The Role of Procoagulant Activity in Fulminant Viral Hepatitis
Gary A. Levy, Edward H. Cole in Procoagulant Activity in Health and Disease, 2019
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.
Order Nidovirales
Paul Pumpens, Peter Pushko, Philippe Le Mercier in Virus-Like Particles, 2022
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).
Determination of Antiviral Activity
Adorjan Aszalos in Modern Analysis of Antibiotics, 2020
The only nonhuman animal species susceptible to type A hepatitis virus are the chimpanzee [151,152] and marmoset monkeys [153,154]; in each, hepatic disease is seen and the virus can be propagated. The paucity of available susceptible animals and their high cost has made the use of either chimpanzee or marmoset unreasonable for routine viral chemotherapy experiments. As an alternative, the investigator may wish to consider one of the many RNA viruses that are known to induce hepatitis in lower animals for such chemotherapy experiments. Perhaps most ideal has been the murine hepatitis virus, a corona-virus that induces a rapidly fulminating, fetal hepatic disease in mice; the infection induced by the MHV3 strain of this virus has been used for antiviral studies by Stone et al. [155], with increases in the percentage of mortality and mean survival time used as criteria for evaluation of drug efficacy. We have used the Braunsteiner-Friend strain of murine hepatitis virus in the initial hepatitis studies with ribavirin [156], using, in addition to mortality data, reduction of histopathologic lesions in the liver and levels of serum glutamic oxalacetic transaminase, serum glutamic pyruvate transaminase, and bilirubin as additional parameters. We have recently also been able to titrate infectious recoverable virus from the liver of the murine hepatitis virus-infected mice, using as assay cytopathic effect in mouse liver (NCTC 1469) cells. Ribavirin has proven highly efficacious against the disease induced in this murine model; since the drug also appears effective against type A hepatitis in humans, it seems reasonable to assume that the murine hepatitis model may be predictive for efficacy in humans. Other RNA viruses that induce hepatitis in animals include Rift Valley fever virus, which causes a rapidly fatal disease in mice, hamsters, rats, ferrets, monkeys, and sheep [157]; yellow fever virus, which will induce varying types of hepatitis in monkeys according to the species used [157]; and turkey hepatitis virus, a provisionally classified member of the Piconaviridae family that is particularly infective for very young turkeys [158]. There is also a duck hepatitis virus member of the Picornaviridae family, which is not to be confused with the type B hepatitis-related virus of ducks discussed earlier. The RNA-containing duck hepatitis virus causes in young ducklings an acute form of hepatitis accompanied by swelling of both spleen and kidneys [159].
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].
Vaccination against SARS-CoV-2 and disease enhancement – knowns and unknowns
Published in Expert Review of Vaccines, 2020
Raphaël M. Zellweger, T. Anh Wartel, Florian Marks, Manki Song, Jerome H. Kim
A virus-like particle (VLP) based vaccine composed of SARS-CoV spike (S) protein (that mediates attachment to the receptor on host target cell) and the nucleocapsid (N), envelope (E) and membrane (M) proteins from the murine coronavirus mouse hepatitis virus (MHV) also induced both protection and eosinophil infiltration in the lungs upon challenge in mice [25]. Subunit spike protein vaccine candidates also induced both protection and eosinophilia with and without alum when mice were challenged [25,27], and the immunopathology was reduced when the spike protein was adjuvanted in delta inulin [27]. In contrast, vaccination of mice with SARS-CoV receptor-binding-domain fused to Fc (RBD-Fc) in Freund’s complete adjuvant (FCA) and boosted with RBD-Fc in Freund’s incomplete adjuvant (FIA) induced neutralizing responses and reduced viral load in the lungs upon challenge [32], but no sign of lung pathology was observed. Finally, immunization of hamsters with trimers of the full-length spike protein of SARS-CoV in alum was immunogenic, protective and did not induce lung pathology [33].
Immune responses during COVID-19 infection
Published in OncoImmunology, 2020
Cléa Melenotte, Aymeric Silvin, Anne-Gaëlle Goubet, Imran Lahmar, Agathe Dubuisson, Alimuddin Zumla, Didier Raoult, Mansouria Merad, Bertrand Gachot, Clémence Hénon, Eric Solary, Michaela Fontenay, Fabrice André, Markus Maeurer, Giuseppe Ippolito, Mauro Piacentini, Fu-Sheng Wang, Florent Ginhoux, Aurélien Marabelle, Guido Kroemer, Lisa Derosa, Laurence Zitvogel
The majority of studies addressing the functional impact of T cell responses against respiratory virus infections come from mice infected with a variety of natural and mouse-adapted pathogens. Virus clearance during a primary response to infection depends on virus-specific CD4+ and CD8+ T cells and the rapidity of virus clearance correlates with the magnitude of CD4+ and CD8+ T cell responses. Zhao et al. adoptively transferred SARS-CoV-specific effector CD4+ or CD8+ T cells into immunodeficient mice and observed rapid virus clearance and amelioration of lung infection. Priming virus-specific CD8+ T cells in vivo using viral peptide-pulsed DCs also resulted in a robust T cell response, accelerated virus clearance and increased survival in SARS-CoV-MA-15 challenged BALB/c mice.98 Similar to SARS-CoV-specific T cells, MERS-CoV specific CD8+ T cells play an important role in clearing MERS-CoV in both BALB/c and C57BL/6 mice.92 Another group II coronavirus, the murine hepatitis virus MHV-3, which causes enteritis, pneumonia, hepatitis, and demyelinating encephalomyelitis, could be kept in check by an effective Th1 (but not Th2) cell response.99
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