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Development of a model for marburgvirus based on severe-combined immunodeficiency mice.

Warfield KL, Alves DA, Bradfute SB, Reed DK, VanTongeren S, Kalina WV, Olinger GG, Bavari S - Virol. J. (2007)

Bottom Line: Here, we demonstrate that serially passaging liver homogenates from MARV-infected severe combined immunodeficient (scid) mice was highly successful in reducing the time to death in scid mice from 50-70 days to 7-10 days after MARV-Ci67, -Musoke, or -Ravn challenge.We performed serial sampling studies to characterize the pathology of these scid mouse-adapted MARV strains.These scid mouse-adapted MARV models appear to have many similar properties as the MARV models previously developed in guinea pigs and nonhuman primates.

View Article: PubMed Central - HTML - PubMed

Affiliation: United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA. kelly.warfield@us.army.mil

ABSTRACT
The filoviruses, Ebola (EBOV) and Marburg (MARV), cause a lethal hemorrhagic fever. Human isolates of MARV are not lethal to immmunocompetent adult mice and, to date, there are no reports of a mouse-adapted MARV model. Previously, a uniformly lethal EBOV-Zaire mouse-adapted virus was developed by performing 9 sequential passages in progressively older mice (suckling to adult). Evaluation of this model identified many similarities between infection in mice and nonhuman primates, including viral tropism for antigen-presenting cells, high viral titers in the spleen and liver, and an equivalent mean time to death. Existence of the EBOV mouse model has increased our understanding of host responses to filovirus infections and likely has accelerated the development of countermeasures, as it is one of the only hemorrhagic fever viruses that has multiple candidate vaccines and therapeutics. Here, we demonstrate that serially passaging liver homogenates from MARV-infected severe combined immunodeficient (scid) mice was highly successful in reducing the time to death in scid mice from 50-70 days to 7-10 days after MARV-Ci67, -Musoke, or -Ravn challenge. We performed serial sampling studies to characterize the pathology of these scid mouse-adapted MARV strains. These scid mouse-adapted MARV models appear to have many similar properties as the MARV models previously developed in guinea pigs and nonhuman primates. Also, as shown here, the scid-adapted MARV mouse models can be used to evaluate the efficacy of candidate antiviral therapeutic molecules, such as phosphorodiamidate morpholino oligomers or antibodies.

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Gross liver abnormalities upon necropsy of scid mice infected with 'scid-adapted' MARV. (A) Livers of uninfected scid mice appear normal at the time of necropsy. (B) The livers from MARV-Ci67-infected scid mice were diffusely enlarged with rounded edges filling up to one-third of the abdominal cavity and mildly displacing abdominal organs. Additionally, the livers had become distinctively pale with an accentuated reticulated pattern.
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Figure 4: Gross liver abnormalities upon necropsy of scid mice infected with 'scid-adapted' MARV. (A) Livers of uninfected scid mice appear normal at the time of necropsy. (B) The livers from MARV-Ci67-infected scid mice were diffusely enlarged with rounded edges filling up to one-third of the abdominal cavity and mildly displacing abdominal organs. Additionally, the livers had become distinctively pale with an accentuated reticulated pattern.

Mentions: Besides the noticeable and steady weight loss observed beginning around 4–5 days after infection, the most obvious and consistent gross necropsy finding in mice infected with the "scid-adapted" MARV occurred in the liver. When compared to uninfected scid mice (Figure 4A), livers from MARV-infected scid mice were diffusely enlarged with rounded edges filling up to one-third of the abdominal cavity and mildly displacing abdominal organs (Figure 4B). Furthermore, the livers had become diffusely yellowish-tan with an accentuated reticulated pattern and were extremely friable. Also consistently noted was that the blood of the 'scid-adapted' MARV-infected mice failed to clot post-mortem. To further characterize the lethal mouse models of MARV-Musoke, -Ravn, and -Ci67, histological analysis was performed on tissues from scid mice at 0, 2, 4, 6 and 8 days after infection. Histological lesions were mainly limited to the lymphoid organs and the liver.


Development of a model for marburgvirus based on severe-combined immunodeficiency mice.

Warfield KL, Alves DA, Bradfute SB, Reed DK, VanTongeren S, Kalina WV, Olinger GG, Bavari S - Virol. J. (2007)

Gross liver abnormalities upon necropsy of scid mice infected with 'scid-adapted' MARV. (A) Livers of uninfected scid mice appear normal at the time of necropsy. (B) The livers from MARV-Ci67-infected scid mice were diffusely enlarged with rounded edges filling up to one-third of the abdominal cavity and mildly displacing abdominal organs. Additionally, the livers had become distinctively pale with an accentuated reticulated pattern.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2164958&req=5

Figure 4: Gross liver abnormalities upon necropsy of scid mice infected with 'scid-adapted' MARV. (A) Livers of uninfected scid mice appear normal at the time of necropsy. (B) The livers from MARV-Ci67-infected scid mice were diffusely enlarged with rounded edges filling up to one-third of the abdominal cavity and mildly displacing abdominal organs. Additionally, the livers had become distinctively pale with an accentuated reticulated pattern.
Mentions: Besides the noticeable and steady weight loss observed beginning around 4–5 days after infection, the most obvious and consistent gross necropsy finding in mice infected with the "scid-adapted" MARV occurred in the liver. When compared to uninfected scid mice (Figure 4A), livers from MARV-infected scid mice were diffusely enlarged with rounded edges filling up to one-third of the abdominal cavity and mildly displacing abdominal organs (Figure 4B). Furthermore, the livers had become diffusely yellowish-tan with an accentuated reticulated pattern and were extremely friable. Also consistently noted was that the blood of the 'scid-adapted' MARV-infected mice failed to clot post-mortem. To further characterize the lethal mouse models of MARV-Musoke, -Ravn, and -Ci67, histological analysis was performed on tissues from scid mice at 0, 2, 4, 6 and 8 days after infection. Histological lesions were mainly limited to the lymphoid organs and the liver.

Bottom Line: Here, we demonstrate that serially passaging liver homogenates from MARV-infected severe combined immunodeficient (scid) mice was highly successful in reducing the time to death in scid mice from 50-70 days to 7-10 days after MARV-Ci67, -Musoke, or -Ravn challenge.We performed serial sampling studies to characterize the pathology of these scid mouse-adapted MARV strains.These scid mouse-adapted MARV models appear to have many similar properties as the MARV models previously developed in guinea pigs and nonhuman primates.

View Article: PubMed Central - HTML - PubMed

Affiliation: United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA. kelly.warfield@us.army.mil

ABSTRACT
The filoviruses, Ebola (EBOV) and Marburg (MARV), cause a lethal hemorrhagic fever. Human isolates of MARV are not lethal to immmunocompetent adult mice and, to date, there are no reports of a mouse-adapted MARV model. Previously, a uniformly lethal EBOV-Zaire mouse-adapted virus was developed by performing 9 sequential passages in progressively older mice (suckling to adult). Evaluation of this model identified many similarities between infection in mice and nonhuman primates, including viral tropism for antigen-presenting cells, high viral titers in the spleen and liver, and an equivalent mean time to death. Existence of the EBOV mouse model has increased our understanding of host responses to filovirus infections and likely has accelerated the development of countermeasures, as it is one of the only hemorrhagic fever viruses that has multiple candidate vaccines and therapeutics. Here, we demonstrate that serially passaging liver homogenates from MARV-infected severe combined immunodeficient (scid) mice was highly successful in reducing the time to death in scid mice from 50-70 days to 7-10 days after MARV-Ci67, -Musoke, or -Ravn challenge. We performed serial sampling studies to characterize the pathology of these scid mouse-adapted MARV strains. These scid mouse-adapted MARV models appear to have many similar properties as the MARV models previously developed in guinea pigs and nonhuman primates. Also, as shown here, the scid-adapted MARV mouse models can be used to evaluate the efficacy of candidate antiviral therapeutic molecules, such as phosphorodiamidate morpholino oligomers or antibodies.

Show MeSH
Related in: MedlinePlus