Table 1.
Experimental data on the role of airway proteases in the activation of influenza-, corona- and paramyxoviruses
| Protease | Virus | In vitro evidence | In vivo evidence |
|---|---|---|---|
| TMPRSS2 | Influenza A and B virus | The HA0s from H1N1, H2N2, H3N2 or influenza B are cleaved in cells overexpressing TMPRSS2 enabling trypsin-independent replication [25••, 36, 66]. Knockdown of TMPRSS2 in Calu-3 cells inhibits cleavage of H1N1 [67] | TMPRSS2-KO mice survive lethal infection with influenza H1N1 or H7N9 [15, 16]. In contrast, influenza B virus is lethal in TMPRSS2-KO mice [37] |
| SARS, MERS and 229E coronaviruses | The coronavirus S-protein is cleaved when co-expressed with TMPRSS2 [31, 62•, 64, 68] | ||
| Metapneumovirus and parainfluenzavirus | The viruses efficiently replicate in cells overexpressing TMPRSS2 and their F protein is cleaved [58, 59] | ||
| TMPRSS4 | Influenza A virus | HA0 from H1N1 is cleaved in TMPRSS4-expressing cells. Knockdown of TMPRSS2 and TMPRSS4 reduces H1N1 virus replication [19, 20, 21] | H3N2 replication is significantly reduced but not abolished, in TMPRSS2/TMPRSS4-double KO mice [21] |
| HAT | Influenza A and B virus | The HA0s from H1N1, H2N2 and H3N2 or influenza B are cleaved in cells overexpressing HAT enabling trypsin-independent replication [25••, 36, 54, 66] | This remains to be investigated in the HAT-KO mouse model [26] |
| SARS and MERS coronaviruses | The coronavirus S-protein is cleaved when co-expressed with HAT [31], hence activating the S protein for cell-cell fusion [69] | ||
| TMPRSS13/MSPL | Influenza A virus; SARS and MERS coronaviruses | The HA0s from subtypes H1, H2 or H3; and HPAIV H5 and H7 with KKKR motif (not recognized by furin), and S-proteins from SARS or MERS coronavirus, are cleaved when co-expressed with MSPL or its splice variant TMPRSS13 [11, 31] | This remains to be investigated in MSPL-KO mice, which display abnormal skin development [70] |
| Matriptase | Influenza A virus | Knockdown of matriptase in Calu-3 cells leads to reduced growth of H1N1 virus [28] Overexpressed HA0 from subtypes H1 or H9 (with RSSR/RSRR motif) is cleaved when cells are exposed to recombinant matriptase [29, 30] |
These studies are hindered by the fact that matriptase-KO mice are unviable [32] |
| DESC1 | Influenza A virus; SARS and MERS coronaviruses | The influenza HA0s subtypes H1, H2 and H3, and S-proteins from SARS or MERS coronavirus are cleaved when co-expressed with DESC1 [29] | |
| KLK5, KLK12 | Influenza A virus | Exogenous KLK5 cleaves overexpressed HA0 from subtypes H1 or H3, whereas KLK12 activates subtypes H1 and H2 [35] | |
| Plasmin | Influenza A/H1N1, strain A/WSN/33 | A/WSN/33 neuraminidase recruits plasminogen, which after conversion into plasmin leads to HA0 cleavage [34] | |
| Soluble serine proteases, for example tryptase Clara | Influenza A virus | Lungs from rats or pigs contain diverse trypsin-like proteases which, when isolated, cleave the HA0 protein of influenza H3N2. The relevance for infections of humans is uncertain [33, 71, 72, 73] | |
TMPRSS2: transmembrane protease serine 2; TMPRSS4: transmembrane protease serine 4; HAT: human airway trypsin-like protease; TMPRSS13: transmembrane protease serine 13; MSPL: mosaic serine protease large-form; DESC1: differentially expressed in squamous cell carcinoma 1; KLK: kallikrein.