Virus-Induced NETs – Critical Component of Host Defense or Pathogenic Mediator?

Much of the effort to understand and regulate the host antiviral response has been focused on adaptive immunity including high affinity, neutralizing antibody production, and the generation of specific ‘‘killer’’ CD8+ T cells. Current vaccine approaches target these effector pathways, and antibody titers or numbers of antigenspecific lymphocytes are often used as measures of the immune responses. Although these responses are dominated by lymphocytes, the innate immune system also plays a central role in the host antiviral response. Innate immunity is essential for antigen presentation and cytokine production, helping to direct and shape the ensuing adaptive response. Also of note is the observation that most viral infections elicit a robust, multifaceted inflammatory response. If we stop and consider the bigger picture, the presence of an inflammatory response should not be all that surprising. Innate immunity, and by extension inflammation, is often our body’s first line of defense, functioning to isolate and limit infection. Furthermore, the innate immune system expresses several pattern recognition receptors (PRR) specific for viral ligands (TLR3, 7, 8, RIG-I, MDA5) and produces a number of potent antiviral mediators (IFN, TNF-a, IL-15, IL-18) [1–3], illustrating that innate immunity has evolved to directly deal with viruses. Although neutrophils are central players in this acute inflammatory response and are rapidly recruited to sites of viral infection (often comprising more than 70% of the leukocyte infiltrate), their specific role in host viral immunity remains somewhat confusing. In some studies, using highly pathogenic strains of influenza, neutrophils have been demonstrated to be critical in limiting viral replication and disease progression during the early phases of infection [4,5], whereas others have reported that neutrophil recruitment to the lung in response to viral infection is associated with increased epithelial cell death, fibrin deposition, and a worse prognosis [3,6,7]. Some of the confusion regarding the role neutrophils play in viral infection can be attributed to an incomplete understanding regarding the effector mechanisms neutrophils use to deal with viruses.