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The Role of Procoagulant Activity in Fulminant Viral Hepatitis
Published in Gary A. Levy, Edward H. Cole, Procoagulant Activity in Health and Disease, 2019
Stephen W. Chung, Chao-Ying Li, Julian Leibowitz, Gary A. Levy
In an experimental murine model of viral hepatitis, murine hepatitis virus strain 3 (MHV) infection produces a strain-dependent spectrum of disease.33,41 Mice of the A and SJL strains are fully resistant to the effects of viral infection, whereas mice of semisusceptible strains (C3H/HeJ) develop acute hepatitis which progresses to varying degrees of chronic hepatitis. Mice of fully susceptible strains (Balb/cJ, C57BL/6J) die of fulminant hepatic failure (Table 1). The resistance of the A strain mice cannot be explained by lack of a cellular receptor for MHV since viral binding occurs on cells from these resistant mice.42,43 Furthermore, restriction of viral replication does not explain resistance since resistance occurs despite the presence of active viral replication. Bang and Warwick previously reported that differences in viral replication in cultures of macrophages reflected the relative susceptibility/resistance (S/R) to viral infection.44 However, several laboratories have shown that MHV replicates in cultures of macrophages, endothelial cells, and hepatocytes from both susceptible and resistant animals,4,43,45,46 although viral replication occurs to a lesser degree in cells derived from resistant animals.4,47 Thus, absolute differences in viral replication do not account for the strain-dependent S/R pattern seen in MHV infection.
Animal Models of Human Respiratory Viral Infections
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
Kayla A. Weiss, Cory J. Knudson, Allison F. Christiaansen, Steven M. Varga
There are multiple strains of mouse hepatitis virus (MHV) with tropisms for the liver and brain, making these murine coronaviruses a commonly used animal model for investigating hepatitis and encephalitis in humans. In addition, intranasal infection of A/J mice with MHV-1 has been described as a model for SARS-CoV-induced disease and pathology in humans.109 MHV-1 primarily replicates in the lungs of A/J mice; although it does disseminate from the lungs with virus detected in the brain, liver, and spleen.109 Cellular infiltration, pulmonary edema, alveolar thickening, fibrin deposits, and multinucleated giant cells are observed early following MHV-1 infection similar to fatal SARS-CoV infection in humans.94,109 In addition, lung consolidation was observed by day 10 p.i. following virus-induced mortality of A/J mice.109 Work in this model demonstrates that T cells contribute to the morbidity and mortality observed in A/J mice following MHV-1 infection.110 These data support the use of MHV-1 infection in A/J mice as a model for the clinical disease and pulmonary pathology of SARS-CoV in humans.
Order Nidovirales
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
The early coronavirus studies were performed with murine hepatitis virus (MHV), a member of the Murine coronavirus species. Thus, Krijnse Locker et al. (1995) performed the vaccinia virus-driven expression of the MHV gene encoding the membrane glycoprotein M and found that the independently synthesized protein M accumulated in the Golgi apparatus in homomultimeric, detergent-insoluble structures, presumably as part of its retention mechanism. When Opstelten et al. (1995) used the vaccinia virus-driven coexpression of the MHV proteins M and S, the formation of the heteromultimeric M-S complexes was detected in the absence of other coronaviral proteins. Vennema et al. (1996) described the assembly of the MHV envelope independent of a nucleocapsid. The membrane particles containing coronaviral envelope proteins were assembled in and released from animal cells coexpressing the corresponding genes from transfected plasmids. Of the three viral membrane proteins, only two were required for particle formation, namely the membrane glycoprotein M and the small envelope protein E, while the spike protein S was dispensable but was incorporated when present. Therefore, the nucleocapsid protein N was neither required nor taken into the particles when present. The envelope vesicles formed a homogeneous population of spherical particles indistinguishable from authentic coronavirions in size (~100 nm in diameter) and shape but less dense than the virions (Vennema et al. 1996). Remarkably, Maeda et al. (1999) have found that the expression of the MHV protein E alone was sufficient for the VLP production. Godeke et al. (2000) constructed the two chimeric proteins S of MHV and an alphacoronavirus, namely feline infectious peritonitis virus (FIPV), or feline coronavirus (FCoV), a member of the Tegacovirus subgenus, which is described earlier. The chimeric MHV-FIPV proteins S consisted of the ectodomain of the one virus and the transmembrane and endodomain of the other. They were found to assemble only into viral particles of the species from which their C-terminal domain originated. Thus, the 64-terminal-residue sequence sufficed to draw the 1,308 (MHV)- or 1,433 (FIPV)-aa-long mature S protein into the VLPs (Godeke et al. 2000).
An overview of the preclinical discovery and development of remdesivir for the treatment of coronavirus disease 2019 (COVID-19)
Published in Expert Opinion on Drug Discovery, 2022
Pasquale Pagliano, Carmine Sellitto, Giuliana Scarpati, Tiziana Ascione, Valeria Conti, Gianluigi Franci, Ornella Piazza, Amelia Filippelli
Following an in vitro study on infected Vero E6 cells, RDV was demonstrated to most actively inhibit SARS-CoV-2 among seven putative antiviral drugs with an IC50 of 770 nM and an IC90 of 1760 nM. The same study demonstrated that cytotoxic concentrations were achieved after concentrations of RDV above 100 mM were added to the experimental assay. RDV activity is measured through the quantification of viral copy numbers in the cell supernatant via quantitative real-time reverse transcription-polymerase chain reaction and visualization of viral nucleoprotein expression through immunofluorescence microscopy 48 h post-infection [40]. The same study suggested that chloroquine could also be evaluated in COVID-19 treatment, although its IC50 and IC90 were lower than those reported for RDV. However, it is important to note that mutations causing RDV resistance are also possible. Indeed, previous studies have reported that in murine hepatitis virus, an amino acid mutation alters the binding pocket of RDV and confers resistance to the treatment [41]. The main problem is that this region presents the homolog residues V557 and F480 in the SARS-CoV-2-RdRp complex, which can lead to the possibility of developing resistant or less effective mutants in the future (Tab. 3) [42,44].
Evaluating the role of chemokines and chemokine receptors involved in coronavirus infection
Published in Expert Review of Clinical Immunology, 2022
Gema Olivarria, Thomas E. Lane
These findings were further confirmed through use of a recombinant mouse hepatitis virus (MHV) expressing the T cell-chemoattractant CXCL10 (MHV-CXCL10) [44]. Instillation of MHV-CXCL10 into the CNS of Cxcl10-/- mice resulted in viral infection and replication in both brain and liver [45]. Expression of virally encoded CXCL10 within the brain protected mice from death and correlated with increased infiltration of T lymphocytes and accelerated viral clearance when compared with mice infected with an isogenic control virus. Similarly, viral clearance from the livers of MHV-CXCL10-infected mice was accelerated in comparison to MHV-infected mice and allowed for protection from severe hepatitis as evidenced by reduced pathology and serum alanine aminotransferase levels. Treatment of MHV-CXCL10-infected Cxcl10-/- mice with an anti-CXCL10 blocking antibody resulted in increased clinical disease, correlating with enhanced viral recovery from the brain and liver as well as increased serum alanine aminotransferase levels. These studies further highlight that CXCL10 expression promotes protection from coronavirus-induced disease in the CNS, and functions in a similar capacity in other peripheral organs such as the liver.
Can the Coronavirus Disease 2019 (COVID-19) Affect the Eyes? A Review of Coronaviruses and Ocular Implications in Humans and Animals
Published in Ocular Immunology and Inflammation, 2020
The murine CoV mouse hepatitis virus (MHV) is a collection of strains that demonstrate very different organ tropisms. MHV can be divided into two main biotypes: the first biotype affects mainly the gastrointestinal tract and is usually responsible for the MHV outbreaks in house rodent colonies such as those within the lab. The biotype includes strains such as the MHV-D, MHV-Y, MHV-RI, MHV-S/CDC, LIVIM, and DVIM.41 The other biotype contains strains that can affect multiple organs including the central nervous, hepatic, and pulmonary systems. MHV has been extensively utilized to create models of human disease including multiple sclerosis, viral hepatitis, and pneumonitis.42–44