EV71 infection inhibits PI3K/AKT/mTOR pathway and induces autophagy through TLR2 signaling to participate in lung injury

Enterovirus 71 (EV71) is one of the main pathogens causing hand, foot and mouth disease (HFMD), which mainly infects children under 5 years old. Severe infection can be complicated by severe lung injury, nervous system injury and multiple organ failure. Methods: A neonatal mouse model of EV71 infection was established and treated with TLR2 specific inhibitor C29. Body weight changes and clinical disease scores were recorded. HE staining was used to observe the pathological changes of lung tissue; Western blot was used to detect the protein levels of viral protein (VP1), key molecules of TLR2 pathway (TLR2, MYD88), PI3K/AKT/mTOR pathway and their phosphorylation, and autophagy markers (p62, LC3B, Beclin-1); Immunofluorescence was used to observe the localization of key proteins in lung tissue. Results: After EV71 infection, Suckling BALB/c mice showed significant weight loss, lethargy, hind limb weakness, arched back, and thinning hair. Lung tissue showed obvious pathological damage, manifested as obvious alveolar wall thickening, structural destruction, septal edema, etc. Compared with the normal control group, the expression of viral capsid proteins VP1, TLR2 and MYD88 in lung tissues of neonatal mice infected with EV71 was significantly increased. At the same time, the phosphorylation levels of PI3K/AKT/mTOR pathway (p-PI3K, p-AKT, p-mTOR) were significantly decreased, the levels of autophagy markers LC3B-II and Beclin-1 were increased, and the level of p62 was decreased. These results suggest that EV71 infection can inhibit the PI3K/AKT/mTOR pathway by activating TLR2 signaling, accompanied by the enhancement of autophagy-related processes. After C29 intervention, the expression of VP1, TLR2 and MYD88 was down-regulated, the levels of p-PI3K, p-AKT, p-mTOR and p62 were increased, and the levels of LC3B-II and Beclin-1 were decreased. At the same time, the pathological damage of lung tissue, disease score and weight loss were significantly improved. Conclusions: EV71 infection can inhibit the PI3K/AKT/mTOR pathway and induce autophagy-related processes through TLR2 signaling to participate in lung tissue injury in neonatal mice.