Neutrophil Extracellular Traps in Viral Infections

Abstract

Neutrophils are the most abundant immune cells in the human body. Neutrophil extracellular traps (NETs) have recently garnered significant attention as a novel, non-traditional mechanism for combating pathogenic microorganisms. Recent studies have shown that NETs play a crucial role in antiviral immunity, providing new perspectives on how neutrophils defend against viral invasion. Viruses not only induce NET formation through various mechanisms but have also developed multiple escape strategies targeting NETs. It is worth noting that NETs are a double-edged sword for the host: while they possess antiviral effects that inhibit viral spread and replication, their constituent components may also exacerbate tissue damage and play important pathological roles in the progression of certain viral infections. Therefore, a thorough understanding of the regulatory mechanisms and dynamic balance of NETs in viral infections is of critical importance. Additionally, since the components of NETs may vary depending on the stimulus, NET-related markers have the potential to serve as biomarkers for the severity and prognosis of viral diseases. This article provides a systematic review of the induction mechanisms, antiviral effects, viral escape strategies, and virus-induced NET-related immunopathological damage in viral infections, offering new insights for antiviral immunotherapy.

Keywords: immune evasions; immunologic injury; neutrophil; neutrophil extracellular traps; viral infections.

Figure 1

The antiviral mechanisms of NETs. (A): NETs are anchored in the interstitium by fibronectin and capture viruses through their sticky DNA scaffold and positively charged histones. (B): NETs directly combat viral pathogens through an arsenal of neutrophil-derived proteins with virucidal or inhibitory functions. (C): NETs contribute to antiviral immunity by releasing DAMPs that activate and recruit other immune cells, thereby initiating a broader immune cascade.

Figure 2

NET-mediated host immunopathological mechanisms. (A): Neutrophil-derived proteins are highly toxic to lung epithelial cells and contribute to the progression of diseases such as viral pneumonia, airway obstruction, and pulmonary fibrosis. (B): Virus-induced NETs can contribute to procoagulant activity through multiple mechanisms. Neutrophil-derived cytotoxic proteins can injure endothelial cells, leading to the exposure of TF. NETs may also promote the degradation of TFPI or activate platelets to release extracellular vesicles and α-granules enriched in TF, thereby enhancing coagulation and amplifying the immune response. Meanwhile, the negatively charged DNA backbone of NETs can attract the aggregation of coagulation factor XII, initiating the intrinsic coagulation pathway. Additionally, NETs and fibrin nets can form dense structures that resist the action of plasmin. (C): HBV stimulates hepatocytes to release HMGB1 and S100A9, which are DAMP molecules that activate NETosis. On the one hand, neutrophils further damage hepatocytes by releasing neutrophil-derived proteins, thereby exacerbating hepatitis and promoting liver failure. On the other hand, neutrophil-derived proteins promote the expression of VEGF and MMPs in endothelial cells and facilitate EMT, thereby promoting tumor angiogenesis and enhancing tumor growth and migration rates. (D): Virus-induced NETs disrupt the blood–brain barrier through neutrophil-derived proteins, damage DRGs and neurons, and induce neuronal apoptosis by activating caspase-3.