Neutrophil Extracellular Traps Mediate a Host Defense Response to Human Immunodeficiency Virus-1

Abstract

Neutrophils contribute to pathogen clearance by producing neutrophil extracellular traps (NETs), which are genomic DNA-based net-like structures that capture bacteria and fungi. Although NETs also express antiviral factors, such as myeloperoxidase and α-defensin, the involvement of NETs in antiviral responses remains unclear. We show that NETs capture human immunodeficiency virus (HIV)-1 and promote HIV-1 elimination through myeloperoxidase and α-defensin. Neutrophils detect HIV-1 by Toll-like receptors (TLRs) TLR7 and TLR8, which recognize viral nucleic acids. Engagement of TLR7 and TLR8 induces the generation of reactive oxygen species that trigger NET formation, leading to NET-dependent HIV-1 elimination. However, HIV-1 counteracts this response by inducing C-type lectin CD209-dependent production of interleukin (IL)-10 by dendritic cells to inhibit NET formation. IL-10 suppresses the reactive oxygen species-dependent generation of NETs induced upon TLR7 and TLR8 engagement, resulting in disrupted NET-dependent HIV-1 elimination. Therefore, NET formation is an antiviral response that is counteracted by HIV-1.

Changing world of neutrophils

“…In recent years their antimicrobial spectrum has been broadened by demonstration of their involvement in defense against HIV-1 [97], mycobacteria [68] and parasites such as malaria [85] and Leishmania [75,82].…”

“…NETs were shown to kill various bacteria and Candida albicans [15,110] but most recently they were reported to be also involved in defense against human immunodeficiency virus [97]. The mechanism of microbe elimination is not fully understood but probably relies on multiple parallel pathways.…”

Chromatin remodelling and autocrine TNFα are required for optimal interleukin-6 expression in activated human neutrophils

“…These comprise cell shape changes, CD62L shedding, priming for enhanced respiratory burst 17,[47][48][49] , chemotaxis, phagocytosis 17,50 and neutrophil extracellular trap formation induction 51 , lipid mediator production 18 , prolonged survival 49,52 and cytokine production (using, however, less pure neutrophil populations than in this study), including TNFa 53 and IL-6 (refs 48,53,54). Similarly, two studies 55,56 have reported that human neutrophils cultured in the presence of infectious respiratory syncytial virus produce IL-6 at 1 ng ml À 1 per 5 Â 10 6 cells per 3 h (498% neutrophil purity 55 ), or at 100 pg ml À 1 per 5 Â 10 5 cells per 12 h (497% purity 56 ).…”

Human neutrophils produce extracellular traps against Paracoccidioides brasiliensis

“…An increasing number of bacteria, fungi, viruses and protozoan parasites have been shown to induce NETs (Brinkmann et al, 2004;Guimarães-Costa et al, 2009;Urban et al, 2009;Saitoh et al, 2012;Jenne et al, 2013) but to date only three fungal species (Candida albicans, Aspergillus spp. and Cryptococcus gattii) have been reported to activate their production (Urban et al, 2006;Bruns et al, 2010;Springer et al, 2010;Bianchi et al, 2011).…”