Abstract
The human respiratory syncytial virus (hRSV) is the most common cause of severe lower respiratory tract diseases in young children worldwide, leading to a high number of hospitalizations and significant expenditures for health systems. Neutrophils are massively recruited to the lung tissue of patients with acute respiratory diseases. At the infection site, they release neutrophil extracellular traps (NETs) that can capture and/or inactivate different types of microorganisms, including viruses. Evidence has shown that the accumulation of NETs results in direct cytotoxic effects on endothelial and epithelial cells. Neutrophils stimulated by the hRSV-F protein generate NETs that are able to capture hRSV particles, thus reducing their transmission. However, the massive production of NETs obstructs the airways and increases disease severity. Therefore, further knowledge about the effects of NETs during hRSV infections is essential for the development of new specific and effective treatments. This study evaluated the effects of NETs on the previous or posterior contact with hRSV-infected Hep-2 cells. Hep-2 cells were infected with different hRSV multiplicity of infection (MOI 0.5 or 1.0), either before or after incubation with NETs (0.5-16 μg/mL). Infected and untreated cells showed decreased cellular viability and intense staining with trypan blue, which was accompanied by the formation of many large syncytia. Previous contact between NETs and cells did not result in a protective effect. Cells in monolayers showed a reduced number and area of syncytia, but cell death was similar in infected and non-treated cells. The addition of NETs to infected tissues maintained a similar virus-induced cell death rate and an increased syncytial area, indicating cytotoxic and deleterious damages. Our results corroborate previously reported findings that NETs contribute to the immunopathology developed by patients infected with hRSV.
Highlights
The human respiratory syncytial virus was first described in 1957 as the agent responsible for bronchiolitis in children, especially those under five years of age (Hall, 2001). hRSV infections affect people of all ages, but mostly children and the elderly
The results of the treatment with viral inoculum at a MOI of 0.5 demonstrated that previous contact of the cells with neutrophil extracellular traps (NETs) did not result in total protection from hRSV infection, it resulted in a reduction in the number and area of syncytia (Figure 1)
We observed that only NET concentrations of 8 and 16 μg/mL showed trend to reducing number of syncytia, but that was not statistically significant compared with non-treated cells (Figure 1A, left)
Summary
The human respiratory syncytial virus (hRSV) was first described in 1957 as the agent responsible for bronchiolitis in children, especially those under five years of age (Hall, 2001). hRSV infections affect people of all ages, but mostly children and the elderly. The F-protein, located on the hRSV surface, activates the release of neutrophil extracellular traps (NETs) from neutrophils in the infected tissue (Funchal et al, 2015). NETs were first described in 2004; their release is stimulated by several inflammatory mediators and pathogens (Brinkmann et al, 2004). These traps are composed of nuclear/mitochondrial DNA and proteins from the nucleus, cytoplasm, and cytoplasmic granules (Fuchs et al, 2007; Urban et al, 2009), and have a microbicidal and viricidal role (Jenne et al, 2013; Saitoh et al, 2012; Brinkmann et al, 2004). In some chronic respiratory diseases, such as cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD), airway obstruction by a dense mass of DNA and protein-rich mucus is a pathological marker (Dubois et al, 2012; Manzenreiter et al, 2012; Papayannopoulos et al, 2011; Wright et al, 2016)
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