A clinically authentic mouse model of enterovirus 71 (EV-A71)-induced neurogenic pulmonary oedema

Abstract

Enterovirus 71 (EV-A71) is a neurotropic virus that sporadically causes fatal neurologic illness among infected children. Animal models of EV-A71 infection exist, but they do not recapitulate in animals the spectrum of disease and pathology observed in fatal human cases. Specifically, neurogenic pulmonary oedema (NPE)—the main cause of EV-A71 infection-related mortality—is not observed in any of these models. This limits their utility in understanding viral pathogenesis of neurologic infections. We report the development of a mouse model of EV-A71 infection displaying NPE in severely affected animals. We inoculated one-week-old BALB/c mice with an adapted EV-A71 strain and identified clinical signs consistent with observations in human cases and other animal models. We also observed respiratory distress in some mice. At necropsy, we found their lungs to be heavier and incompletely collapsed compared to other mice. Serum levels of catecholamines and histopathology of lung and brain tissues of these mice strongly indicated onset of NPE. The localization of virally-induced brain lesions also suggested a potential pathogenic mechanism for EV-A71-induced NPE. This novel mouse model of virally-induced NPE represents a valuable resource for studying viral mechanisms of neuro-pathogenesis and pre-clinical testing of potential therapeutics and prophylactics against EV-A71-related neurologic complications.

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.…”

“…Pulmonary edema is mainly responsible for fatal HFMD [3,4], which could be defined as an extra-vascular increasing fluid in the lungs [27]. L m , EG-VEGF and NA are known as the indicators of pulmonary edema [28][29][30]. 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.…”

Pulmonary edema following central nervous system lesions induced by a non- mouse-adapted EV71 strain in neonatal BALB/c mice

“…Animal experiments have indicated that 3-day-old BALB/c mice is high susceptible to ZZ1350 and exhibit a various repertoire of clinical symptoms [ 5 ] ranging from skin lesions to paralysis, ataxia, tremors, acute encephalomyelitis and even respiratory disorders under intracerebral, intramuscular, intraperitoneal inoculation. Unlike other animal models [ 9 , 18 , 19 ], ZZ1350 was directly used to infect neonatal mice without pre-acclimated to mouse or mouse cell lines, making it more clinically relevant. Pathological changes were found in skeletal muscle, heart, skin, spleen and small intestine from infected mice.…”

“…These results suggested ZZ1350 infection led to pulmonary edema with different degrees. Previous publications also reported pulmonary edema model in neonatal mice via intraperitoneal inoculation using mouse adapted strains [ 19 , 21 ]. Hence, the occurrence of pulmonary edema after infection has nothing to do with inoculation routes.…”

“…Hence, the occurrence of pulmonary edema after infection has nothing to do with inoculation routes. Large numbers of publications from animal experiments or clinical monitor indicated that the occurrence of pulmonary edema was of neurogenic origin due to CNS injury [ 19 , 33 , 34 ]. A controversial conclusion was reported that EV71 primarily replicated in skeletal muscle tissues, causing severe necrotizing myositis of respiratory-related muscles that further resulted in severe restrictive hypoventilation and subsequent hypoxia, which may explain the fatality of EV71-infected mice [ 35 ].…”