How influenza's neuraminidase promotes virulence and creates localized lung mucosa immunodeficiency

Abstract

Neuraminidase (NA) is an enzyme coded for by the genome of influenza critical for its pathogenicity and survival. Three currently accepted roles for this NA in promoting influenza virulence are: 1. NA cleaves newly formed virus particles from the host cell membrane. Without NA, newly formed virus would remain attached to the cell within which it was produced. 2. NA prevents newly released virus particles from aggregating to each other, preventing clumping that would reduce dissemination. 3. NA promotes viral penetration of sialic acid-rich mucin that bathes and protects respiratory epithelium through which the virus must spread and replicate. We outline here previous research evidence of two further, albeit hypothetical, functions of NA that together could cause disruption the mucosa-IgA axis, creating localized partial immunosuppressed state, enhancing both influenza infection itself and secondary bacterial pneumonia: 4. IgA provides primary immunoglobulin defense of mucosal surfaces. The hinge region of IgA is normally sialylated. IgA denuded of sialic acid is recognized, bound, and cleared by hepatic asialoglycoprotein receptor (ASGPR). Thus, IgA exposed to free NA would be so denuded and have increased hepatic clearance. 5. NA removes sialic acid moieties from mucosa-residing gamma/delta T cells or IgA producing B cells. Previous work indicates desialylation of these lymphocytes' outer cell membrane results in altered homing, to bone marrow, away from mucosa. Currently marketed NA inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza) are FDA approved in USA for influenza prophylaxis and treatment. These NA inhibitors lower incidence of secondary bacterial infection in cases where an influenza infection occurs despite their use. Moreover, they are ameliorative in patients with secondary bacterial infections treated with antibiotics, a benefit that surpasses the treatment of antibiotics alone. We interpret these last two points as indicating our ascription of localized immunosuppression to influenza's NA could be correct and lead to new treatments of infections generally.