Enteroviruses (EVs) are common RNA viruses that can cause various types of human diseases and conditions such as hand, foot, and mouth disease (HFMD), myocarditis, meningitis, sepsis, and respiratory disorders. Although EV infections in most patients are generally mild and self-limiting, a small number of young children can develop serious complications such as encephalitis, acute flaccid paralysis, myocarditis, and cardiorespiratory failure, resulting in fatalities. Established evidence has suggested that certain non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs) are involved in the occurrence and progression of many human diseases. Recently, the involvement of ncRNAs in the course of EV infection has been reported. Herein, the authors focus on recent advances in the understanding of ncRNAs in EV infection from basic viral pathogenesis to clinical prospects, providing a reference basis and new ideas for disease prevention and research directions.

Enterovirus A71 (EV-A71) is a common small RNA virus that is highly neuroinvasive. Emerging evidence indicates that the complement fragment C5a and its receptor C5aR1 are important drivers of neuroinflammation. However, the potential role of the C5a–C5aR1 axis in EV-A71 encephalitis remains largely elusive. Our previous studies revealed that EV-A71 can infect astrocytes and result in complement activation in vivo . Here, we investigated how complement factors interact with astrocytes to promote a severe inflammatory response upon EV-A71 infection. Our data revealed that EV-A71 infected mainly astrocytes and caused astrocyte activation in the mouse brain, which was further verified in patients with EV-A71 infection and U87-MG cells. Notably, EV-A71 infection led to activation of the C5a–C5aR1 axis in U87-MG cells, and knockdown (siC5aR1) or blockade (PMX53) of C5aR1 significantly suppressed EV-A71-induced astrocyte activation and proinflammatory cytokine (e.g., CXCL1) production. Next, the activation of the C5a–C5aR1 axis in mouse astrocytes was confirmed. Compared with C5aR1 knockout mice, wild-type mice presented more severe symptoms and lower survival rates after EV-A71 infection. C5aR1 deficiency or blockade significantly reduced EV-A71-induced pathological damage and proinflammatory cytokine production in the mouse brain. Importantly, an increased level of soluble C5a was strongly correlated with the severity of symptoms in patients with EV-A71 infection. By using confocal microscopy, primary astrocytes, and human specimens, we observed that the increase in CXCL1 levels resulted mainly from astrocytes. Neutralizing CXCL1 significantly alleviated the neuropathological changes caused by EV-A71 infection, and the production of CXCL1 in astrocytes was regulated by p38 MAPK signaling. Taken together, our findings indicate that the activation of the C5a–C5aR1 axis in astrocytes facilitates the neuropathological changes resulting from EV-A71 infection, emphasizing the potential role of p38 MAPK-mediated CXCL1 production in these alterations. IMPORTANCE: Enterovirus A71 (EV-A71) is a common small RNA virus with highly neuroinvasive tendencies. Our previous studies took the view that EV-A71 could infect astrocytes and result in complement activation in vivo . We investigated how complement interacts with astrocytes to promote a severe inflammatory response upon EV-A71 infection in the study. As expected, our data demonstrate that EV-A71 triggers robust activation of the C5a–C5aR1 axis in astrocytes and that knockout or blockade of C5aR1 in animals exposed to lethal doses of EV-A71 significantly enhances survival by diminishing the production of the chemokines CXCL1 and IL-6. In addition, neutralizing CXCL1 significantly alleviates the neuropathogenesis caused by EV-A71 infection. Thus, inhibiting the C5a–C5aR1 axis has emerged as a potential therapeutic strategy to mitigate neural damage caused by EV-A71 infection.

Coxsackievirus A2 (CVA2) has emerged as an active pathogen that has been implicated in hand, foot, and mouth disease (HFMD) and herpangina outbreaks worldwide. It has been reported that severe cases with CVA2 infection develop into heart injury, which may be one of the causes of death. However, the mechanisms of CVA2-induced heart injury have not been well understood. In this study, we used a neonatal mouse model of CVA2 to investigate the possible mechanisms of heart injury. We detected CVA2 replication and apoptosis in heart tissues from infected mice. The activity of total aspartate transaminase (AST) and lactate dehydrogenase (LDH) was notably increased in heart tissues from infected mice. CVA2 infection also led to the disruption of cell-matrix interactions in heart tissues, including the increases of matrix metalloproteinase (MMP)3, MMP8, MMP9, connective tissue growth factor (CTGF) and tissue inhibitors of metalloproteinases (TIMP)4. Infiltrating leukocytes (CD45⁺ and CD11b⁺ cells) were observed in heart tissues of infected mice. Correspondingly, the expression levels of inflammatory cytokines in tissue lysates of hearts, including tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), IL6 and monocyte chemoattractant protein-1 (MCP-1) were significantly elevated in CVA2 infected mice. Inflammatory signal pathways in heart tissues, including phosphatidylinositol 3-kinase (PI3K)-AKT, mitogen-activated protein kinases (MAPK) and nuclear factor kappa B (NF-κB), were also activated after infection. In summary, CVA2 infection leads to heart injury in a neonatal mouse model, which might be related to viral replication, increased expression levels of MMP-related enzymes and excessive inflammatory responses.

Fine particulate matter (PM_2.5) and ozone (O₃) are key air pollutants linked to a higher risk of cardiovascular diseases. However, the effects of combined PM_2.5 and O₃ exposure on cardiovascular health remain unclear. In this study, C57BL/6 J mice were exposed to PM_2.5 suspension (6 mg/kg body weight) and/or O₃ (1.00 ppm) for 8 weeks, resulting in abnormal myocardial enzyme profiles. Sirius Red and Masson's trichrome staining confirmed myocardial fibrosis and collagen deposition in the mice. Further experiments demonstrated that PM_2.5 and O₃ subchronic co-exposure increased cardiac inflammatory factors, phosphorylation of p38, ERK1/2, and JNK, as well as cardiomyocyte apoptosis. Subsequently, an atherosclerosis model was established using ApoE-/- mice, which were exposed to PM_2.5 suspension (6 mg/kg b.w.) and O₃ (1.00 ppm) for 8 consecutive weeks. During this period, the mice were treated with quercetin, a flavonoid antioxidant derived from plants. Our findings demonstrated that PM_2.5 and O₃ co-exposure promoted the progression of atherosclerosis. In contrast, administration of quercetin in PM_2.5- and O₃-exposed ApoE-/- mice significantly reduced cardiac enzyme markers, myocardial fibrosis, collagen deposition, cardiomyocyte apoptosis, and activation of the MAPK signaling pathway. Omics results revealed that quercetin primarily exerted its protective effects in atherosclerotic mice by modulating phosphatidylcholine, phosphatidylethanolamine, as well as the inflammatory signaling pathways. In summary, subchronic exposure to PM_2.5 and O₃ contributes to cardiac injury and accelerates the progression of atherosclerosis in mice and this detrimental effect can be mitigated by the administration of quercetin. Our study presents novel strategies aimed at mitigating the cardiovascular health impacts of air pollution.

Severe hand, foot, and mouth disease (HFMD) poses a risk of serious multi-organ complications in children. While renal dysfunction has been observed in some cases, detailed investigations on kidney injury and molecular mechanisms remain limited. Coxsackievirus A6 (CVA6) has emerged as a major pathogen responsible for HFMD. To reveal the underlying pathways of CVA6-associated renal injury, we enrolled 90 children diagnosed with CVA6 infection and 45 healthy children. The levels of uric acid (UA), creatinine (CREA) and UREA in the serum were measured. We found that serum levels of UA, CREA, and UREA were significantly elevated in CVA6-infected children compared to healthy children. Subsequently, a previously established mouse model of CVA6 infection was used to assess urinary retention, kidney inflammation, and histopathological changes. Consistent with the clinical findings, infected mice exhibited increased CREA, UREA, and UA levels, urinary retention, and renal inflammation. Electron microscopy revealed glomerular atrophy and basement membrane thickening in CVA6-infected mice, accompanied by reduced expression of VEGF, Occludin, and VE-cadherin. Furthermore, complement deposition was also observed in glomeruli and renal tubules. Finally, CVA6 infection significantly increased phospho-p38 levels in mouse kidneys. To investigate the role of the p38-MAPK signaling pathway in CVA6-induced renal injury, we treated the CVA6-infected mice with PD169316, a specific inhibitor of p38/MAPK signaling pathway, and observed that the kidney injury in the treated group was alleviated. Overall, our findings highlight a critical role for the p38 phosphorylation in CVA6-induced renal injury, and provide new insights into the management of severe HFMD-associated kidney complications.