the autumn of 2020 are needed to further support our findings.


Subject(s)
Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , COVID-19/diagnosis , COVID-19/immunology , COVID-19/pathology , Adult , Aged , Female , Humans , Male , Middle Aged , Pilot Projects , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Retrospective Studies , SARS-CoV-2
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