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Susceptibility of Marmosets (Callithrix jacchus) to Monkeypox Virus: A Low Dose Prospective Model for Monkeypox and Smallpox Disease.

Mucker EM, Chapman J, Huzella LM, Huggins JW, Shamblin J, Robinson CG, Hensley LE - PLoS ONE (2015)

Bottom Line: Although current nonhuman primate models of monkeypox and smallpox diseases provide some insight into disease pathogenesis, they require a high titer inoculum, use an unnatural route of infection, and/or do not accurately represent the entire disease course.In our studies, we altered half of the test system by using a New World nonhuman primate host, the common marmoset.Based on dose finding studies, we found that marmosets are susceptible to monkeypox virus infection, produce a high viremia, and have pathological features consistent with smallpox and monkeypox in humans.

View Article: PubMed Central - PubMed

Affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America; Tulane University School of Medicine, New Orleans, Louisianna, United States of America.

ABSTRACT
Although current nonhuman primate models of monkeypox and smallpox diseases provide some insight into disease pathogenesis, they require a high titer inoculum, use an unnatural route of infection, and/or do not accurately represent the entire disease course. This is a concern when developing smallpox and/or monkeypox countermeasures or trying to understand host pathogen relationships. In our studies, we altered half of the test system by using a New World nonhuman primate host, the common marmoset. Based on dose finding studies, we found that marmosets are susceptible to monkeypox virus infection, produce a high viremia, and have pathological features consistent with smallpox and monkeypox in humans. The low dose (48 plaque forming units) required to elicit a uniformly lethal disease and the extended incubation (preclinical signs) are unique features among nonhuman primate models utilizing monkeypox virus. The uniform lethality, hemorrhagic rash, high viremia, decrease in platelets, pathology, and abbreviated acute phase are reflective of early-type hemorrhagic smallpox.

No MeSH data available.


Related in: MedlinePlus

Histopathological, immunohistochemical, and electron microscopic findings in the liver.Animal #3 (2.4 x 107 PFU group). A) Hepatocellular degeneration and necrosis with prominent eosinophilic intracytoplasmic inclusions (arrows). HE. B) Immunohistochemistry demonstrates vaccinia viral antigen in the liver. Immunoperoxidase method with hematoxylin counterstain. C) Transmission electron micrograph of inclusion in hepatocyte. Note the varying stages of virion from immature (arrowheads) to mature (arrows). VP—viroplasm; M—mitochondira. D) Transmission electron micrograph of inclusion in hepatocyte containing endoplasmic reticulum (double arrowheads) and free ribosomes.
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pone.0131742.g010: Histopathological, immunohistochemical, and electron microscopic findings in the liver.Animal #3 (2.4 x 107 PFU group). A) Hepatocellular degeneration and necrosis with prominent eosinophilic intracytoplasmic inclusions (arrows). HE. B) Immunohistochemistry demonstrates vaccinia viral antigen in the liver. Immunoperoxidase method with hematoxylin counterstain. C) Transmission electron micrograph of inclusion in hepatocyte. Note the varying stages of virion from immature (arrowheads) to mature (arrows). VP—viroplasm; M—mitochondira. D) Transmission electron micrograph of inclusion in hepatocyte containing endoplasmic reticulum (double arrowheads) and free ribosomes.

Mentions: There was hepatocellular degeneration and loss (17/18), with most affected cells containing prominent eosinophilic intracytoplasmic inclusions (Fig 10A). There were significant bone marrow alterations with depletion of white blood cell precursors, often with areas of necrosis (17/18). The only exception, in the animal that was found dead on day 4 due to causes unrelated to experimental infection, was no significant splenic, hepatic, or bone marrow pathology likely due to the animal succumbing quickly relative to exposure. There were varying degrees of pathology in the skin and mucous membranes in all 18 animals ranging from mild epithelial hyperplasia with vacuolar degeneration and multinucleated syncytial cells, to vesicular and hemorrhagic dermatitis with necrosis (Fig 11A). In all 18 animals there were lesions in the adrenal glands, ranging from mild vacuolar degeneration to necrosis (Fig 12A) and hemorrhage. In some areas of degeneration there were prominent eosinophilic intracytoplasmic inclusions within adrenal cortical cells. Other lesions present, but less consistent across dose ranges, included hemorrhage and edema within the lungs, heart, gastrointestinal tract, genitourinary system, and meninges.


Susceptibility of Marmosets (Callithrix jacchus) to Monkeypox Virus: A Low Dose Prospective Model for Monkeypox and Smallpox Disease.

Mucker EM, Chapman J, Huzella LM, Huggins JW, Shamblin J, Robinson CG, Hensley LE - PLoS ONE (2015)

Histopathological, immunohistochemical, and electron microscopic findings in the liver.Animal #3 (2.4 x 107 PFU group). A) Hepatocellular degeneration and necrosis with prominent eosinophilic intracytoplasmic inclusions (arrows). HE. B) Immunohistochemistry demonstrates vaccinia viral antigen in the liver. Immunoperoxidase method with hematoxylin counterstain. C) Transmission electron micrograph of inclusion in hepatocyte. Note the varying stages of virion from immature (arrowheads) to mature (arrows). VP—viroplasm; M—mitochondira. D) Transmission electron micrograph of inclusion in hepatocyte containing endoplasmic reticulum (double arrowheads) and free ribosomes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492619&req=5

pone.0131742.g010: Histopathological, immunohistochemical, and electron microscopic findings in the liver.Animal #3 (2.4 x 107 PFU group). A) Hepatocellular degeneration and necrosis with prominent eosinophilic intracytoplasmic inclusions (arrows). HE. B) Immunohistochemistry demonstrates vaccinia viral antigen in the liver. Immunoperoxidase method with hematoxylin counterstain. C) Transmission electron micrograph of inclusion in hepatocyte. Note the varying stages of virion from immature (arrowheads) to mature (arrows). VP—viroplasm; M—mitochondira. D) Transmission electron micrograph of inclusion in hepatocyte containing endoplasmic reticulum (double arrowheads) and free ribosomes.
Mentions: There was hepatocellular degeneration and loss (17/18), with most affected cells containing prominent eosinophilic intracytoplasmic inclusions (Fig 10A). There were significant bone marrow alterations with depletion of white blood cell precursors, often with areas of necrosis (17/18). The only exception, in the animal that was found dead on day 4 due to causes unrelated to experimental infection, was no significant splenic, hepatic, or bone marrow pathology likely due to the animal succumbing quickly relative to exposure. There were varying degrees of pathology in the skin and mucous membranes in all 18 animals ranging from mild epithelial hyperplasia with vacuolar degeneration and multinucleated syncytial cells, to vesicular and hemorrhagic dermatitis with necrosis (Fig 11A). In all 18 animals there were lesions in the adrenal glands, ranging from mild vacuolar degeneration to necrosis (Fig 12A) and hemorrhage. In some areas of degeneration there were prominent eosinophilic intracytoplasmic inclusions within adrenal cortical cells. Other lesions present, but less consistent across dose ranges, included hemorrhage and edema within the lungs, heart, gastrointestinal tract, genitourinary system, and meninges.

Bottom Line: Although current nonhuman primate models of monkeypox and smallpox diseases provide some insight into disease pathogenesis, they require a high titer inoculum, use an unnatural route of infection, and/or do not accurately represent the entire disease course.In our studies, we altered half of the test system by using a New World nonhuman primate host, the common marmoset.Based on dose finding studies, we found that marmosets are susceptible to monkeypox virus infection, produce a high viremia, and have pathological features consistent with smallpox and monkeypox in humans.

View Article: PubMed Central - PubMed

Affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America; Tulane University School of Medicine, New Orleans, Louisianna, United States of America.

ABSTRACT
Although current nonhuman primate models of monkeypox and smallpox diseases provide some insight into disease pathogenesis, they require a high titer inoculum, use an unnatural route of infection, and/or do not accurately represent the entire disease course. This is a concern when developing smallpox and/or monkeypox countermeasures or trying to understand host pathogen relationships. In our studies, we altered half of the test system by using a New World nonhuman primate host, the common marmoset. Based on dose finding studies, we found that marmosets are susceptible to monkeypox virus infection, produce a high viremia, and have pathological features consistent with smallpox and monkeypox in humans. The low dose (48 plaque forming units) required to elicit a uniformly lethal disease and the extended incubation (preclinical signs) are unique features among nonhuman primate models utilizing monkeypox virus. The uniform lethality, hemorrhagic rash, high viremia, decrease in platelets, pathology, and abbreviated acute phase are reflective of early-type hemorrhagic smallpox.

No MeSH data available.


Related in: MedlinePlus