Neutrophil subsets and their differential roles in viral respiratory diseases

Abstract

Neutrophils play significant roles in immune homeostasis and as neutralizers of microbial infections. Recent evidence further suggests heterogeneity of neutrophil developmental and activation states that exert specialized effector functions during inflammatory disease conditions. Neutrophils can play multiple roles during viral infections, secreting inflammatory mediators and cytokines that contribute significantly to host defense and pathogenicity. However, their roles in viral immunity are not well understood. In this review, we present an overview of neutrophil heterogeneity and its impact on the course and severity of viral respiratory infectious diseases. We focus on the evidence demonstrating the crucial roles neutrophils play in the immune response toward respiratory infections, using influenza as a model. We further extend the understanding of neutrophil function with the studies pertaining to COVID-19 disease and its neutrophil-associated pathologies. Finally, we discuss the relevance of these results for future therapeutic options through targeting and regulating neutrophil-specific responses.

Keywords: COVID-19; Influenza A; Viral Respiratory Diseases; anti-viral functions; heterogeneity; neutrophils; tissue damage.

FIGURE 1

Characterization of neutrophil subsets in mice and humans. Neutrophil development is historically characterized by various morphologic structures and granules using bone marrow smears. Undifferentiated myeloblasts differentiate into promyelocytes, myelocytes, nonproliferating meta‐myelocytes, band cells, and finally mature as segmented neutrophils. These stages are accompanied by stage‐specific granules. The advent of high dimensional single‐cell phenotyping technologies enabled both the transcriptome and protein expression characterization of the developmental continuum, giving rise to the identification of discrete subsets proposed by various groups. These enable the study of neutrophils in viral inflammatory conditions and discover subset‐specific functions leading to disease pathology and resolution. Created with BioRender.com

FIGURE 2

Neutrophil recruitment and action in the infected airway tract. Evidence now shows the presence of developing neutrophil precursors in the circulation during viral infections. These subsets may provide immunosuppressive or effector functions that are not fully understood. In the infected lungs, through recruitment by cytokines (such as IL‐1b, LTB4, C5a, and TNF‐α), TLRs, and pattern recognition receptors (PRRs), neutrophils perform various functions that help control the infection. Left unchecked, these actions lead toward increased disease severity and tissue damage. Created with BioRender.com