Limits...
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.

Show MeSH

Related in: MedlinePlus

Use of the 'scid-adapted' MARV model to assess the efficacy of potential therapeutics for MARV. Scid mice were infected IP with ~1000 pfu of 'scid-adapted' MARV-Ci67. At 1 h postchallenge, groups of scid mice (n = 10) were treated IP with 1 ml of convalescent serum from guinea pigs that had survived MARV or EBOV challenge. Alternately, groups of mice were treated with 1 mg each of VP24, VP35, NP and L PMOs or saline alone as a vehicle control. The mice were monitored for >70 days for survival and the data are presented on a Meier-Kaplan curve as percent survival for each group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2164958&req=5

Figure 9: Use of the 'scid-adapted' MARV model to assess the efficacy of potential therapeutics for MARV. Scid mice were infected IP with ~1000 pfu of 'scid-adapted' MARV-Ci67. At 1 h postchallenge, groups of scid mice (n = 10) were treated IP with 1 ml of convalescent serum from guinea pigs that had survived MARV or EBOV challenge. Alternately, groups of mice were treated with 1 mg each of VP24, VP35, NP and L PMOs or saline alone as a vehicle control. The mice were monitored for >70 days for survival and the data are presented on a Meier-Kaplan curve as percent survival for each group.

Mentions: To demonstrate the utility of our recently developed and characterized 'scid-adapted' MARV (Ci67, Musoke, and Ravn) in screening potential anti-MARV therapeutics, we treated scid mice that were infected with 'scid-adapted' MARV-Ci67. Since the scid mice do not have functional B or T cells and cannot mount an adaptive response to clear the virus, we only expected to see a delay in the mean time-to-death and not a survival benefit in these experiments. In the first portion of this experiment, 1 ml of pooled sera from convalescent guinea pigs that were previously infected with EBOV-Zaire or MARV-Musoke was administered IP 1 h after challenge to the MARV (Ci67)-infected scid mice. The scid mice that were treated with MARV convalescent sera had a MTD of >23 days (Figure 9). This was greatly increased when compared to the scid mice that had been treated with sera from EBOV convalescent guinea pigs (MTD = 12 days, P value < 0.001). Additionally, 40% of scid mice receiving anti-MARV sera survived until euthanasia at >70 days post infection with scid-adapted MARV-Ci67. In the second portion of this experiment, we tested the efficacy of a combination of four anti-MARV PMOs targeting VP24, VP35, NP and L (Figure 9). Scid mice that received the combination of anti-MARV PMO molecules at 1 h postinfection with 'scid-adapted' MARV-Ci67 had a significant delay in their mean time to death of 14 days, as compared to those receiving only saline (MTD = 9 days, P value < 0.001). Because transfer of antibody [23,24] or treatment with anti-MARV PMOs [Warfield et al., unpublished data] can protect guinea pigs, we feel that the delay to death observed in this model is an important indicator of anti-viral activity of these potential MARV treatments.


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)

Use of the 'scid-adapted' MARV model to assess the efficacy of potential therapeutics for MARV. Scid mice were infected IP with ~1000 pfu of 'scid-adapted' MARV-Ci67. At 1 h postchallenge, groups of scid mice (n = 10) were treated IP with 1 ml of convalescent serum from guinea pigs that had survived MARV or EBOV challenge. Alternately, groups of mice were treated with 1 mg each of VP24, VP35, NP and L PMOs or saline alone as a vehicle control. The mice were monitored for >70 days for survival and the data are presented on a Meier-Kaplan curve as percent survival for each group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 9: Use of the 'scid-adapted' MARV model to assess the efficacy of potential therapeutics for MARV. Scid mice were infected IP with ~1000 pfu of 'scid-adapted' MARV-Ci67. At 1 h postchallenge, groups of scid mice (n = 10) were treated IP with 1 ml of convalescent serum from guinea pigs that had survived MARV or EBOV challenge. Alternately, groups of mice were treated with 1 mg each of VP24, VP35, NP and L PMOs or saline alone as a vehicle control. The mice were monitored for >70 days for survival and the data are presented on a Meier-Kaplan curve as percent survival for each group.
Mentions: To demonstrate the utility of our recently developed and characterized 'scid-adapted' MARV (Ci67, Musoke, and Ravn) in screening potential anti-MARV therapeutics, we treated scid mice that were infected with 'scid-adapted' MARV-Ci67. Since the scid mice do not have functional B or T cells and cannot mount an adaptive response to clear the virus, we only expected to see a delay in the mean time-to-death and not a survival benefit in these experiments. In the first portion of this experiment, 1 ml of pooled sera from convalescent guinea pigs that were previously infected with EBOV-Zaire or MARV-Musoke was administered IP 1 h after challenge to the MARV (Ci67)-infected scid mice. The scid mice that were treated with MARV convalescent sera had a MTD of >23 days (Figure 9). This was greatly increased when compared to the scid mice that had been treated with sera from EBOV convalescent guinea pigs (MTD = 12 days, P value < 0.001). Additionally, 40% of scid mice receiving anti-MARV sera survived until euthanasia at >70 days post infection with scid-adapted MARV-Ci67. In the second portion of this experiment, we tested the efficacy of a combination of four anti-MARV PMOs targeting VP24, VP35, NP and L (Figure 9). Scid mice that received the combination of anti-MARV PMO molecules at 1 h postinfection with 'scid-adapted' MARV-Ci67 had a significant delay in their mean time to death of 14 days, as compared to those receiving only saline (MTD = 9 days, P value < 0.001). Because transfer of antibody [23,24] or treatment with anti-MARV PMOs [Warfield et al., unpublished data] can protect guinea pigs, we feel that the delay to death observed in this model is an important indicator of anti-viral activity of these potential MARV treatments.

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