Neutrophils in respiratory viral infections

Abstract

Viral respiratory infections are a common cause of severe disease, especially in infants, people who are immunocompromised, and in the elderly. Neutrophils, an important innate immune cell, infiltrate the lungs rapidly after an inflammatory insult. The most well-characterized effector mechanisms by which neutrophils contribute to host defense are largely extracellular and the involvement of neutrophils in protection from numerous bacterial and fungal infections is well established. However, the role of neutrophils in responses to viruses, which replicate intracellularly, has been less studied. It remains unclear whether and, by which underlying immunological mechanisms, neutrophils contribute to viral control or confer protection against an intracellular pathogen. Furthermore, neutrophils need to be tightly regulated to avoid bystander damage to host tissues. This is especially relevant in the lung where damage to delicate alveolar structures can compromise gas exchange with life-threatening consequences. It is inherently less clear how neutrophils can contribute to host immunity to viruses without causing immunopathology and/or exacerbating disease severity. In this review, we summarize and discuss the current understanding of how neutrophils in the lung direct immune responses to viruses, control viral replication and spread, and cause pathology during respiratory viral infections.

Fig. 1. Neutrophils in disease.

During a respiratory viral infection, neutrophils are recruited to and activated in the lung. In non-symptomatic or mild disease, neutrophil numbers peak early during infection and neutrophils exert their effector functions and aid in tissue repair and resolution of inflammation. In a severe infection, more neutrophils are recruited over a longer period. This results in more tissue damage and a delay or block in resolution of inflammation and tissue repair.

Fig. 2. Multiple ways to activate a neutrophil.

Neutrophils receive many different signals from the inflammatory environment that can lead to cell activation and elicit effector functions. These activating signals include PAMPs, DAMPs, the process of migration, neutrophil chemoattractants, and cytokines.

Fig. 3. Neutrophils exhibit a plethora of effector functions.

Neutrophil activation can trigger degranulation whereby neutrophils secrete mediators and proteolytic enzymes such as MMPs, MPO, and NE, which are prestored in cytoplasmic granules. Neutrophils can also mediate pathogen clearance by producing ROS, which can either occur intracellularly in the phagolysosome to kill internalized microbes or extracellularly, to combat larger pathogens. Phagocytosis of pathogens can limit microbial spread, while phagocytosis of cellular debris and apoptotic material can contribute to the resolution of inflammation. Neutrophils can also restrict microbial spread by secreting their chromatin as NETs, trapping pathogens. Finally, it is increasingly appreciated that neutrophils can have direct and indirect interactions with other cells such as alveolar macrophages (AM), dendritic cells (DC), and T cells, which can contribute to both innate and adaptive immunity.

Fig. 4. Possible beneficial and detrimental effects of neutrophils during respiratory viral infections.

Neutrophils infiltrating the lungs during viral infections can aid the ongoing antiviral response by contributing to the production of antiviral cytokines and chemokines, as well as producing antimicrobial peptides. As phagocytes, neutrophils can clear pathogens and debris. These functions can aid in viral control/clearance as well as resolution of inflammation. An excess of activated neutrophils can contribute to lung tissue damage by excessive production of MPO, NE, MMPs, oxidative burst, and NETs, exacerbating disease severity.