Membrane ectopeptidases targeted by human coronaviruses

Abstract

Six coronaviruses, including the recently identified Middle East respiratory syndrome coronavirus, are known to target the human respiratory tract causing mild to severe disease. Their interaction with receptors expressed on cells located in the respiratory tract is an essential first step in the infection. Thus far three membrane ectopeptidases, dipeptidyl peptidase 4 (DPP4), angiotensin-converting enzyme 2 (ACE2) and aminopeptidase N (APN), have been identified as entry receptors for four human-infecting coronaviruses. Although the catalytic activity of the ACE2, APN, and DPP4 peptidases is not required for virus entry, co-expression of other host proteases allows efficient viral entry. In addition, evolutionary conservation of these receptors may permit interspecies transmissions. Because of the physiological function of these peptidase systems, pathogenic host responses may be potentially amplified and cause acute respiratory distress.

Figure 1

Immunohistochemical detection of DPP4 expression in the lower respiratory tract of non-human primates. Lungs from naïve Cynomolgus macaques were inflated with formalin and subsequently processed for paraffin embedding. Sections were stained with goat polyclonal antibodies against human DPP4 and the second antibody step that was conjugated with peroxidase was visualized with substrate. Shown are positive cells in the bronchus (a) and alveoli (b).

Figure 2

MERS-CoV and ADA binding sites on DPP4. (a) Cartoon representation of human DPP4 (hDPP4; β-propellor and hydrolase domain in orange respectively gray) in complex with — in blue — MERS-CoV receptor binding domain (MERS-RBD) or bovine adenosine deaminase (bADA). Left panels: Surface representation of the hDPP4 region with the footprints of ADA and MERS-CoV RBD. Contacting residues (based on Refs [43•, 44•]) are assigned in single-letter code and sequence number and colored orange for contacting residues commonly binding MERS-RBD and ADA, or in green for residues specifically contacting MERS-CoV or ADA. Figures were created using PyMol (www.pymol.org) (b) Amino acid sequence alignment of region of DPP4 binding ADA and MERS. Residues in the alignment identical to that of human DPP4 are indicated by a dot. Green triangles on top indicate amino acids in hDPP4 engaged in complex formation with MERS-CoV or ADA as indicated. Orange triangles indicate amino acids in hDPP4 engaged in complex formation with MERS and ADA. Boxed regions indicate the MERS-CoV-contacting residues of DPP4. DPP4 accession numbers: Homo sapiens ref|NP_001926.2|, Macaca mulatta ref|NP_001034279.1|, Oryctolagus cuniculus ref|XP_002712206.1|, Equus caballus ref|XP_005601601.1|, Cavia porcellus ref|XP_003478612.2|, Myotis lucifugus ref|XP_006083275.1|, Capra hircus ref|XP_005676104.1|, Bos Taurus ref|NP_776464.1|, Ovis aries ref|XP_004004709.1|, Camelus ferus ref|XP_006176871.1|, Vicugna pacos ref|XP_006196279.1|, Sus scrofa ref|NP_999422.1|, Felis catus ref|NP_001009838.1|, Mus musculus ref|XP_006498756.1|, Mustela putorius furo ref|XP_004744010.1|.