Biology Reference
In-Depth Information
Cell Entry Pathways of Coronaviruses
Syncytium formation is generally observed in cultured cells infected with
various MHV strains under a wide range of pH environments. This is
attributed to the S protein, as cells expressing the MHV S protein alone
are fused, similar to their infections.
40
The replication of MHV is, in gen-
eral, hardly affected by lysosomotropic agents.
41
These observations sug-
gest that MHV enters the cells from the cell surface after binding to its
receptor. Thus, MHV is thought to take a non-endosomal pathway
(Fig. 2). Exceptions are also reported. A mutant virus isolated from
persistent infection fails to induce fusion formation under neurtral pH,
but it causes cell fusion when the cells are treated by low pH.
41
This situ-
ation is very similar to that found in cases of influenza or VSV fusion for-
mation,
21
and thus suggested that this particular virus takes an endosomal
pathway; in the endosomal acidic environment, the S protein is fusogeni-
cally activated. MHV-2, a non-syncytium formerly under a wide range of
pH culture conditions, has a unique feature for fusion formation. Infected
cells undergo fusion formation when the cells are treated with trypsin,
42
which is very similar to the case with SARS-CoV fusion formation.
43,44
The SARS-CoV entry pathway is thought to be via endosomes —
i.e., the endosomal pathway
43
— though the entry mechanism of this
virus seems to be different from that of influenza or VSV (Fig. 2).
SARS-CoV infection in cultured cells does not induce syncytium for-
mation under a wide range of pH environments, even under low pH
conditions, but cell fusion can be induced when the infected cells are
treated with trypsin.
43,44
The environmental pH does not affect the
fusion activity of trypsin. Moreover, SARS-CoV infection is affected by
a lysosomtropic agent, such as bafilomycin or ammonium chloride.
43
These findings suggest that SARS-CoV is trafficked to the endosome
after binding to ACE2, where the S protein is fusogenically activated
by the trypsin-like protease which is presumably supplied by the lyso-
some fused with endosome. Recently, cathepsin L was reported to be
a possible protease to activate the SARS-CoV S protein for fusion.
45
Trypsin treatment produces a fragment of about 100 kDa of S from ca.
180-kDa uncleaved S protein. This 100-kDa fragment corresponds to
S2. The transition from 180 kDa to 100 kDa of S protein is caused by
not only trypsin, but also by other proteases such as thermolysin or
