Pathogenicity of Lloviu and Bombali Viruses in Type I Interferon Receptor Knockout Mice

Abstract

Type I interferon receptor knockout (IFNAR-/-) mice are not able to generate a complete innate immune response; therefore, these mice are often considered to assess the pathogenicity of emerging viruses. We infected IFNAR-/- mice with a low or high dose of Lloviu virus (LLOV) or Bombali virus (BOMV) by the intranasal (IN) or intraperitoneal (IP) route and compared virus loads at early and late time points after infection. No signs of disease and no viral RNA were detected after IN infection regardless of LLOV dose. In contrast, IP infections resulted in increased viral loads in the high-dose LLOV and BOMV groups at the early time point. The low-dose LLOV and BOMV groups achieved higher viral loads at the late time point. However, there was 100% survival in all groups and no signs of disease. In conclusion, our results indicate a limited value of the IFNAR-/- mouse model for investigation of the pathogenicity of LLOV and BOMV.

Keywords: Cuevavirus; Ebolavirus; emerging filovirus; intranasal infection; intraperitoneal infection.

Figure 1.

Intranasal LLOV infection. IFNAR^−/− mice (n = 10) were infected intranasally with either 100 (low-dose) or 100 000 (high-dose) TCID₅₀ of LLOV, RESTV, or EBOV. At 7 days postinfection, 4 mice in each group were euthanized for sample analysis. A, Viral RNA in blood, lung, liver, and spleen. Geometric mean and standard deviation are depicted. B, Body weight changes over time. C, LLOV GP-specific IgG in serum at study end (day 28). B, C Mean and standard error of the mean are depicted. Statistical significance is indicated as ****P < .0001. Abbreviations: EBOV, Ebola virus; GP, glycoprotein; IFNAR^−/−, type I interferon receptor knockout; IgG, immunoglobulin G; LLOV, Lloviu virus; RESTV, Reston virus; TCID₅₀, 50% tissue culture infectious dose; wt, wild type.

Figure 2.

Intraperitoneal infections of emerging filoviruses. IFNAR^−/− mice were infected intraperitoneally with either 100 (low-dose) TCID₅₀ EBOV, rgLLOV, wtLLOV, or BOMV, or 100 000 (high-dose) TCID₅₀ of rgLLOV, wtLLOV, BOMV, or RESTV. At 3 or 6 days postinfection, 4 mice in each group were euthanized for sample analysis. A and D, Viral RNA in blood, liver, and spleen. B and E, Body weight changes over time. C, LLOV GP-specific or (F) BOMV GP-specific IgG in serum at study end (day 28). A, C, D, F Geometric mean and geometric standard deviation are depicted. B, E Mean and standard error of the mean are depicted. Statistical significance indicated as ****P < .0001. Abbreviations: BOMV, Bombali virus; EBOV, Ebola virus; FFU, focus-forming unit; GP, glycoprotein; IFNAR^−/−,type I interferon receptor knockout; IgG, immunoglobulin G; RESTV, Reston virus; rgLLOV, reverse genetics Lloviu virus; TCID₅₀, 50% tissue culture infectious dose; wtLLOV, wild-type Lloviu virus.