Abstract
Rabbit Hemorrhagic disease virus (RHDV), a calicivirus of the Lagovirus genus, and responsible for rabbit hemorrhagic disease (RHD), kills rabbits between 48 to 72 hours post infection with mortality rates as high as 50–90%. Caliciviruses, including noroviruses and RHDV, have been shown to bind histo-blood group antigens (HBGA) and human non-secretor individuals lacking ABH antigens in epithelia have been found to be resistant to norovirus infection. RHDV virus-like particles have previously been shown to bind the H type 2 and A antigens. In this study we present a comprehensive assessment of the strain-specific binding patterns of different RHDV isolates to HBGAs. We characterized the HBGA expression in the duodenum of wild and domestic rabbits by mass spectrometry and relative quantification of A, B and H type 2 expression. A detailed binding analysis of a range of RHDV strains, to synthetic sugars and human red blood cells, as well as to rabbit duodenum, a likely gastrointestinal site for viral entrance was performed. Enzymatic cleavage of HBGA epitopes confirmed binding specificity. Binding was observed to blood group B, A and H type 2 epitopes in a strain-dependent manner with slight differences in specificity for A, B or H epitopes allowing RHDV strains to preferentially recognize different subgroups of animals. Strains related to the earliest described RHDV outbreak were not able to bind A, whereas all other genotypes have acquired A binding. In an experimental infection study, rabbits lacking the correct HBGA ligands were resistant to lethal RHDV infection at low challenge doses. Similarly, survivors of outbreaks in wild populations showed increased frequency of weak binding phenotypes, indicating selection for host resistance depending on the strain circulating in the population. HBGAs thus act as attachment factors facilitating infection, while their polymorphism of expression could contribute to generate genetic resistance to RHDV at the population level.
Highlights
Rabbit hemorrhagic disease virus (RHDV), a single stranded positive-sense RNA virus belonging to the Lagovirus genus of the Caliciviridae family, is the cause of rabbit hemorrhagic disease (RHD), a disease affecting wild and domestic rabbits of the Oryctolagus cuniculus species
RHDV binds to histo-blood group antigens (HBGA) and in this report we characterize binding of strains of all genetic groups of RHDV to different HBGAs
We demonstrate HBGAs to function as attachment factors in a challenge experiment
Summary
Rabbit hemorrhagic disease virus (RHDV), a single stranded positive-sense RNA virus belonging to the Lagovirus genus of the Caliciviridae family, is the cause of rabbit hemorrhagic disease (RHD), a disease affecting wild and domestic rabbits of the Oryctolagus cuniculus species. RHD was first described in Angora rabbits in China in 1984. RHDV usually kills rabbits within 48 to 72 hours of infection. There are three different clinical courses of RHD, the peracute form is distinguished by sudden death with no previous clinical signs. The acute form of RHD involves depression, anorexia, apathy, rapid respiration, anemia and some animals show signs of abdominal distress. Animals perish after one to three days. The sub acute form involves slight clinical symptoms and the animals recover within 2–3 days [2,3]. Kittens can become infected and shed virus but do not show clinical signs of the disease. The most common routes of infection are the oral and upper respiratory routes, mainly through direct
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