Enterovirus 71 Infection Causes Severe Pulmonary Lesions in Gerbils, Meriones unguiculatus, Which Can Be Prevented by Passive Immunization with Specific Antisera

Abstract

Neurogenic pulmonary edema caused by severe brainstem encephalitis is the leading cause of death in young children infected by Enterovirus 71 (EV71). However, no pulmonary lesions have been found in EV71-infected transgenic or non-transgenic mouse models. Development of a suitable animal model is important for studying EV71 pathogenesis and assessing effect of therapeutic approaches. We had found neurological disorders in EV71-induced young gerbils previously. Here, we report severe pulmonary lesions characterized with pulmonary congestion and hemorrhage in a gerbil model for EV71 infection. In the EV71-infected gerbils, six 21-day-old or younger gerbils presented with a sudden onset of symptoms and rapid illness progression after inoculation with 1×105.5 TCID50 of EV71 via intraperitoneal (IP) or intramuscular (IM) route. Respiratory symptoms were observed along with interstitial pneumonia, pulmonary congestion and extensive lung hemorrhage could be detected in the lung tissues by histopathological examination. EV71 viral titer was found to be peak at late stages of infection. EV71-induced pulmonary lesions, together with severe neurological disorders were also observed in gerbils, accurately mimicking the disease process in EV71-infected patients. Passive transfer with immune sera from EV71 infected adult gerbils with a neutralizing antibody (GMT=89) prevented severe pulmonary lesion formation after lethal EV71 challenge. These results establish this gerbil model as a useful platform for studying the pathogenesis of EV71-induced pulmonary lesions, immunotherapy and antiviral drugs.

Mast cells contribute to Enterovirus 71 infection-induced pulmonary edema in neonatal mice

“…In our study, we found increased lung mass, L m , EG-VEGF and NA in lung lysates, mucus production and erythrocytefilled fluid in the alveolar spaces of mice lungs after infection. These features were similar to previous reports involving EV71 infection-induced pulmonary edema in vivo and human fatal cases [29,31,32]. Interestingly, inflammatory cytokines such as eotaxin-1, eotaxin-2, ICAM-1, IL-7, IL-13 and IL-17 were clearly elevated in lung lysates after EV71 infection, while G-CSF, IFN-γ and IL-10 were drastically decreased.…”

“…In the present study, we found that MCs number in brain, lung and skeletal muscle posed a positive correlation with the severity of symptoms-induced by EV71 infection, especially for lung disorders. Severe mice with pulmonary edema exhibited higher viral titters in lung tissue, which was also found in previous study [32]. The release of histamine and other vasoactive mediators from mast cell can increase vascular permeability and local blood flow, and act on smooth muscle to increase the expulsion of mucosal parasites [9,10,13].…”

Coxsackievirus A16 induced neurological disorders in young gerbils which could serve as a new animal model for vaccine evaluation

“…S1 ). Compared with IP administration, gerbils were less sensitive to infection via the OL route, which was also found in the EV71-infected gerbil model in our previous work 27 . The IP route might therefore be a better choice than the OL route for CA16 inoculation of gerbils.…”

Innate Immunity and Immune Evasion by Enterovirus 71

“…In experimental models, EV71 infected gerbils displayed pulmonary lesions characterized with interstitial pneumonia, pulmonary congestion and excessive lung haemorrhage along with neurologic symptoms [ 13 ]. Rhesus monkeys infected with EV71 demonstrated substantial inflammation in lungs.…”