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

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 mouseadapted 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 MARVCi67, -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.

Disease modeling for Ebola and Marburg viruses

“…Filovirus infection is also lethal for adult immunodeficient mice such as the severe combined immunodeficient (SCID) mouse, which lacks functional B-and T-cell responses (Table 2). Unlike humans or other animal models, SCID mice remain healthy for several weeks, then develop gradual, progressive weight loss and slowing of activity, and then die 20-25 or 50-70 days after ZEBOV or MARV challenge, respectively (Bray, 2001;Warfield et al, 2007). Mice lacking a complete type I IFN response (innate immune response), such as knockout mice that do not express STAT or the IFN receptor α/β, uniformly die within a week of subcutaneous challenge with a variety of filovirus strains (Bray, 2001) (Table 2).…”

“…A recent report has described a SCID mouse model, which uses liver homogenates from MARV-infected SCID mice that have been serially passaged ten times, that reduces the time to death from between 50-70 days to 7-10 days (Warfield et al, 2007). At 3-4 days post-inoculation, infected mice showed weight loss, a hunched appearance and exhibited decreased grooming; some mice appeared to have hemorrhages and some developed hind-leg paralysis.…”

“…After infection, profound thrombocytopenia, as well as notable alterations in serum chemistry levels (especially liver enzymes), occurred with progressively increasing severity (Warfield et al, 2007).…”

Aerosol Exposure to the Angola Strain of Marburg Virus Causes Lethal Viral Hemorrhagic Fever in Cynomolgus Macaques

“…These models have been described in several primary and review articles. 6,9,12,19,23,28,34,35,71,72,[88][89][90] The features of disease in these models depend on a variety of factors, including virus strain, dose and route of administration, and the age, species, and strain of animal involved. Whereas NHPs are often susceptible to lethal infection by wild-type strains of EBOV and MARV, immunocompetent adult mice and guinea pigs are not; they are susceptible to some attenuated strains, however.…”

Stimulation of Ebola virus production from persistent infection through activation of the Ras/MAPK pathway

“…Although this would have implications for transmission through the close approximation of infected rodent/shrew species to human populations, as has been reported for Lassa virus (13), because of the close affiliation of these rodents to human populations and the sporadic nature of human outbreaks, it is unlikely that these species are involved in the transmission of EBOV to humans. Rodent species have been used as model systems for studying filovirus pathogenesis; nonetheless, these species do not exhibit lethality after wildtype infection, but require adaptation through serial passage (14)(15)(16)(17)(18). Through such studies, many details of the pathogenesis have been deciphered, including the type I interferon (IFN) response, which plays a key role in the resistance of normal mice to mouseadapted Zaire ebolavirus (MA-ZEBOV) (15,19).…”