Protein Disulfide Isomerase A3 Regulates Influenza Neuraminidase Activity and Influenza Burden in the Lung

Abstract

Influenza (IAV) neuraminidase (NA) is a glycoprotein required for the viral exit from the cell. NA requires disulfide bonds for proper function. We have recently demonstrated that protein disulfide isomerase (PDI)A3 is required for oxidative folding of IAV hemagglutinin (HA), and viral propagation. However, it not known whether PDIs are required for NA maturation or if these interactions represent a putative target for the treatment of influenza infection. We sought to determine whether PDIA3 is required for disulfide bonds of NA, its activity, and propagation of the virus. Requirement of disulfides for NA oligomerization and activity were determined using biotin switch and redox assays in WT and PDIA3−/− in A549 cells. A PDI specific inhibitor (LOC14) was utilized to determine the requirement of PDIs in NA activity, IAV burden, and inflammatory response in A549 and primary mouse tracheal epithelial cells. Mice were treated with the inhibitor LOC14 and subsequently examined for IAV burden, NA activity, cytokine, and immune response. IAV-NA interacts with PDIA3 and this interaction is required for NA activity. PDIA3 ablation or inhibition decreased NA activity, viral burden, and inflammatory response in lung epithelial cells. LOC14 treatment significantly attenuated the influenza-induced inflammatory response in mice including the overall viral burden. These results provide evidence for PDIA3 inhibition suppressing NA activity, potentially providing a novel platform for host-targeted antiviral therapies.

Thiol Modifications in the Extracellular Space—Key Proteins in Inflammation and Viral Infection

“…PDIs bind capsid spike proteins of human astroviruses, the cause of gastroenteritis, thereby inhibiting viral entry, more precisely uncoating of the viral genome ( 147 ). PDIs regulate the redox state of hemagglutinin and neuraminidase and thereby virus attachment and influenza infection ( 148 , 149 ). Also, in coronavirus disease 2019 (COVID-19), the spike glycoprotein of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) that binds to its receptor angiotensin-converting enzyme 2 contains two disulfide bonds (Cys379-Cys432 and Cys391-Cys525).…”

Host–Pathogen Interaction 3.0

“…Of course, humans are also infected by viruses. Prominent examples are SARS-CoV-2 [ 38 , 39 ], influenza [ 40 , 41 ], Ebola virus [ 42 ] and human papillomavirus [ 43 ]. Other papers submitted to this Special Issue serial are focusing on viruses infecting animals such as pigs [ 44 ] and ducks [ 45 ].…”