Activation of influenza viruses by proteases from host cells and bacteria in the human airway epithelium

Abstract

Influenza is an acute infection of the respiratory tract, which affects each year millions of people. Influenza virus infection is initiated by the surface glycoprotein hemagglutinin (HA) through receptor binding and fusion of viral and endosomal membranes. HA is synthesized as a precursor protein and requires cleavage by host cell proteases to gain its fusion capacity. Although cleavage of HA is crucial for virus infectivity, little was known about relevant proteases in the human airways for a long time. Recent progress in the identification and characterization of HA-activating host cell proteases has been considerable however and supports the idea of targeting HA cleavage as a novel approach for influenza treatment. Interestingly, certain bacteria have been demonstrated to support HA activation either by secreting proteases that cleave HA or due to activation of cellular proteases and thereby may contribute to virus spread and enhanced pathogenicity. In this review, we give an overview on activation of influenza viruses by proteases from host cells and bacteria with the main focus on recent progress on HA cleavage by proteases HAT and TMPRSS2 in the human airway epithelium. In addition, we outline investigations of HA-activating proteases as potential drug targets for influenza treatment.

Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Inflammation

“…A serine protease inhibitor, camostat, reduced the amount of HA1 in the supernatants (Figure 3). These findings are consistent with reports that host proteases promote proteolytic activation of influenza virus HA in the trans-Golgi network and/or plasma membrane (Table 1) [76,77]. Newly synthesized influenza virus with cleaved HA may bud from the epithelial cell membrane.…”

Proteolytic enzymes in embryonated chicken eggs sustain the replication of egg-grown low-pathogenicity avian influenza viruses in cells in the absence of exogenous proteases

“…In case of highly pathogenic avian influenza viruses (HPAIV), the cleavage site is polybasic and is recognized readily by ubiquitous subtilisin-like proteases enabling systemic replication of the virus (Stieneke-Grober et al, 1992; Webster and Rott, 1987). In humans, host cells and bacteria in the airway epithelium play a role in HA cleavage (Bottcher-Friebertshauser, Klenk, and Garten, 2013). In tissue culture, replication of LPIVs but not HPAIVs requires the addition of exogenous proteases such as tosyl phenylalanyl chloromethyl ketone (TPCK)-treated trypsin to cleave the HA protein.…”

Advances and Remaining Challenges in the Study of Influenza and Anthrax Infection in Lung Cell Culture

“…Primary lung cell influenza A virus (IAV) studies have been published characterizing host lung responses to both human and avian influenza strains [8][9][10][11]. What makes primary lung cells highly relevant for IAV study is the cell's ability to naturally secrete a class of proteases that cleave influenza hemagglutinin (HA) for viral cell entry [12]. Prior to the development of lung cell culturing at ALI, submerged immortalized cells (Figure 1, left) were cultured in medium supplemented with exogenous trypsin (~1 µg/mL) serving as an artificial way to cleave the viral HA through proteolysis to initiate infection [13].…”