Enterovirus 71 (EV71) is an important pathogen causing death in children under 5 years old worldwide. However, the underlying pathogenesis remains unclear. This study reveals that EV71 infection in rhabdomyosarcoma (RD) and neuroblastoma (SK-N-SH) cells stimulated the autophagic process, which was demonstrated by an increase of punctate GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3), the level of autophagosome-bound LC3-II protein and double-membrane autophagosome formation. EV71-induced autophagy benefited EV71 replication, which was confirmed by the autophagic inducer rapamycin and the inhibitor 3-methyladenine. Signaling pathway investigation revealed that the decreased expression of phosphorylated mTOR and phosphorylated p70S6K is involved in EV71-induced autophagy in a cell-specific manner. The expression of phosphorylated extracellular signal-regulated kinase (Erk) was suppressed consistently in EV71-infected cells. However it did not participate in the autophagic response of the cell. Other signaling pathway molecules, such as Erk, PI3K/Akt, Bcl-2, BNIP3, and Beclin-1 were not affected by infection with EV71. Electron microscopy showed co-localization of autophagosome-like vesicles with either EV71-VP1 or LC3 protein in neurons of the cervical spinal cord in ICR mice infected with EV71. In conclusion, EV71 infection triggered autophagic flux and induced autophagosome formation both in vitro and in vivo. Autophagy induced by EV71 is beneficial for viral replication. Understanding the role of autophagy induced by EV71 in vitro and the formation of autophagosome-like vesicle in vivo provide new insights into the pathogenesis of EV71 infection.
ABSTRACT. Background. The pathogenesis of acute pulmonary edema and cardiac collapse after enterovirus 71 (EV71) infection are not completely understood.Objective. To determine the hemodynamic features and the mechanism of pulmonary edema (PE) after EV71 infection by direct intracardiac monitoring.Design. Prospective clinical and laboratory study at a tertiary medical center.Participants. Five consecutive infants, ages 2 to 13 months, with EV71 infection-proved by viral isolation in 4 and antibody in 1-with PE were enrolled. The clinical characteristics were systemically assessed. Hemodynamic profiles were determined every 4 hours by simultaneously implanted pulmonary arterial and central venous catheters during the acute stage.Results. Magnetic resonance imaging revealed that all 5 infants had brainstem lesions. All patients had tachycardia and hyperthermia. Transient systolic hypertension was noted in 1 patient, and 1 presented with hypotension. Pulmonary artery pressure in all 5 infants was normal or mildly elevated (26 -31 mm Hg), and central venous pressure ranged from 10 to 22 mm Hg. Pulmonary artery occlusion pressures were normal or slightly elevated (13-16 mm Hg). Systemic and pulmonary vascular resistances were transiently increased in only 1 patient. The stroke volume index decreased to 15.3 to 35.7 mL/M 2 (normal: 30 -60 mL/M 2 ), but because of the elevated heart rate, the cardiac index did not decrease. All hemodynamics normalized within days.Conclusion. Fulminant EV71 infection may lead to severe neurologic complications and acute PE. The acute PE and cardiopulmonary decompensation in EV71 infection are not directly caused by viral myocarditis. The mechanism of PE may be related to increased pulmonary vascular permeability caused by brainstem lesions and/or systemic inflammatory response instead of increased pulmonary capillary hydrostatic pressure. Pediatrics 2002;109(2). URL: http://www.pediatrics.org/ cgi/content/full/109/2/e26; enterovirus 71, pulmonary edema, pathogenesis, hemodynamics, hand-foot-mouth disease.
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