Abstract
The Chikungunya virus (CHIKV) is a re-emerging arbovirus, in which its infection causes a febrile illness also commonly associated with severe joint pain and myalgia. Although the immune response to CHIKV has been studied, a better understanding of the virus-host interaction mechanisms may lead to more effective therapeutic interventions. In this context, neutrophil extracellular traps (NETs) have been described as a key mediator involved in the control of many pathogens, including several bacteria and viruses, but no reports of this important protective mechanism were documented during CHIKV infection. Here we demonstrate that the experimental infection of mouse-isolated neutrophils with CHIKV resulted in NETosis (NETs release) through a mechanism dependent on TLR7 activation and reactive oxygen species generation. In vitro, mouse-isolated neutrophils stimulated with phorbol 12-myristate 13-acetate release NETs that once incubated with CHIKV, resulting in further virus capture and neutralization. In vivo, NETs inhibition by the treatment of the mice with DNase resulted in the enhanced susceptibility of IFNAR−/− mice to CHIKV experimental acute infection. Lastly, by accessing the levels of MPO-DNA complex on the acutely CHIKV-infected patients, we found a correlation between the levels of NETs and the viral load in the blood, suggesting that NETs are also released in natural human infection cases. Altogether our findings characterize NETosis as a contributing natural process to control CHIKV acute infection, presenting an antiviral effect that helps to control systemic virus levels.
Highlights
The Chikungunya virus (CHIKV) is a single-stranded RNA virus that is transmitted to humans by the bite of the infected mosquitoes from the Aedes family [1]
The peak of the neutrophil extracellular traps (NETs) production was similar at 8 hpi, negative control cells were activated at later time points (8 hpi), probably as a consequence of cell stress
To further confirm NETs release, we performed an immunofluorescence assay from the virus-stimulated neutrophils in which the NETs were identified as extracellular complexes that were simultaneously costained for free DNA (DAPI) and citrullinated histone H3 (H3cit) (Figure 1B and Supplementary Figure 1A)
Summary
The Chikungunya virus (CHIKV) is a single-stranded RNA virus that is transmitted to humans by the bite of the infected mosquitoes from the Aedes family [1]. After inoculation by a mosquito, CHIKV infects the resident cells—including fibroblasts, macrophages, and endothelial cells— and starts to proliferate [4] These cells recognize the virus via innate receptors and produce proinflammatory mediators, recruiting and activating immune cells to eliminate the pathogen [5]. The emigrated neutrophils start to produce reactive oxygen species (ROS) and other cytotoxic mediators, which may dampen the virus infection [9] It has become clear in the literature that the neutrophils are able to release neutrophil extracellular traps (NETs), which are a sticky web of DNA conjugated with antimicrobial enzymes (such as myeloperoxidase and histones), resulting in the capture and the killing of different pathogens, including viruses [9, 10]
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