Immune response in influenza virus infection and modulation of immune injury by viral neuraminidase

Abstract

Influenza A viruses cause severe respiratory illnesses in humans and animals. Overreaction of the innate immune response to influenza virus infection results in hypercytokinemia, which is responsible for mortality and morbidity. The influenza A virus surface glycoprotein neuraminidase (NA) plays a vital role in viral attachment, entry, and virion release from infected cells. NA acts as a sialidase, which cleaves sialic acids from cell surface proteins and carbohydrate side chains on nascent virions. Here, we review progress in understanding the role of NA in modulating host immune response to influenza virus infection. We also discuss recent exciting findings targeting NA protein to interrupt influenza-induced immune injury.

Keywords: CD83; Cytokine storm; Immune response; Influenza virus; Neuraminidase.

Fig. 1

Neuraminidase structure. Neuraminidase is comprised of N-terminal cytoplasmic tail, transmembrane, NA stalk and NA head. A tetramer dimensions about 10 nm × 15 nm from snapshot

Fig. 2

The relationship of virus, immunity response, cytokine and lung. (1) Factor: from virus (NA activity, NA stalk length and transmembrane), from host (age, obesity and host factor), and these factors can affect immune response; (2) Phospholipid and p21 locate in the pulmonary epithelium, S1PR1 locate in the pulmonary endothelium, SOCS3 as inhibitory cytokine, pulmonary endothelium is central orchestrator of cytokine amplification. When virus invade body, p21 expression reduced, SOCS3 and S1PR1 signaling improved, immune cells are activated, frequent the number of cytokines is reduced, lung injury was decreased; (3) When body is infected with influenza virus, phospholipid increased, then the number of cytokines is increased, immune cells are inhibited, lead to cytokine storm and finally cause lung injury; (4) When virus invaded, TGF-β is activated through virus NA, then upregulated expression of cellular adhesins, immune cells are inhibited, and lead to cytokine storm, cause bacterial pneumonia

Fig. 3

Neuraminidase-CD83 axis. When mice were infected with influenza virus, mainly component is neuraminidase, CD83 is a sialylated protein and sialylated CD83 delivers inhibiting signaling to DCs, CD83 expression level was upregulated on dendritic cells and macrophages in the lung. NA removed sialic acid and released superfluous cytokines, frequent causing lung injury; when using anti-CD83Ab for restrained NA across, reduced cytokines production, and reduction of lung injury