A murine oral enterovirus 71 infection model with central nervous system involvement

Abstract

Enterovirus 71 (EV71) infection causes a myriad of diseases from mild hand-foot-and-mouth disease or herpangina to fatal meningoencephalitis complicated with neurogenic pulmonary oedema. Its pathogenesis, especially the CNS involvement, is not clearly understood. The aim of this study was to set up a mouse EV71 infection model with CNS involvement. EV71 virus was administrated orally to neonatal mice. The EV71-infected mice manifested a skin rash at an early stage and hind limb paralysis or death at a later stage. Immunohistochemical staining and virus isolation demonstrated that EV71 replicated in the small intestine, induced viraemia and spread to various organs. Kinetic studies showed that EV71 antigen was first detected in the intestine at 6 h, in the thoracic spinal cord at 24 h, in the cervical spinal cord at 50 h and in the brain stem at 78 h post-infection. Leukocyte infiltration was evident in the spinal cord and brain stem. Furthermore, EV71 virus could be transmitted to littermates within the same cage.

Pathogenesis study of enterovirus 71 infection in rhesus monkeys

“…In contrast, studies in cynomolgus monkeys and mice revealed that no EV71 replication occurred in the main organs of the animals, except for the CNS. 27,29 However, it can be argued that oral infection with the strain adapted to mice was capable of inducing virus distribution in some organs, including the heart, lungs and kidneys in mice; 32 infection with the ts strain via the intravenous route in cynomolgus monkeys 27 and infection via the intracerebral, intramuscular, intraperitoneal and subcutaneous routes in mice did not yield a similar distribution of the virus. 29 Our results indicate that virus was present in some organs of the monkeys that were infected via the intravenous and intratracheal routes.…”

“…31 Subsequently, the viruses proliferate in these primary organs and directly enter the bloodstream to establish systemic viremia, which is frequently linked to pathogenesis and the further infection of target tissues, such as the CNS and the myocardium. 32,33 In particular, some previous data suggest that poliovirus is not only neuro-tropic but also lymph node tropic. 31 Although many aspects of EV71 pathogenesis are currently unclear, some preliminary human autopsy reports and well-established murine and cynomolgus monkey models have demonstrated that, in some cases, EV71 pathogenesis occurs by causing neurological lesions in the CNS.…”

“…31 Although many aspects of EV71 pathogenesis are currently unclear, some preliminary human autopsy reports and well-established murine and cynomolgus monkey models have demonstrated that, in some cases, EV71 pathogenesis occurs by causing neurological lesions in the CNS. 18,32,34 The observation of EV71-induced encephalomyelitis in human autopsies revealed that the CNS is a focal point for pathological lesions, although the data are limited. 28 Therefore, a detailed investigation of EV71 pathogenesis relies on the development of an animal model; indeed, mice and cynomolgus monkeys have already been used for this purpose.…”

“…32 Studies in mice and cynomolgus monkeys have demonstrated that adapted and mutated EV71 strains are capable of inducing neurological lesions and manifesting clinical symptoms in these two animals. 5,19 The common neuropathological changes that were observed in these studies have provided data to understand the pathogenesis of EV71 encephalomyelitis, but the exact roles of these changes in pathogenesis still need to be investigated.…”

The 3C Protein of Enterovirus 71 Inhibits Retinoid Acid-Inducible Gene I-Mediated Interferon Regulatory Factor 3 Activation and Type I Interferon Responses

“…Notably, EV71 induces skin rash at the early stage and hind limb paralysis or death at the late stage. Oral infection leads to initial replication in the intestine and subsequent spread to various organs such as the spinal cord and the brain stem (8). Intriguingly, EV71 does not facilitate the production of type I interferon (IFN), a family of cytokines involved in first-line defense against virus infection.…”