Local immune dysregulation and subsequent inflammatory response contribute to pulmonary edema caused by Enterovirus infection in mice

Abstract

Pulmonary edema that comes on suddenly is the leading cause of mortality in handfoot-and-mouth disease (HFMD) patients; however, its pathogenesis is still largely unclear. A range of research suggest immunopathogenesis during the occurrence of pulmonary edema in severe HFMD patients. Herein, to investigate the potential mechanism of immune dysregulation in the development of pulmonary edema upon Enterovirus (EV) infection, we established mouse infection models for Enteroviruses (EVs) including Coxsackievirus (CV) A6, Enterovirus A71 (EVA71), and CVA2 exhibiting a high incidence of pulmonary edema. We found that EVs infection induced an immune system disorder by reducing the numbers of pulmonary and circulatory T cells, B cells, macrophages, and monocytes and increasing the numbers of lung neutrophils, myeloid-derived suppressor cells (MDSCs), and activated T cells. In addition, the concentrations of C−X−C motif chemokine ligand 1 (CXCL-1), tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and interleukin 6 were increased in EV-infected lungs. Moreover, we found that EVs replication in mice lungs lead to apoptosis of lung cells and degradation of tight junction proteins. In conclusion, EVs infection likely triggered a complexed immune defense mechanism and caused dysregulation of innate immune cells (MDSCs, neutrophils, monocytes, and macrophages) and adaptive cellular immunity (B cells, T cells). This dysregulation increased the release of cytokines and other inflammatory factors from activated immune-related cells and caused lung barrier damage and pulmonary edema.

Study on the epidemiological characteristics of enterovirus among pediatric patients in Hangzhou, China: A comparison between the pre‐COVID‐19, COVID‐19 pandemic, and post‐COVID‐19 periods

“…19 Due to its potential for severe manifestations, including neurological complications and, in rare cases, sudden-onset pulmonary edema leading to fatalities, this disease has gained increased amounts of attention. 20,21 Its prevalence has been on the rise in recent years, leading to greater focus and efforts in disease management. EV-A71 and CV-A16 were the most common viral types associated with HFMD more than 10 years ago, while other enterovirus subtypes became the main subtypes in recent years.…”

“…Outbreaks of HFMD and HA have been reported in various regions worldwide, with an increasing number of cases and associated complications 19 . Due to its potential for severe manifestations, including neurological complications and, in rare cases, sudden‐onset pulmonary edema leading to fatalities, this disease has gained increased amounts of attention 20,21 . Its prevalence has been on the rise in recent years, leading to greater focus and efforts in disease management.…”

Severe noncardiogenic pulmonary edema after cardiopulmonary bypass: Case report

“…Previous research has indicated that inflammatory reactions could lead to alterations in pulmonary capillary permeability and severe pulmonary edema [ 7 , 8 ]. Factors such as viral infections and inflammatory cytokines may cause damage to the pulmonary barrier and result in pulmonary edema [ 9 ]. In this case, the patient was diagnosed with infective endocarditis, and despite empirical antibiotic treatment, the infection remained quite severe.…”