A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo

Day, Craig W.; Baric, Ralph S.; Cai, Sui Xiong; Frieman, Matt; Kumaki, Yohichi; Morrey, John D.; Smee, Donald F.; Barnard, Dale L.

doi:10.1016/j.virol.2009.09.023

Cited by 133 publications

(181 citation statements)

References 96 publications

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“…In the present study prestimulation of J774A.1 macrophages with poly I:C, a potent type I IFN inducer, resulted in a strong IFN-β response that triggered antiviral immunity and protected macrophages from MHV infection before and after virus adsorption. In support of our data, a poly I:C analog Ampligen TM (Poly I:Poly C 12 U) was successfully tested in SARS-CoV animal models [45,46]. BALB/c mice were treated with Ampligen TM intraperitoneally (i.p.)…”

Section: Resultsmentioning

confidence: 70%

Protective Role of Toll-like Receptor 3-Induced Type I Interferon in Murine Coronavirus Infection of Macrophages

Mazaleuskaya

Veltrop

Ikpeze

et al. 2012

Viruses

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Toll-like Receptors (TLRs) sense viral infections and induce production of type I interferons (IFNs), other cytokines, and chemokines. Viral recognition by TLRs and other pattern recognition receptors (PRRs) has been proven to be cell-type specific. Triggering of TLRs with selected ligands can be beneficial against some viral infections. Macrophages are antigen-presenting cells that express TLRs and have a key role in the innate and adaptive immunity against viruses. Coronaviruses (CoVs) are single-stranded, positive-sense RNA viruses that cause acute and chronic infections and can productively infect macrophages. Investigation of the interplay between CoVs and PRRs is in its infancy. We assessed the effect of triggering TLR2, TLR3, TLR4, and TLR7 with selected ligands on the susceptibility of the J774A.1 macrophage cell line to infection with murine coronavirus (mouse hepatitis virus, [MHV]). Stimulation of TLR2, TLR4, or TLR7 did not affect MHV production. In contrast, pre-stimulation of TLR3 with polyinosinic-polycytidylic acid (poly I:C) hindered MHV infection through induction of IFN-β in macrophages. We demonstrate that activation of TLR3 with the synthetic ligand poly I:C mediates antiviral immunity that diminishes (MHV-A59) or suppresses (MHV-JHM, MHV-3) virus production in macrophages.

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Section: Resultsmentioning

confidence: 70%

Protective Role of Toll-like Receptor 3-Induced Type I Interferon in Murine Coronavirus Infection of Macrophages

Mazaleuskaya

Veltrop

Ikpeze

et al. 2012

Viruses

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“…The best current small animal models for SARS-CoV infection and disease are Balb/c mice (Day et al, 2009; Nagata et al, 2008; Roberts et al, 2007). The establishment of mouse cell lines susceptible to SARS320 CoV was therefore of high interest, so that in vitro and in vivo evaluations with the mouse adapted SARS-CoV could take place in the same species environment and using the same cellular receptor.…”

Section: Discussionmentioning

confidence: 99%

“…To overcome these limitations, SARS-CoV was adapted to grow in mice by passing the virus in lung for 10, 15, or 25 times (Day et al, 2009; Nagata et al, 2008; Roberts et al, 2007). Infection of Balb/c mice with the resulting mouse adapted (MA) viruses reproduced many aspects of human SARS, including pathological changes in the lung, viremia, neutrophilia, and lethality (Day et al, 2009; Nagata et al, 2008; Roberts et al, 2007). This inbred mouse model of human SARS disease has many advantages compared to the other animal models, such as small animal size, low cost, availability of the animals, the possibility to genetically manipulate the host animals (i.e.…”

Section: Introductionmentioning

confidence: 99%

The replication of a mouse adapted SARS-CoV in a mouse cell line stably expressing the murine SARS-CoV receptor mACE2 efficiently induces the expression of proinflammatory cytokines

Regla-Nava

Jiménez-Guardeño

Nieto-Torres

et al. 2013

Journal of Virological Methods

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Infection of conventional mice with a mouse adapted (MA15) severe acute respiratory syndrome (SARS) coronavirus (CoV) reproduces many aspects of human SARS such as pathological changes in lung, viremia, neutrophilia, and lethality. However, established mouse cell lines highly susceptible to mouse-adapted SARS-CoV infection are not available. In this work, efficiently transfectable mouse cell lines stably expressing the murine SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) have been generated. These cells yielded high SARS-CoV-MA15 titers and also served as excellent tools for plaque assays. In addition, in these cell lines, SARS-CoV-MA15 induced the expression of proinflammatory cytokines and IFN-β, mimicking what has been observed in experimental animal models infected with SARS-CoV and SARS patients. These cell lines are valuable tools to perform in vitro studies in a mouse cell system that reflects the species used for in vivo studies of SARS-CoV-MA15 pathogenesis.

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“…At present, no clear evidence has been provided to support these clinical observations yet (Barnard and Kumaki, 2009). In several mouse models and in vitro , ribavirin was even found to enhance the SARS-CoV infection (Barnard et al, 2006a; Barnard et al, 2006b; Day et al, 2009). Therefore, development of new anti-SARS-CoV agents is urgently needed should SARS-CoV, or a virus closely related to it, emerge or re-emerge to cause disease.…”

Section: Introductionmentioning

confidence: 99%

“…We previously adapted and characterized a new strain of SARS-CoV (strain v2163) that was highly lethal in 5- to 6-week-old BALB/c mice (Day et al, 2009). A number of compounds were tested for efficacy in SARS-CoV-infected BALB/c mice, including UDA.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of severe acute respiratory syndrome coronavirus replication in a lethal SARS-CoV BALB/c mouse model by stinging nettle lectin, Urtica dioica agglutinin

et al. 2011

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Urtica dioica agglutinin (UDA) is a small plant monomeric lectin, 8.7 kDa in size, with an N-acetylglucosamine specificity that inhibits viruses from Nidovirales in vitro. In the current study, we first examined the efficacy of UDA on the replication of different SARS-CoV strains in Vero 76 cells. UDA inhibited virus replication in a dose-dependent manner and reduced virus yields of the Urbani strain by 90% at 1.1 ± 0.4 µg/ml in Vero 76 cells. Then, UDA was tested for efficacy in a lethal SARS-CoV-infected BALB/c mouse model. BALB/c mice were infected with two LD50 (575 PFU) of virus for 4 hours before the mice were treated intraperitoneally with UDA at 20, 10, 5 or 0 mg/kg/day for 4 days. Treatment with UDA at 5 mg/kg significantly protected the mice against a lethal infection with mouse-adapted SARS-CoV (p<0.001), but did not significantly reduce virus lung titers. All virus-infected mice receiving UDA treatments were also significantly protected against weight loss (p<0.001). UDA also effectively reduced lung pathology scores. At day 6 after virus exposure, all groups of mice receiving UDA had much lower lung weights than did the placebo-treated mice. Thus, our data suggest that UDA treatment of SARS infection in mice leads to a substantial therapeutic effect that protects mice against death and weight loss. Furthermore, the mode of action of UDA in vitro was further investigated using live SARS-CoV Urbani strain virus and retroviral particles pseudotyped with SARS-CoV spike (S). UDA specifically inhibited the replication of live SARS-CoV or SARS-CoV pseudotyped virus when added just before, but not after, adsorption. These data suggested that UDA likely inhibits SARS-CoV infection by targeting early stages of the replication cycle, namely, adsorption or penetration. In addition, we demonstrated that UDA neutralizes the virus infectivity, presumably by binding to the SARS-CoV spike (S) glycoprotein. Finally, the target molecule for inhibition of virus replication was partially characterized. When UDA was exposed to N-acetylglucosamine and then UDA was added to cells just prior to adsorption, UDA did not inhibit the virus infection. These data support the conclusion that UDA might bind to N-acetylglucosamine-like residues present on the glycosylated envelope glycoproteins, thereby preventing virus attachment to cells.

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A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo

Cited by 133 publications

References 96 publications

Protective Role of Toll-like Receptor 3-Induced Type I Interferon in Murine Coronavirus Infection of Macrophages

Protective Role of Toll-like Receptor 3-Induced Type I Interferon in Murine Coronavirus Infection of Macrophages

The replication of a mouse adapted SARS-CoV in a mouse cell line stably expressing the murine SARS-CoV receptor mACE2 efficiently induces the expression of proinflammatory cytokines

Inhibition of severe acute respiratory syndrome coronavirus replication in a lethal SARS-CoV BALB/c mouse model by stinging nettle lectin, Urtica dioica agglutinin

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