Immunocompetent hamsters as a model for orthobunyavirus-induced neuroinvasion and neuropathology

Abstract

Bunyavirus infections, including those caused by Bunyamwera serogroup orthobunyaviruses, represent a significant and yet likely still vastly underappreciated cause of mild to moderate human febrile infections. In severe cases, these infections can also cause neurological disease, particularly meningitis and encephalitis, and infection can even be fatal. However, with a few exceptions, information regarding the mechanisms underlying the neuroinvasion and neuropathogenesis of such infections is limited. This is due in part to a lack of animal models to facilitate such studies. In an effort to develop an immunocompetent model of infection with Bunyamwera serogroup orthobunyaviruses, we infected 4-6-week-old female hamsters via either the intraperitoneal or subcutaneous route with 10⁶ pfu/animal of Bunyamwera virus (BUNV), Batai virus or Ngari virus. Only BUNV infection resulted in clinical disease, which was characterized by weight loss, lethargy and neurological signs (i.e. tremor of the head or limbs, loss of righting reflex, “waltzing”). While symptoms were of similar severity for both routes, they occurred more frequently following subcutaneous inoculation. Consistent with these clinical signs, both antigen staining and histopathological abnormalities were found extensively throughout the brain. The reported hamster model of BUNV infection provides a new tool for studying orthobunyavirus infection, and particularly neuroinvasion and the development of neuropathology. This model is particularly significant because it makes use of immunologically competent animals and relies on a subcutaneous inoculation route that more closely mimics the natural infection route for arboviruses, thereby providing a more authentic cellular and immunological context at the initial site of infection. Bunyaviruses cause a significant number of human infections, and while most are relatively benign, in severe cases encephalitis and/or meningitis can develop. Little is known about the biological processes that allow bunyaviruses to enter the brain, and why this results in neuropathology in some cases. Available models are frequently based on direct intracranial infection in animals with impaired or underdeveloped immune systems. Here we have infected subadult hamsters via either the intraperitoneal or the subcutaneous route with one of three different bunyaviruses: Bunyamwera virus (BUNV), Batai virus or Ngari virus. Only BUNV infection resulted in clinical disease, with infected animals exhibiting weight loss, lethargy and neurological signs of disease. Consistent with these observations pathological abnormalities and viral antigen were found extensively throughout the brain. The establishment of this new model is significant because it makes use of immunologically competent animals and relies on an inoculation route that more closely mimics the natural route of infection through insect bites. As such, it provides an important basis for studying neuroinvasion and the development of neuropathology during bunyavirus infection as well as for the testing of antiviral approaches targeting these viruses.