Neutrophil Extracellular Traps Go Viral

Abstract

Neutrophils are the most numerous immune cells. Their importance as the first line of defense against bacterial and fungal pathogens is well described. In contrast, the role of neutrophils in controlling viral infections is less clear. Bacterial and fungal pathogens can stimulate neutrophils extracellular traps (NETs) in a process called NETosis. Although NETosis has previously been described as a special form of programmed cell death, there are forms of NET production that do not end with the demise of neutrophils. As an end result of NETosis, genomic DNA complexed with microbicidal proteins is expelled from neutrophils. These structures can kill pathogens or at least prevent their local spread within host tissue. On the other hand, disproportionate NET formation can cause local or systemic damage. Only recently, it was recognized that viruses can also induce NETosis. In this review, we discuss the mechanisms by which NETs are produced in the context of viral infection and how this may contribute to both antiviral immunity and immunopathology. Finally, we shed light on viral immune evasion mechanisms targeting NETs.

Keywords: immunopathogenesis; neutrophil extracellular traps; neutrophils; viral immune evasion; viruses.

Figure 1

Induction, antiviral effect, and viral evasion of NETs. (1) Formation of NETs is induced directly by virions (red) through PRRs (blue) expressed by neutrophils on the surface (TLR4, β2 integrins) or in endosomes (TLR7, 8) or indirectly by proinflammatory mediators (e.g., IL-8), which are released from virus-infected cells (orange). In addition, viral activation of the platelet/neutrophil axis can trigger NETosis (green). As a consequence, granules fuse with the nucleus, which subsequently loses its characteristic lobulated shape and ruptures. Finally, neutrophils rupture releasing sticky strings of NETs. (2) NETs have antiviral effects by immobilizing or inactivating free virions, thereby preventing viral spread. NETs also potentiate the release of type I interferon by pDC (not shown), thus increasing the resistance of local cells to further infection. (3) Digestion of the DNA backbone by DNases releases trapped virions. These virions, if not already inactivated, opsonized, or degraded, can attempt to infect further cells. Moreover, viruses can interfere with NETosis by inducing cellular IL-10 or by expressing viral IL-10 homologs (not shown).

Figure 2

Systemic pathology driven by virus-induced NET formation. Virus-induced NETs may start to circulate and become systemic under certain circumstances. First, systemic infection with viruses that have a strong NET-stimulatory capacity, such as hantaviruses, may overwhelm intact NET-degrading function of DNAses (20). Second, persistent viruses with low NET-inducing capacity, such as herpesviruses, may produce systemic NET excess if DNAse activity is compromised. As a result of NET overflow, self-reactive memory B cells are stimulated to release autoantibodies after binding and internalizing NET components through their B cell receptor (91). NETs are enriched in oxidized mitochondrial DNA inducing a strong inflammatory response (52). NETs stimulate pDCs to release type I IFN that adds momentum to the vicious cycle by further activating and expanding autoreactive B cells (–50). Immune complexes are formed which not only cause systemic pathology as observed in several disease entities such as SLE but also promote the autoimmune process by driving a positive feedback loop.