DNA Vaccination against La Crosse Virus

Abstract

For the development of effective conventional vaccines or DNA vaccines against viruses, the availability of suitable animal models is an essential prerequisite. For many recently emerging zoonotic viruses, suitable animal models are still missing. We have established a novel small animal model for DNA vaccines using mice lacking a functional interferon-α/β receptor (IFNAR-1). IFNAR-1-deficient mice are highly susceptible to many different viruses despite their ability to mount a normal humoral and cellular immune response. Taking advantage of this animal model, we show that mice can be completely protected from lethal challenge with a single injection of plasmid DNA encoding the viral envelope proteins G1 and G2. By contrast, vaccination with a plasmid encoding the internal nucleocapsid protein N had little effect. In an effort to enhance the protective immune response to N we assessed the efficacy of vaccination with plasmid DNA encoding N in combination with a plasmid encoding the cytokine IL-12 as adjuvant. IL-12 enhanced the survival of mice following viral challenge, but the effect was independent of N indicating the involvement of components of the innate immune system such as NK cells.

Age-Dependent Myeloid Dendritic Cell Responses Mediate Resistance to La Crosse Virus-Induced Neurological Disease

“…In previous studies, deficiency in Ifnar1 increased susceptibility to LACV in adult mice (10). Similarly, infection of Irf3…”

“…Infected weanling mice develop neurological disease with high CNS viral titers (8,9). In contrast, adult mice do not generally show signs of neurological disease and have minimal titers of virus in the CNS (9)(10)(11). However, adult mice develop neurological disease when LACV is administered intracerebrally (i.c.…”

“…Adult Ifnar1 Ϫ/Ϫ mice are susceptible to LACV-induced neurological disease, indicating that type I IFN responses are necessary for resistance (10). However, whether type I IFN responses are deficient in young mice and whether these IFN responses are responsible for age-related differences in susceptibility have not been determined.…”

The CARD9-Associated C-Type Lectin, Mincle, Recognizes La Crosse Virus (LACV) but Plays a Limited Role in Early Antiviral Responses against LACV

“…Type-I interferon responses in mice were shown to be crucial for LACV clearance and reduction of LACV-induced neurological diseases [14,47,48]. In the LACV stimulation experiments using Mincle −/− , CARD9 −/− , and WT DCs, a decreased type-I interferon-β (IFN-β) production could be detected only in CARD9 −/− DCs by luminescence IFN-β ELISA (Figure S3).…”

Vaccines and animal models for arboviral encephalitides

“…Because LACV infects and causes encephalitis only in newborn mice and mice become resistant to infection as adults, there is a need to develop new animal models to test potential vaccines and antiviral drugs. Recently, there have been attempts to develop a DNA vaccine against LACV by using interferon type I (IFNAR-1) knockout mice (Schuh et al, 1999;Pavlovic et al, 2000). Previous studies showed that IFNAR-1 knockout mice are highly susceptible to infections with LACV and develop encephalitis regardless of their age (Muller et al, 1994;Hefti et al, 1999).…”