Cathepsin L, transmembrane peptidase/serine subfamily member 2/4, and other host proteases in COVID-19 pathogenesis – with impact on gastrointestinal tract

Table 1 Receptors/proteases involved in Severe acute respiratory syndrome coronavirus-2 invasion of human cells

Receptor/protease	Experimental model	Observation	Ref.
ACE2 and TMPRSS2/4	Human small intestinal enteroids; HEK-293T cell line transfected with ACE2, TMPRSS2, or TMPRSS4	Productive infection of SARS-CoV-2 in ACE2 (+) mature enterocytes; Correlation of ACE2, TMPRSS2 and 4 with SARS-CoV-2 invasiveness	Zang et al[11]
ACE2 and TMPRSS2	ACE2 and TMPRSS2 expressing C2BBe1, Caco-2, and Calu-3 cell lines	Persistent invasion and replication of SARS-CoV-2 in the cells; Correlation of TMPRSS2 (but not ACE2) with SARS-CoV-2 RNA	Lee et al[33]
ACE2, TMPRSS2, and CCs	HEK-293T cell line transfected with ACE2; Caco-2 cells overexpressing TMPRSS2	Inhibition of SARS-CoV-2 pseudovirus entry into HEK-293T ACE2(+)/TMPRSS2(-) by pH increase and E-64 inhibitor; Inhibition of SARS-CoV-2 pseudovirus entry into Caco-2 TMPRSS2(+) by pH increase, CCs inhibitor (E-64d), and TMPRSS2 inhibitor (camostat mesylate)	Hoffmann et al[3]
ACE2, TMPRSS 2, 4, 11A, 11D, 11E, and CCs (cathepsin L)	HEK-293T cell line transfected with ACE2	Inhibition of SARS-CoV-2 pseudovirus entry into the cells with CCs inhibitor (E-64d) and cathepsin L inhibitor (but not cathepsin B inhibitor); Intensification of SARS-CoV-2 S protein-mediated cell–cell fusion, caused by expression of TMPRSS 2, 4, 11A, 11D, and 11E on 293/hACE2 cells	Ou et al[20]
ACE2 and TMPRSS2	ACE2 and TMPRSS2 expressing Caco-2 and T84 cell lines	Persistent invasion and replication of SARS-CoV-2 in the cells	Stanifer et al[35]
ACE2, furin, TMPRSS2, and CCs	ACE2-expressing HeLa, Calu-3, and MRC-5 cell lines	Reduction of SARS-CoV-2 pseudovirus entry into cells by inhibitors of PCs, CCs and TMPRSS2	Shang et al[8]
NRP1, ACE2, and TMPRSS2	HEK-293T cell line transfected with ACE2, TMPRSS2, or NRP1	Augmentation of SARS-CoV-2 infectivity when NRP1 was coexpressed with ACE2 and TMPRSS2	Cantuti-Castelvetri et al[21]

ACE2: Angiotensin converting enzyme 2; NRP1: Neuropilin 1 (receptor which binds furin-cleaved substrates); TMPRSS2/4: Transmembrane peptidase/serine subfamily member 2/4; CCs: Cysteine cathepsins; HEK-293T: Human embryonic kidney 293T cells; Caco-2: Human colorectal adenocarcinoma cell line; C2BBe1: A subclone of Caco-2; T84: Human colon carcinoma cell line; HeLa: Human cervical cell line; Calu-3: Human lung epithelial cell line; MRC-5: Human lung fibroblast cell line; PCs: Proprotein convertases.