A Mouse Model of Lethal Infection for Evaluating Prophylactics and Therapeutics against Monkeypox Virus

Stabenow, Jennifer; Buller, R. Mark; Schriewer, Jill; West, Cheri L.; Sagartz, John E.; Parker, Scott

doi:10.1128/jvi.02012-09

Cited by 90 publications

(90 citation statements)

References 61 publications

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“…Like MPXV, MYXV pathogenesis is restricted to only certain species and has little or no capability for pathogenesis in all others (29,30). For both MYXV and MPXV, restriction in mice requires signaling through the type I and type II IFN pathways (20,30). This is similar to the restriction in pathogenesis that we have seen with VACV lacking an intact E3 N-terminal domain (11).…”

Section: Discussionsupporting

confidence: 54%

“…Thus, suppression of PKR activation during MPXV infection may be a factor in promoting pathogenesis in humans and nonhuman primates. On the other hand, MPXV is not pathogenic in most strains of inbred mice, unless IFN signaling is abrogated (20). Similarly, VACV in which the region coding for the N-terminal domain of E3 is deleted is as pathogenic as wt VACV in IFNAR Ϫ/Ϫ mice (11).…”

Section: Discussionmentioning

confidence: 99%

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Evasion of the Innate Immune Type I Interferon System by Monkeypox Virus

Arndt

Cotsmire

Trainor

et al. 2015

J Virol

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The vaccinia virus (VACV) E3 protein has been shown to be important for blocking activation of the cellular innate immune system and allowing viral replication to occur unhindered. Mutation or deletion of E3L severely affects viral host range and pathogenesis. While the monkeypox virus (MPXV) genome encodes a homologue of the VACV E3 protein, encoded by the F3L gene, the MPXV gene is predicted to encode a protein with a truncation of 37 N-terminal amino acids. VACV with a genome encoding a similarly truncated E3L protein (VACV-E3L⌬37N) has been shown to be attenuated in mouse models, and infection with VACV-E3L⌬37N has been shown to lead to activation of the host antiviral protein kinase R pathway. In this report, we present data demonstrating that, despite containing a truncated E3 homologue, MPXV phenotypically resembles a wild-type (wt) VACV rather than VACV-E3L⌬37N. Thus, MPXV appears to contain a gene or genes that can suppress the phenotypes associated with an N-terminal truncation in E3. The suppression maps to sequences outside F3L, suggesting that the suppression is extragenic in nature. Thus, MPXV appears to have evolved mechanisms to minimize the effects of partial inactivation of its E3 homologue. IMPORTANCEPoxviruses have evolved to have many mechanisms to evade host antiviral innate immunity; these mechanisms may allow these viruses to cause disease. Within the family of poxviruses, variola virus (which causes smallpox) is the most pathogenic, while monkeypox virus is intermediate in pathogenicity between vaccinia virus and variola virus. Understanding the mechanisms of monkeypox virus innate immune evasion will help us to understand the evolution of poxvirus innate immune evasion capabilities, providing a better understanding of how poxviruses cause disease.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Evasion of the Innate Immune Type I Interferon System by Monkeypox Virus

Arndt

Cotsmire

Trainor

et al. 2015

J Virol

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“…49,92,119 However, mice with severe combined immune deficiency were found to be highly susceptible to MPXV when inoculated IP or IN. Consistent virus-associated histologic lesions in the mice challenged IP included ovarian necrosis and inflammation, intestinal serositis, and multifocal epidermal ballooning degeneration.…”

Section: 106mentioning

confidence: 99%

“…119 This model was used in vaccine and antiviral efficacy trials. 119 Subsequent to the 2003 human monkeypox outbreak in the United States, there have been several attempts to develop rodent models of human smallpox and human monkeypox by experimentally infecting 13-lined ground squirrels (Spermophilus tridecemlineatus), black-tailed prairie dogs (Cynomys ludovicianus), and an African species of dormouse (Graphiurus kelleni) with different strains of MPXV using various viral doses and routes of inoculation. IP or IN inoculation of ground squirrels with high doses of MPXV-USA resulted in 100% mortality in 6 to 7 days for the IP route and 8 to 9 days for the IN route.…”

Section: 106mentioning

confidence: 99%

Animal Models of Orthopoxvirus Infection

et al. 2010

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Smallpox was one of the most devastating diseases known to humanity. Although smallpox was eradicated through a historically successful vaccination campaign, there is concern in the global community that either Variola virus (VARV), the causative agent of smallpox, or another species of Orthopoxvirus could be used as agents of bioterrorism. Therefore, development of countermeasures to Orthopoxvirus infection is a crucial focus in biodefense research, and these efforts rely on the use of various animal models. Smallpox typically presented as a generalized pustular rash with 30 to 40% mortality, and although smallpox-like syndromes can be induced in cynomolgus macaques with VARV, research with this virus is highly restricted; therefore, animal models with other orthopoxviruses have been investigated. Monkeypox virus causes a generalized vesiculopustular rash in rhesus and cynomolgus macaques and induces fatal systemic disease in several rodent species. Ectromelia virus has been extensively studied in mice as a model of orthopoxviral infection in its natural host. Intranasal inoculation of mice with some strains of vaccinia virus produces fatal bronchopneumonia, as does aerosol or intranasal inoculation of mice with cowpox virus. Rabbitpox virus causes pneumonia and fatal systemic infections in rabbits and can be naturally transmitted between rabbits by an aerosol route similar to that of VARV in humans. No single animal model recapitulates all known aspects of human Orthopoxvirus infections, and each model has its advantages and disadvantages. This article provides a brief review of the Orthopoxvirus diseases of humans and the key pathologic features of animal models of Orthopoxvirus infections.

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“…However, as experimental systems, each has limitations with regard to unavailability of commercial breeding, genetic heterogeneity and absence of immunological and other reagents. Laboratory mice, including BALB/c, C57BL/6, and several other mouse strains tested, were found to be resistant to MPXV disease unless impaired in innate or acquired immunity (10,17,24). In the present study, we tested a large group of distinct inbred strains of mice chosen for genetic diversity, inclusion of classical and wild-derived strains, and commercial availability.…”

mentioning

confidence: 99%

Identification of Wild-Derived Inbred Mouse Strains Highly Susceptible to Monkeypox Virus Infection for Use as Small Animal Models

Americo

Moss

Earl

2010

J Virol

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Infection with monkeypox virus (MPXV) causes disease manifestations in humans that are similar, although usually less severe, than those of smallpox. Since routine vaccination for smallpox ceased more than 30 years ago, there is concern that MPXV could be used for bioterrorism. Thus, there is a need to develop animal models to study MPXV infection. Accordingly, we screened 38 inbred mouse strains for susceptibility to MPXV. Three highly susceptible wild-derived inbred strains were identified, of which CAST/EiJ was further developed as a model. Using an intranasal route of infection with an isolate of the Congo Basin clade of MPXV, CAST/EiJ mice exhibited weight loss, morbidity, and death in a dose-dependent manner with a calculated 50% lethal dose (LD 50 ) of 680 PFU, whereas there were no deaths of BALB/c mice at a 10,000-fold higher dose. CAST/EiJ mice exhibited greater MPXV sensitivity when infected via the intraperitoneal route, with an LD 50 of 14 PFU. Both routes resulted in MPXV replication in the lung, spleen, and liver. Intranasal infection with an isolate of the less-pathogenic West African clade yielded an LD 50 of 7,600 PFU. The immune competence of CAST/EiJ mice was established by immunization with vaccinia virus, which induced antigen-specific T-and B-lymphocyte responses and fully protected mice from lethal doses of MPXV. The new mouse model has the following advantages for studying pathogenesis of MPXV, as well as for evaluation of potential vaccines and therapeutics: relative sensitivity to MPXV through multiple routes, genetic homogeneity, available immunological reagents, and commercial production.

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A Mouse Model of Lethal Infection for Evaluating Prophylactics and Therapeutics against Monkeypox Virus

Cited by 90 publications

References 61 publications

Evasion of the Innate Immune Type I Interferon System by Monkeypox Virus

Evasion of the Innate Immune Type I Interferon System by Monkeypox Virus

Animal Models of Orthopoxvirus Infection

Identification of Wild-Derived Inbred Mouse Strains Highly Susceptible to Monkeypox Virus Infection for Use as Small Animal Models

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