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.
Highlights
Enterovirus 71 (EV71), a member of the genus Enterovirus within the family Picornavirus, affects mostly infants and young children [1,2,3]
In order to examine the susceptibility of gerbils at different ages to EV71 infection, three groups of gerbils at the age of 7, 14 and 21 days were IP inoculated with 1×105.5 TCID50 of EV71 (n = 6 for each age groups)
There was no mortality in the 35-day-old group with only two gerbils presenting with hind limb paralysis (Fig. 1A, S1–S5 Tables). These data demonstrated that gerbils aged 7–21 days were most sensitive to the EV71 infection
Summary
Enterovirus 71 (EV71), a member of the genus Enterovirus within the family Picornavirus, affects mostly infants and young children [1,2,3]. EV71 infection usually leads to hand, foot, and mouth disease (HFMD) and sometimes causes severe neurological manifestations including aseptic meningitis, encephalitis, acute flaccid paralysis, and pulmonary edema, with the percentage of pulmonary edema or hemorrhage considerably high in the fatal cases [4,5]. In 2010 alone, at least 1.7 million HFMD cases were reported with 905 deaths [7]. Between 2008 and 2012, there were 7.2 million probable HFMD cases and a potential 2,457 EV71-related deaths reported to Chinese Center for Disease Control and Prevention [8]. The 1998 Taiwanese outbreak resulted in 65 HFMD deaths of EV71-infected children, mainly due to pulmonary edema or hemorrhage[4]. EV71 was confirmed as the major pathogen in the 2008 Chinese outbreak that resulted in 4.89 million HFMD cases and 126 deaths [10]
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