Animal Models of <i>Orthopoxvirus</i> Infection

Chapman, Jennifer L.; Nichols, Donald K.; Martinez, M. J.; Raymond, Jo Lynne

doi:10.1177/0300985810378649

Cited by 117 publications

(134 citation statements)

References 113 publications

(227 reference statements)

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“…Maximum mean peak fold changes in IFN-␥ (8,028), IL-1ra (4,854), and IL-6 (3,207) were recorded on a variety of days (8). In this study, the mean peak changes in the biomarkers IFN-␥ (1,322 pg ml Ϫ1 ), IL-1ra (3,335 pg ml Ϫ1 ), and IL-6 (570 pg ml Ϫ1 ) occurred on day 8 postchallenge.…”

Section: Discussionmentioning

confidence: 48%

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Sequence of Pathogenic Events in Cynomolgus Macaques Infected with Aerosolized Monkeypox Virus

Tree

Hall

Pearson

et al. 2015

J Virol

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To evaluate new vaccines when human efficacy studies are not possible, the FDA's "Animal Rule" requires well-characterized models of infection. Thus, in the present study, the early pathogenic events of monkeypox infection in nonhuman primates, a surrogate for variola virus infection, were characterized. Cynomolgus macaques were exposed to aerosolized monkeypox virus (10 5 PFU). Clinical observations, viral loads, immune responses, and pathological changes were examined on days 2, 4, 6, 8, 10, and 12 postchallenge. Viral DNA (vDNA) was detected in the lungs on day 2 postchallenge, and viral antigen was detected, by immunostaining, in the epithelium of bronchi, bronchioles, and alveolar walls. Lesions comprised rare foci of dysplastic and sloughed cells in respiratory bronchioles. By day 4, vDNA was detected in the throat, tonsil, and spleen, and monkeypox antigen was detected in the lung, hilar and submandibular lymph nodes, spleen, and colon. Lung lesions comprised focal epithelial necrosis and inflammation. Body temperature peaked on day 6, pox lesions appeared on the skin, and lesions, with positive immunostaining, were present in the lung, tonsil, spleen, lymph nodes, and colon. By day 8, vDNA was present in 9/13 tissues. Blood concentrations of interleukin 1ra (IL-1ra), IL-6, and gamma interferon (IFN-␥) increased markedly. By day 10, circulating IgG antibody concentrations increased, and on day 12, animals showed early signs of recovery. These results define early events occurring in an inhalational macaque monkeypox infection model, supporting its use as a surrogate model for human smallpox. IMPORTANCEBioterrorism poses a major threat to public health, as the deliberate release of infectious agents, such smallpox or a related virus, monkeypox, would have catastrophic consequences. The development and testing of new medical countermeasures, e.g., vaccines, are thus priorities; however, tests for efficacy in humans cannot be performed because it would be unethical and field trials are not feasible. To overcome this, the FDA may grant marketing approval of a new product based upon the "Animal Rule," in which interventions are tested for efficacy in well-characterized animal models. Monkeypox virus infection of nonhuman primates (NHPs) presents a potential surrogate disease model for smallpox. Previously, the later stages of monkeypox infection were defined, but the early course of infection remains unstudied. Here, the early pathogenic events of inhalational monkeypox infection in NHPs were characterized, and the results support the use of this surrogate model for testing human smallpox interventions.

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Section: Discussionmentioning

confidence: 48%

“…Recently, the majority of the human population has not been vaccinated; consequently, a proportion of the population lacks protective immunity (3). Concerns over the use of variola virus or monkeypox virus (a closely related orthopoxvirus) as a biological weapon remain high, as a deliberate release would have catastrophic consequences on global health (4).…”

mentioning

confidence: 99%

Sequence of Pathogenic Events in Cynomolgus Macaques Infected with Aerosolized Monkeypox Virus

Tree

Hall

Pearson

et al. 2015

J Virol

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“…In rabbits (rabbitpox virus), macaques (monkeypox virus), and mice (vaccinia virus), necrotizing or fibrinonecrotic bronchopneumonia occurs. 7 In humans, infection with smallpox leads to bronchopneumonia, which is described as a frequent complication of the disease. However, it remains unclear if bronchopneumonia is directly related to the virus infection or due to secondary bacterial infections.…”

Section: Discussionmentioning

confidence: 99%

“…To study CPXV infections, various mouse models have been developed in the past using intradermal, intratracheal, intraperitoneal, and intranasal infection routes. 7 These CPXV mouse models have provided a deeper understanding of Orthopoxvirus infection, including virushost interactions and pathogenesis, especially regarding viral immunomodulation.…”

mentioning

confidence: 99%

Clinical Course and Pathology in Rats (Rattus norvegicus) After Experimental Cowpox Virus Infection by Percutaneous and Intranasal Application

et al. 2012

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Recently, several cases of human cowpox virus (CPXV) infections were reported in France and Germany, which had been acquired through close contact with infected pet rats. The animals exhibited respiratory signs or skin lesions and died shortly after purchase. After natural infection of white rats with CPXV in the USSR in 1978, a peracute pulmonary form, a milder dermal form, and a mixed form exhibiting features of both have been described. To the best of the authors' knowledge, 3 experimental cowpox virus infection studies using rats have been performed to date; however, neither results of histomorphological examinations nor immunohistochemical analyses have yet been reported in rats after experimental infections. To investigate the impact of the infection route on the clinical course, the development of lesions, and tropism, rats were infected intradermally, intranasally, or by a combination of both routes. The authors found a correlation between clinical manifestation, pathology, and infection routes. Intradermal and contact exposure yielded a mild dermal form, characterized by the development of vesiculopustular dermatitis. In contrast, intranasally infected animals died peracutely, showing severe dyspnea. Occasionally, a combination of the dermal and the respiratory form occurred after intranasal infection. Immunohistochemically, CPXV antigen was detected in the epithelial and mesenchymal cells of the upper respiratory tract and affected skin lesions and rarely in mesenchymal cells of lymph nodes. This is the first histomorphological and immunohistochemical analysis of CPXV in rats after experimental infection.

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“…For instance, the human pathogen variola virus (VARV) penetrated through the respiratory epithelium to spread lymphohematogenously through the mediastinal lymph nodes. Thus, smallpox was chiefly a systemic and not a respiratory disease (3,4). Similarly, some of the gravest complications of the smallpox vaccine, which is made with live vaccinia virus (VACV), are due to lymphohematogenous (LH) dissemination (5-7).…”

mentioning

confidence: 99%

The Mature Virion of Ectromelia Virus, a Pathogenic Poxvirus, Is Capable of Intrahepatic Spread and Can Serve as a Target for Delayed Therapy

Roscoe

et al. 2013

J Virol

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Orthopoxviruses (OPVs), which include the agent of smallpox (variola virus), the zoonotic monkeypox virus, the vaccine and zoonotic species vaccinia virus, and the mouse pathogen ectromelia virus (ECTV), form two types of infectious viral particles: the mature virus (MV), which is cytosolic, and the enveloped virus (EV), which is extracellular. It is believed that MVs are required for viral entry into the host, while EVs are responsible for spread within the host. Following footpad infection of susceptible mice, ECTV spreads lymphohematogenously, entering the liver at 3 to 4 days postinfection (dpi). Afterwards, ECTV spreads intrahepatically, killing the host. We found that antibodies to an MV protein were highly effective at curing mice from ECTV infection when administered after the virus reached the liver. Moreover, a mutant ECTV that does not make EV was able to spread intrahepatically and kill immunodeficient mice. Together, these findings indicate that MVs are sufficient for the spread of ECTV within the liver and could have implications regarding the pathogenesis of other OPVs, the treatment of emerging OPV infections, as well as strategies for preparedness in case of accidental or intentional release of pathogenic OPVs.

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Animal Models of Orthopoxvirus Infection

Cited by 117 publications

References 113 publications

Sequence of Pathogenic Events in Cynomolgus Macaques Infected with Aerosolized Monkeypox Virus

Sequence of Pathogenic Events in Cynomolgus Macaques Infected with Aerosolized Monkeypox Virus

Clinical Course and Pathology in Rats (Rattus norvegicus) After Experimental Cowpox Virus Infection by Percutaneous and Intranasal Application

The Mature Virion of Ectromelia Virus, a Pathogenic Poxvirus, Is Capable of Intrahepatic Spread and Can Serve as a Target for Delayed Therapy

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