Lethality and pathogenesis of airborne infection with filoviruses in A129 α/β −/− interferon receptor-deficient mice

Abstract

Normal immunocompetent mice are not susceptible to non-adapted filoviruses. There are therefore two strategies available to establish a murine model of filovirus infection: adaptation of the virus to the host or the use of genetically modified mice that are susceptible to the virus. A number of knockout (KO) strains of mice with defects in either their adaptive or innate immunity are susceptible to non-adapted filoviruses. In this study, A129 α/β -/- interferon receptor-deficient KO mice, strain A129 IFN-α/β -/-, were used to determine the lethality of a range of filoviruses, including Lake Victoria marburgvirus (MARV), Zaire ebolavirus (ZEBOV), Sudan ebolavirus (SEBOV), Reston ebolavirus (REBOV) and Côte d'Ivoire ebolavirus (CIEBOV), administered by using intraperitoneal (IP) or aerosol routes of infection. One hundred percent mortality was observed in all groups of KO mice that were administered with a range of challenge doses of MARV and ZEBOV by either IP or aerosol routes. Mean time to death for both routes was dose-dependent and ranged from 5.4 to 7.4 days in the IP injection challenge, and from 10.2 to 13 days in the aerosol challenge. The lethal dose (50 % tissue culture infective dose, TCID(50)) of ZEBOV for KO mice was <1 TCID(50) ml(-1) when administered by either the IP or aerosol route of infection; for MARV the lethal dose was <1 TCID(50) ml(-1) by the IP route of infection and <10 TCID(50) ml(-1) by the aerosol route. In contrast, there was no mortality after infection with SEBOV or REBOV by either IP or aerosol routes of infection; all the mice lost weight (~15 % loss of group mean body weight with SEBOV and ~7 % with REBOV) but recovered to their original weights by day 14 post-challenge. There was no mortality in mice administered with CIEBOV via the IP route of infection and no clinical signs of infection were observed. The progression of disease was faster following infection with ZEBOV than with MARV but ultimately both viruses caused widespread infection with high titres of the infectious viruses in multiple organs. Histopathological observations were consistent with other animal models and showed widespread organ damage. This study suggests that MARV and ZEBOV are more virulent when administered via the IP route rather than by aerosol infection, although both are highly virulent by either route. The KO mouse may provide a useful model to test potential antiviral therapeutics against wild-type filoviruses.

Cytokines and Viral Hemorrhagic Fever: Potential for Therapeutic Intervention

“…This is in sharp contrast to the rapid onset acute disease seen in IFN-knockout mice inoculated with Ebola virus or immune-competent mice inoculated with mouse-adapted Ebola or mouse-adapted Marburg viruses [9,11,31]. There are no published analyses that examine the levels of pro-inflammatory cytokines in severe combined immunodeficiency mice infected with wild-type Ebola or Marburg viruses; however such analyses have the potential to be highly informative with respect to the possible relationship between cytokine storm and hemorrhagic phenotype.…”

“…Therefore some VHF mouse models have been developed using immunocompromized strains. For example, IFN knockout mice have been used to model Ebola, Marburg, CCHF, Dengue and Junin infections, mimicking the disease seen in humans with varying degrees of success [7][8][9][10]. Another approach has been to use adapted viruses.…”

Antibody-dependent-cellular-cytotoxicity-inducing antibodies significantly affect the post-exposure treatment of Ebola virus infection

“…Until now, many candidate vaccines, neutralizing antibodies, and other antiviral agents specific to the GP protein have been assessed with mouse infection models using a lethal EBOV mouse-adapted virus2627. Interestingly, inbred laboratory mice were resistant to infection with non-adapted EBOV28, but are permissive to infection with the GP-pseudotyped virus, which suggests that EBOV infection in rodents is not blocked at the step at which the virus binds to its receptor or at the membrane fusion step. GP-pseudotyped HIV has also clarified the role of GP in EBOV pathogenesis.…”

Evaluation of the Operator Protection Factors Offered by Positive Pressure Air Suits against Airborne Microbiological Challenge

“…Published aerosol infective doses for Ebola virus in rhesus monkeys are as low as 400 plaque-forming units (pfu) [4,5] and Marburg virus has been shown to be lethal by the aerosol route in rhesus monkeys [6], grivets [7], and has an aerosol infective dose of less than 10 tissue culture infective doses (TCID 50 ) in marmosets (manuscript submitted) and mice [8]. It was shown that 1 pfu was approximately equivalent to 25–30 virions [9].…”