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* Journal List
* Virol J
* v.2; 2005
* PMC1232869
Logo of virolj
Virol J <#>. 2005; 2: 69.
Published online 2005 Aug 22. doi: 10.1186/1743-422X-2-69
PMCID: PMC1232869
PMID: 16115318
Chloroquine is a potent inhibitor of SARS coronavirus infection and spread
Martin J Vincent
,^1
Eric Bergeron
,^2
Suzanne Benjannet
,^2
Bobbie R Erickson
,^1
Pierre E Rollin
,^1
Thomas G Ksiazek
,^1
Nabil G Seidah
,^2
and Stuart T Nichol
^corresponding
author ^1
Martin J Vincent
^1 Special Pathogens Brach, Division of Viral and Rickettsial Diseases,
Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta,
Georgia, 30333, USA
Find articles by Martin J Vincent
Eric Bergeron
^2 Laboratory of Biochemical Neuroendocrinology, Clinical Research
Institute of Montreal, 110 Pine Ave West, Montreal, QCH2W1R7, Canada
Find articles by Eric Bergeron
Suzanne Benjannet
^2 Laboratory of Biochemical Neuroendocrinology, Clinical Research
Institute of Montreal, 110 Pine Ave West, Montreal, QCH2W1R7, Canada
Find articles by Suzanne Benjannet
Bobbie R Erickson
^1 Special Pathogens Brach, Division of Viral and Rickettsial Diseases,
Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta,
Georgia, 30333, USA
Find articles by Bobbie R Erickson
Pierre E Rollin
^1 Special Pathogens Brach, Division of Viral and Rickettsial Diseases,
Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta,
Georgia, 30333, USA
Find articles by Pierre E Rollin
Thomas G Ksiazek
^1 Special Pathogens Brach, Division of Viral and Rickettsial Diseases,
Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta,
Georgia, 30333, USA
Find articles by Thomas G Ksiazek
Nabil G Seidah
^2 Laboratory of Biochemical Neuroendocrinology, Clinical Research
Institute of Montreal, 110 Pine Ave West, Montreal, QCH2W1R7, Canada
Find articles by Nabil G Seidah
Stuart T Nichol
^1 Special Pathogens Brach, Division of Viral and Rickettsial Diseases,
Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta,
Georgia, 30333, USA
Find articles by Stuart T Nichol
Author information <#> Article notes <#> Copyright and License
information <#> Disclaimer
^1 Special Pathogens Brach, Division of Viral and Rickettsial Diseases,
Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta,
Georgia, 30333, USA
^2 Laboratory of Biochemical Neuroendocrinology, Clinical Research
Institute of Montreal, 110 Pine Ave West, Montreal, QCH2W1R7, Canada
^corresponding author Corresponding author.
Martin J Vincent: vog.cdc@tnecnivm ; Eric Bergeron:
ac.cq.mcri@eregreb ; Suzanne Benjannet:
ac.cq.mcri@snajneb ; Bobbie R Erickson:
vog.cdc@1noskcirEB ; Pierre E Rollin: vog.cdc@nilloRP
; Thomas G Ksiazek: vog.cdc@kezaisKT ;
Nabil G Seidah: ac.cq.mcri@nhadies ; Stuart T Nichol:
vog.cdc@lohciNS
Received 2005 Jul 12; Accepted 2005 Aug 22.
Copyright © 2005
Vincent et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0
), which permits
unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited.
This article has been cited by
other
articles in PMC.
Go to: <#>
Abstract
Background
Severe acute respiratory syndrome (SARS) is caused by a newly discovered
coronavirus (SARS-CoV). No effective prophylactic or post-exposure
therapy is currently available.
Results
We report, however, that chloroquine has strong antiviral effects on
SARS-CoV infection of primate cells. These inhibitory effects are
observed when the cells are treated with the drug either before or after
exposure to the virus, suggesting both prophylactic and therapeutic
advantage. In addition to the well-known functions of chloroquine such
as elevations of endosomal pH, the drug appears to interfere with
terminal glycosylation of the cellular receptor, angiotensin-converting
enzyme 2. This may negatively influence the virus-receptor binding and
abrogate the infection, with further ramifications by the elevation of
vesicular pH, resulting in the inhibition of infection and spread of
SARS CoV at clinically admissible concentrations.
Conclusion
Chloroquine is effective in preventing the spread of SARS CoV in cell
culture. Favorable inhibition of virus spread was observed when the
cells were either treated with chloroquine prior to or after SARS CoV
infection. In addition, the indirect immunofluorescence assay described
herein represents a simple and rapid method for screening SARS-CoV
antiviral compounds.
*Keywords: *severe acute respiratory syndrome coronavirus, chloroquine,
inhibition, therapy
Go to: <#>
Background
Severe acute respiratory syndrome (SARS) is an emerging disease that was
first reported in Guangdong Province, China, in late 2002. The disease
rapidly spread to at least 30 countries within months of its first
appearance, and concerted worldwide efforts led to the identification of
the etiological agent as SARS coronavirus (SARS-CoV), a novel member of
the family /Coronaviridae /[1 <#B1>]. Complete genome sequencing of
SARS-CoV [2 <#B2>,3 <#B3>] confirmed that this pathogen is not closely
related to any of the previously established coronavirus groups. Budding
of the SARS-CoV occurs in the Golgi apparatus [4 <#B4>] and results in
the incorporation of the envelope spike glycoprotein into the virion.
The spike glycoprotein is a type I membrane protein that facilitates
viral attachment to the cellular receptor and initiation of infection,
and angiotensin-converting enzyme-2 (ACE2) has been identified as a
functional cellular receptor of SARS-CoV [5 <#B5>]. We have recently
shown that the processing of the spike protein was effected by
furin-like convertases and that inhibition of this cleavage by a
specific inhibitor abrogated cytopathicity and significantly reduced the
virus titer of SARS-CoV [6 <#B6>].
Due to the severity of SARS-CoV infection, the potential for rapid
spread of the disease, and the absence of proven effective and safe /in
vivo /inhibitors of the virus, it is important to identify drugs that
can effectively be used to treat or prevent potential SARS-CoV
infections. Many novel therapeutic approaches have been evaluated in
laboratory studies of SARS-CoV: notable among these approaches are those
using siRNA [7 <#B7>], passive antibody transfer [8 <#B8>], DNA
vaccination [9 <#B9>], vaccinia or parainfluenza virus expressing the
spike protein [10 <#B10>,11 <#B11>], interferons [12 <#B12>,13 <#B13>],
and monoclonal antibody to the S1-subunit of the spike glycoprotein that
blocks receptor binding [14 <#B14>]. In this report, we describe the
identification of chloroquine as an effective pre- and post-infection
antiviral agent for SARS-CoV. Chloroquine, a 9-aminoquinoline that was
identified in 1934, is a weak base that increases the pH of acidic
vesicles. When added extracellularly, the non-protonated portion of
chloroquine enters the cell, where it becomes protonated and
concentrated in acidic, low-pH organelles, such as endosomes, Golgi
vesicles, and lysosomes. Chloroquine can affect virus infection in many
ways, and the antiviral effect depends in part on the extent to which
the virus utilizes endosomes for entry. Chloroquine has been widely used
to treat human diseases, such as malaria, amoebiosis, HIV, and
autoimmune diseases, without significant detrimental side effects [15
<#B15>]. Together with data presented here, showing virus inhibition in
cell culture by chloroquine doses compatible with patient treatment,
these features suggest that further evaluation of chloroquine in animal
models of SARS-CoV infection would be warranted as we progress toward
finding effective antivirals for prevention or treatment of the disease.
Go to: <#>
Results
Preinfection chloroquine treatment renders Vero E6 cells
refractory to SARS-CoV infection
In order to investigate if chloroquine might prevent SARS-CoV infection,
permissive Vero E6 cells [1 <#B1>] were pretreated with various
concentrations of chloroquine (0.1–10 μM) for 20–24 h prior to virus
infection. Cells were then infected with SARS-CoV, and virus antigens
were visualized by indirect immunofluorescence as described in Materials
and Methods. Microscopic examination (Fig. (Fig.1A)1A
) of
the control cells (untreated, infected) revealed extensive
SARS-CoV-specific immunostaining of the monolayer. A dose-dependant
decrease in virus antigen-positive cells was observed starting at 0.1 μM
chloroquine, and concentrations of 10 μM completely abolished SARS-CoV
infection. For quantitative purposes, we counted the number of cells
stained positive from three random locations on a slide. The average
number of positively stained control cells was scored as 100% and was
compared with the number of positive cells observed under various
chloroquine concentrations (Fig. (Fig.1B).1B
).
Pretreatment with 0.1, 1, and 10 μM chloroquine reduced infectivity by
28%, 53%, and 100%, respectively. Reproducible results were obtained
from three independent experiments. These data demonstrated that
pretreatment of Vero E6 cells with chloroquine rendered these cells
refractory to SARS-CoV infection.
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Figure 1
*Prophylactic effect of chloroquine*. Vero E6 cells pre-treated with
chloroquine for 20 hrs. Chloroquine-containing media were removed and
the cells were washed with phosphate buffered saline before they were
infected with SARS-CoV (0.5 multiplicity of infection) for 1 h. in the
absence of chloroquine. Virus was then removed and the cells were
maintained in Opti-MEM (Invitrogen) for 16–18 h in the absence of
chloroquine. SARS-CoV antigens were stained with virus-specific HMAF,
followed by FITC-conjugated secondary antibodies. *(A) *The
concentration of chloroquine used is indicated on the top of each panel.
*(B) *SARS-CoV antigen-positive cells at three random locations were
captured by using a digital camera, the number of antigen-positive cells
was determined, and the average inhibition was calculated. Percent
inhibition was obtained by considering the untreated control as 0%
inhibition. The vertical bars represent the range of SEM.
Postinfection chloroquine treatment is effective in preventing the
spread of SARS-CoV infection
In order to investigate the antiviral properties of chloroquine on
SARS-CoV after the initiation of infection, Vero E6 cells were infected
with the virus and fresh medium supplemented with various concentrations
of chloroquine was added immediately after virus adsorption. Infected
cells were incubated for an additional 16–18 h, after which the presence
of virus antigens was analyzed by indirect immunofluorescence analysis.
When chloroquine was added after the initiation of infection, there was
a dramatic dose-dependant decrease in the number of virus
antigen-positive cells (Fig. (Fig.2A).2A
). As
little as 0.1–1 μM chloroquine reduced the infection by 50% and up to
90–94% inhibition was observed with 33–100 μM concentrations (Fig.
(Fig.2B).2B
). At
concentrations of chloroquine in excess of 1 μM, only a small number of
individual cells were initially infected, and the spread of the
infection to adjacent cells was all but eliminated. A half-maximal
inhibitory effect was estimated to occur at 4.4 ± 1.0 μM chloroquine
(Fig. (Fig.2C).2C
).
These data clearly show that addition of chloroquine can effectively
reduce the establishment of infection and spread of SARS-CoV if the drug
is added immediately following virus adsorption.
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Figure 2
*Post-infection chloroquine treatment reduces SARS-CoV infection and
spread*. Vero E6 cells were seeded and infected as described for Fig. 1
except that chloroquine was added only after virus adsorption. Cells
were maintained in Opti-MEM (Invitrogen) containing chloroquine for
16–18 h, after which they were processed for immunofluorescence. *(A)
*The concentration of chloroquine is indicated on the top. *(B) *Percent
inhibition and SEM were calculated as in Fig. 1B. *(C) *The effective
dose (ED_50 ) was calculated using commercially available software
(Grafit, version 4, Erithacus Software).
Electron microscopic analysis indicated the appearance of significant
amounts of extracellular virus particles 5–6 h after infection [16
<#B16>]. Since we observed antiviral effects by chloroquine immediately
after virus adsorption, we further extended the analysis by adding
chloroquine 3 and 5 h after virus adsorption and examined for the
presence of virus antigens after 20 h. We found that chloroquine was
still significantly effective even when added 5 h after infection (Fig.
(Fig.3);3
);
however, to obtain equivalent antiviral effect, a higher concentration
of chloroquine was required if the drug was added 3 or 5 h after adsorption.
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Figure 3
*Timed post-infection treatment with chloroquine*. This experiment is
similar to that depicted in Fig. 2 except that cells were infected at 1
multiplicity of infection, and chloroquine (10, 25, and 50 μM) was added
3 or 5 h after infection.
Ammonium chloride inhibits SARS-CoV infection of Vero E6 cells
Since chloroquine inhibited SARS-CoV infection when added before or
after infection, we hypothesized that another common lysosomotropic
agent, NH_4 Cl, might also function in a similar manner. Ammonium
chloride has been widely used in studies addressing endosome-mediated
virus entry. Coincidently, NH_4 Cl was recently shown to reduce the
transduction of pseudotype viruses decorated with SARS-CoV spike protein
[17 <#B17>,18 <#B18>]. In an attempt to examine if NH_4 Cl functions
similarly to chloroquine, we performed infection analyses in Vero E6
cells before (Fig. (Fig.4A)4A
) and
after (Fig. (Fig.4B)4B
) they
were treated with various concentrations of NH_4 Cl. In both cases, we
observed a 93–99% inhibition with NH_4 Cl at ≥ 5 mM. These data
indicated that NH_4 Cl (≥ 5 mM) and chloroquine (≥ 10 μM) are very
effective in reducing SARS-CoV infection. These results suggest that
effects of chloroquine and NH_4 Cl in controlling SARS CoV infection and
spread might be mediated by similar mechanism(s).
An external file that holds a picture, illustration, etc. Object name is
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Figure 4
*NH_4 Cl inhibits SARS-CoV during pre or post infection treatment*. NH_4
Cl was added to the cells either before (A) or after (B) infection,
similar to what was done for chloroquine in Figs 1 and 2.
Antigen-positive cells were counted, and the results were presented as
in Fig. 1B.
Effect of chloroquine and NH_4 Cl on cell surface expression of ACE2
We performed additional experiments to elucidate the mechanism of
SARS-CoV inhibition by chloroquine and NH_4 Cl. Since intra-vesicular
acidic pH regulates cellular functions, including N-glycosylation
trimming, cellular trafficking, and various enzymatic activities, it was
of interest to characterize the effect of both drugs on the processing,
glycosylation, and cellular sorting of SARS-CoV spike glycoprotein and
its receptor, ACE2. Flow cytometry analysis was performed on Vero E6
cells that were either untreated or treated with highly effective
anti-SARS-CoV concentrations of chloroquine or NH_4 Cl. The results
revealed that neither drug caused a significant change in the levels of
cell-surface ACE2, indicating that the observed inhibitory effects on
SARS-CoV infection are not due to the lack of available cell-surface
ACE2 (Fig. (Fig.5A).5A
). We
next analyzed the molecular forms of endogenous ACE2 in untreated Vero
E6 cells and in cells that were pre-incubated for 1 h with various
concentrations of either NH_4 Cl (2.5–10 mM) or chloroquine (1 and 10
μM) and labeled with ^35 S-(Met) for 3 h in the presence or absence of
the drugs (Fig. (Fig.5B5B
and
and5C).5C
).
Under normal conditions, we observed two immunoreactive ACE2 forms,
migrating at ~105 and ~113 kDa, respectively (Fig. (Fig.5B,5B
, lane
1). The ~105-kDa protein is endoglycosidase H sensitive, suggesting that
it represents the endoplasmic reticulum (ER) localized form, whereas the
~113-kDa protein is endoglycosidase H resistant and represents the
Golgi-modified form of ACE2 [19 <#B19>]. The specificity of the antibody
was confirmed by displacing the immunoreactive protein bands with excess
cold-soluble human recombinant ACE2 (+ rhACE2; Fig. Fig.5B,5B
, lane
2). When we analyzed ACE2 forms in the presence of NH_4 Cl, a clear
stepwise increase in the migration of the ~113-kDa protein was observed
with increasing concentrations of NH_4 Cl, with a maximal effect
observed at 10 mM NH_4 Cl, resulting in only the ER form of ACE2 being
visible on the gel (Fig. (Fig.5B,5B
,
compare lanes 3–5). This suggested that the trimming and/or terminal
modifications of the N-glycosylated chains of ACE2 were affected by NH_4
Cl treatment. In addition, at 10 mM NH_4 Cl, the ER form of ACE2
migrated with slightly faster mobility, indicating that NH_4 Cl at that
concentration might also affect core glycosylation. We also examined the
terminal glycosylation status of ACE2 when the cells were treated with
chloroquine (Fig. (Fig.5C).5C
).
Similar to NH_4 Cl, a stepwise increase in the electrophoretic mobility
of ACE2 was observed with increasing concentrations of chloroquine. At
25 μM chloroquine, the faster electrophoretic mobility of the
Golgi-modified form of ACE2 was clearly evident. On the basis of the
flow cytometry and immunoprecipitation analyses, it can be inferred that
NH_4 Cl and chloroquine both impaired the terminal glycosylation of
ACE2, while NH_4 Cl resulted in a more dramatic effect. Although ACE2 is
expressed in similar quantities at the cell surface, the variations in
its glycosylation status might render the ACE2-SARS-CoV interaction less
efficient and inhibit virus entry when the cells are treated with NH_4
Cl and chloroquine.
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Figure 5
*Effect of lysomotropic agents on the cell-surface expression and
biosynthesis of ACE2*. *(A) *Vero E6 cells were cultured for 20 h in the
absence (control) or presence of chloroquine (10 μM) or NH_4 Cl (20 mM).
Cells were labeled with anti-ACE2 (grey histogram) or with a secondary
antibody alone (white histogram). *(B) *Biosynthesis of ACE2 in
untreated cells or in cells treated with NH_4 Cl. Vero E6 cells were
pulse-labeled for 3 h with ^35 S-Met, and the cell lysates were
immunoprecipitated with an ACE2 antibody (lane 1). Preincunbation of the
antibody with recombinant human ACE2 (rhACE2) completely abolished the
signal (lane 2). The positions of the endoglycosidase H-sensitive ER
form and the endoglycosidase H-resistant Golgi form of ACE2 are
emphasized. Note that the increasing concentration of NH_4 Cl resulting
in the decrease of the Golgi form of ACE2. *(C) *A similar experiment
was performed in the presence of the indicated concentrations of
chloroquine. Note the loss of terminal glycans with increasing
concentrations of chloroquine. *(D) *The terminal glycosidic
modification of ACE2 was evaluated by neuraminidase treatment of
immunoprecipitated ACE2. Here cells were treated with 1–25 μM
concentrations of chloroquine during starvation, pulse, and 3-h chase.
To confirm that ACE2 undergoes terminal sugar modifications and that the
terminal glycosylation is affected by NH_4 Cl or chloroquine treatment,
we performed immunopreipitation of ^35 S-labeled ACE2 and subjected the
immunoprecipitates to neuraminidase digestion. Proteins were resolved
using SDS-PAGE (Fig (Fig5D).5D
). It
is evident from the slightly faster mobility of the Golgi form of ACE2
after neuraminidase treatment (Fig (Fig5D,5D
,
compare lanes 1 and 2), that ACE2 undergoes terminal glycosylation;
however, the ER form of ACE2 was not affected by neuraminidase. Cells
treated with 10 μM chloroquine did not result in a significant shift;
whereas 25 μM chloroquine caused the Golgi form of ACE2 to resolve
similar to the neuraminidase-treated ACE2 (Fig (Fig5D,5D
,
compare lanes 5 and 6). These data provide evidence that ACE2 undergoes
terminal glycosylation and that chloroquine at anti-SARS-CoV
concentrations abrogates the process.
Effect of chloroquine and NH_4 Cl on the biosynthesis and
processing of SARS-CoV spike protein
We next addressed whether the lysosomotropic drugs (NH_4 Cl and
chloroquine) affect the biosynthesis, glycosylation, and/or trafficking
of the SARS-CoV spike glycoprotein. For this purpose, Vero E6 cells were
infected with SARS-CoV for 18 h. Chloroquine or ammonium chloride was
added to these cells during while they were being starved (1 h), labeled
(30 min) or chased (3 h). The cell lysates were analyzed by
immunoprecipitation with the SARS-specific polyclonal antibody (HMAF).
The 30-min pulse results indicated that pro-spike (proS) was synthesized
as a ~190-kDa precursor (proS-ER) and processed into ~125-, ~105-, and
~80-kDa proteins (Fig. (Fig.6A,6A
, lane
2), a result identical to that in our previous analysis [6 <#B6>].
Except for the 100 μM chloroquine (Fig. (Fig.6A,6A
, lane
3), there was no significant difference in the biosynthesis or
processing of the virus spike protein in untreated or
chloroquine-treated cells (Fig. (Fig.6A,6A
, lanes
4–6). It should be noted that chloroquine at 100 μM resulted in an
overall decrease in biosynthesis and in the levels of processed virus
glycoprotein. In view of the lack of reduction in the biosynthesis and
processing of the spike glycoprotein in the presence of chloroquine
concentrations (10 and 50 μM) that caused large reductions in SARS-CoV
replication and spread, we conclude that the antiviral effect is
probably not due to alteration of virus glycoprotein biosynthesis and
processing. Similar analyses were performed with NH_4 Cl, and the data
suggested that the biosynthesis and processing of the spike protein were
also not negatively affected by NH_4 Cl (Fig. (Fig.6A,6A
, lanes
7–12). Consistent with our previous analysis [6 <#B6>], we observed the
presence of a larger protein, which is referred to here as oligomers.
Recently, Song et al. [20 <#B20>] provided evidence that these are
homotrimers of the SARS-CoV spike protein and were incorporated into the
virions. Interestingly, the levels of the homotrimers in cells treated
with 100 μM chloroquine and 40 and 20 mM NH_4 Cl (Fig. (Fig.6A,6A
, lanes
3, 9, and 10) were slightly lower than in control cells or cells treated
with lower drug concentrations.
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Figure 6
*Effects of NH_4 Cl and chloroquine (CQ) on the biosynthesis,
processing, and glycosylation of SARS-CoV spike protein*. Vero E6 cells
were infected with SARS-CoV as described in Fig. 2. CQ or NH_4 Cl was
added during the periods of starvation (1 h) and labeling (30 min) with
^35 S-Cys and followed by chase for 3 h in the presence of unlabeled
medium. Cells were lysed in RIPA buffer and immunoprecipitated with
HMAF. Virus proteins were resolved using 3–8% NuPAGE gel (Invitrogen).
The cells presented were labeled for 30 min *(A) *and chased for 3 h
*(B)*. The migration positions of the various spike molecular forms are
indicated at the right side, and those of the molecular standards are
shown to the left side. proS-ER and proS-Golgi are the pro-spike of
SARS-Co in the ER and Golgi compartments, respectively and proS-ungly is
the unglycosylated pro-spike ER.
The data obtained from a 30-min pulse followed by a 3-h chase (Fig.
(Fig.6B,6B
, lanes
2 and 8) confirmed our earlier observation that the SARS-CoV spike
protein precursor (proS-ER) acquires Golgi-specific modifications
(proS-Golgi) resulting in a ~210-kDa protein [6 <#B6>]. Chloroquine at
10, 25, and 50 μM had no substantial negative impact on the appearance
of the Golgi form (Fig. (Fig.6B,6B
,
compare lane 2 to lanes 4–6). Only at 100 μM chloroquine was a reduction
in the level of the Golgi-modified pro-spike observed (lane 3). On the
other hand, NH_4 Cl abrogated the appearance of Golgi-modified forms at
≥10 mM (compare lane 8 with 9–11) and had a milder effect at 1 mM (lane
12). These data clearly demonstrate that the biosynthesis and
proteolytic processing of SARS-CoV spike protein are not affected at
chloroquine (25 and 50 μM) and NH_4 Cl (1 mM) doses that cause virus
inhibitory effects. In addition, with 40, 20, and 10 mM NH_4 Cl, there
was an increased accumulation of proS-ER with a concomitant decrease in
the amount of oligomers (Fig. (Fig.6B,6B
, lanes
9–11). When we examined the homotrimers, we found that chloroquine at
100 μM and NH_4 Cl at 40 and 20 mM resulted in slightly faster mobility
of the trimers (Fig. (Fig.6B,6B
, lanes
3, 9, and 10), but lower drug doses, which did exhibit significant
antiviral effects, did not result in appreciable differences. These data
suggest that the newly synthesized intracellular spike protein may not
be a major target for chloroquine and NH_4 Cl antiviral action. The
faster mobility of the trimer at certain higher concentration of the
drugs might be due the effect of these drugs on the terminal
glycosylation of the trimers.
Go to: <#>
Discussion
We have identified chloroquine as an effective antiviral agent for
SARS-CoV in cell culture conditions, as evidenced by its inhibitory
effect when the drug was added prior to infection or after the
initiation and establishment of infection. The fact that chloroquine
exerts an antiviral effect during pre- and post-infection conditions
suggest that it is likely to have both prophylactic and therapeutic
advantages. Recently, Keyaerts et al. [21 <#B21>] reported the antiviral
properties of chloroquine and identified that the drug affects SARS-CoV
replication in cell culture, as evidenced by quantitative RT-PCR. Taken
together with the findings of Keyaerts et al. [21 <#B21>], our analysis
provides further evidence that chloroquine is effective against SARS-CoV
Frankfurt and Urbani strains. We have provided evidence that chloroquine
is effective in preventing SARS-CoV infection in cell culture if the
drug is added to the cells 24 h prior to infection. In addition,
chloroquine was significantly effective even when the drug was added 3–5
h after infection, suggesting an antiviral effect even after the
establishment of infection. Since similar results were obtained by NH_4
Cl treatment of Vero E6 cells, the underlying mechanism(s) of action of
these drugs might be similar.
Apart from the probable role of chloroquine on SARS-CoV replication, the
mechanisms of action of chloroquine on SARS-CoV are not fully
understood. Previous studies have suggested the elevation of pH as a
mechanism by which chloroquine reduces the transduction of SARS-CoV
pseudotype viruses [17 <#B17>,18 <#B18>]. We examined the effect of
chloroquine and NH_4 Cl on the SARS-CoV spike proteins and on its
receptor, ACE2. Immunoprecipitation results of ACE2 clearly demonstrated
that effective anti-SARS-CoV concentrations of chloroquine and NH_4 Cl
also impaired the terminal glycosylation of ACE2. However, the flow
cytometry data demonstrated that there are no significant differences in
the cell surface expression of ACE2 in cells treated with chloroquine or
NH_4 Cl. On the basis of these results, it is reasonable to suggest that
the pre-treatment with NH_4 Cl or chloroquine has possibly resulted in
the surface expression of the under-glycosylated ACE2. In the case of
chloroquine treatment prior to infection, the impairment of terminal
glycosylation of ACE2 may result in reduced binding affinities between
ACE2 and SARS-CoV spike protein and negatively influence the initiation
of SARS-CoV infection. Since the biosynthesis, processing, Golgi
modification, and oligomerization of the newly synthesized spike protein
were not appreciably affected by anti-SARS-CoV concentrations of either
chloroquine or NH_4 Cl, we conclude that these events occur in the cell
independent of the presence of the drugs. The potential contribution of
these drugs in the elevation of endosomal pH and its impact on
subsequent virus entry or exit could not be ruled out. A decrease in
SARS-CoV pseudotype transduction in the presence of NH_4 Cl was observed
and was attributed to the effect on intracellular pH [17 <#B17>,18
<#B18>]. When chloroquine or NH_4 Cl are added after infection, these
agents can rapidly raise the pH and subvert on-going fusion events
between virus and endosomes, thus inhibiting the infection.
In addition, the mechanism of action of NH_4 Cl and chloroquine might
depend on when they were added to the cells. When added after the
initiation of infection, these drugs might affect the endosome-mediated
fusion, subsequent virus replication, or assembly and release. Previous
studies of chloroquine have demonstrated that it has multiple effects on
mammalian cells in addition to the elevation of endosomal pH, including
the prevention of terminal glycosyaltion of immunoglobulins [22 <#B22>].
When added to virus-infected cells, chloroquine inhibited later stages
in vesicular stomatitis virus maturation by inhibiting the glycoprotein
expression at the cell surface [23 <#B23>], and it inhibited the
production of infectious HIV-1 particles by interfering with terminal
glycosylation of the glycoprotein [24 <#B24>,25 <#B25>]. On the basis of
these properties, we suggest that the cell surface expression of
under-glycosylated ACE2 and its poor affinity to SARS-CoV spike protein
may be the primary mechanism by which infection is prevented by drug
pretreatment of cells prior to infection. On the other hand, rapid
elevation of endosomal pH and abrogation of virus-endosome fusion may be
the primary mechanism by which virus infection is prevented under
post-treatment conditions. More detailed SARS CoV spike-ACE2 binding
assays in the presence or absence of chloroquine will be performed to
confirm our findings. Our studies indicate that the impact of NH_4 Cl
and chloroquine on the ACE2 and spike protein profiles are significantly
different. NH_4 Cl exhibits a more pronounced effect than does
chloroquine on terminal glycosylation, highlighting the novel intricate
differences between chloroquine and ammonium chloride in affecting the
protein transport or glycosylation of SARS-CoV spike protein and its
receptor, ACE2, despite their well-established similar effects of
endosomal pH elevation.
The infectivity of coronaviruses other than SARS-CoV are also affected
by chloroquine, as exemplified by the human CoV-229E [15 <#B15>]. The
inhibitory effects observed on SARS-CoV infectivity and cell spread
occurred in the presence of 1–10 μM chloroquine, which are plasma
concentrations achievable during the prophylaxis and treatment of
malaria (varying from 1.6–12.5 μM) [26 <#B26>] and hence are well
tolerated by patients. It recently was speculated that chloroquine might
be effective against SARS and the authors suggested that this compound
might block the production of TNFα, IL6, or IFNγ [15 <#B15>]. Our data
provide evidence for the possibility of using the well-established drug
chloroquine in the clinical management of SARS.
Go to: <#>
Conclusion
Chloroquine, a relatively safe, effective and cheap drug used for
treating many human diseases including malaria, amoebiosis and human
immunodeficiency virus is effective in inhibiting the infection and
spread of SARS CoV in cell culture. The fact that the drug has
significant inhibitory antiviral effect when the susceptible cells were
treated either prior to or after infection suggests a possible
prophylactic and therapeutic use.
Go to: <#>
Methods
SARS-CoV infection, immunofluorescence, and immunoprecipitation
analyses
Vero E6 cells (an African green monkey kidney cell line) were infected
with SARS-CoV (Urbani strain) at a multiplicity of infection of 0.5 for
1 h. The cells were washed with PBS and then incubated in OPTI-MEM
(Invitrogen) medium with or without various concentrations of either
chloroquine or NH_4 Cl (both from Sigma). Immunofluorescence staining
was performed with SARS-CoV-specific hyperimmune mouse ascitic fluid
(HMAF) [8 <#B8>] followed by anti-mouse fluorescein-coupled antibody.
Eighteen hours after infection, the virus-containing supernatants were
removed, and the cells were pulsed with ^35 S-(Cys) for 30 min and
chased for 3 h before lysis in RIPA buffer. Clarified cell lysates and
media were incubated with HMAF, and immunoprecipitated proteins were
separated by 3–8% NuPAGE gel (Invitrogen); proteins were visualized by
autoradiography. In some experiments, cells were chased for 3 h with
isotope-free medium. Clarified cell supernatants were also
immunoprecipitated with SARS-CoV-specific HMAF.
ACE2 flow cytometry analysis and biosynthesis
Vero E6 cells were seeded in Dulbecco's modified Eagle medium
(Invitrogen) supplemented with 10% fetal bovine serum. The next day, the
cells were incubated in Opti-MEM (Invitrogen) in the presence or absence
of 10 μM chloroquine or 20 mM NH_4 Cl. To analyze the levels of ACE2 at
the cell surface, cells were incubated on ice with 10 μg/mL
affinity-purified goat anti-ACE2 antibody (R&D Systems) and then
incubated with FITC-labeled swine anti-goat IgG antibody (Caltag
Laboratories). Labeled cells were analyzed by flow cytometry with a
FACSCalibur flow cytometer (BD Biosciences). For ACE2 biosynthesis
studies, Vero E6 cells were pulsed with 250 μCi ^35 S-(Met) (Perkin
Elmer) for 3 h with the indicated concentrations of chloroquine or NH_4
Cl and then lysed in RIPA buffer. Clarified lysates were
immunoprecipitated with an affinity-purified goat anti-ACE2 antibody
(R&D systems), and the immunoprecipitated proteins were separated by
SDS-polyacrylamide gel electrophoresis.
Go to: <#>
Competing interests
The author(s) declare that they have no competing interests.
Go to: <#>
Authors' contributions
MV did all the experiments pertaining to SARS CoV infection and
coordinated the drafting of the manuscript. EB and SB performed
experiments on ACE2 biosynthesis and FACS analysis. BE performed data
acquisition from the immunofluorescence experiments. PR and TK provided
critical reagents and revised the manuscript critically. NS and SN along
with MV and EB participated in the planning of the experiments, review
and interpretation of data and critical review of the manuscript. All
authors read and approved the content of the manuscript.
Go to: <#>
Acknowledgements
We thank Claudia Chesley and Jonathan Towner for critical reading of the
manuscript. This work was supported by a Canadian PENCE grant (T3), CIHR
group grant #MGC 64518, and CIHR grant #MGP-44363 (to NGS).
Go to: <#>
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* Abstract <#idm140174622490016title>
* Background <#__sec4title>
* Results <#__sec5title>
* Discussion <#__sec11title>
* Conclusion <#__sec12title>
* Methods <#__sec13title>
* Competing interests <#__sec16title>
* Authors' contributions <#__sec17title>
* Acknowledgements <#idm140174624996256title>
* References <#idm140174624994784title>
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* A novel coronavirus associated with severe acute respiratory
syndrome. [N Engl J
Med. 2003]
Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR, Peret T, Emery S, Tong
S, Urbani C, Comer JA, Lim W, Rollin PE, Dowell SF, Ling AE,
Humphrey CD, Shieh WJ, Guarner J, Paddock CD, Rota P, Fields B,
DeRisi J, Yang JY, Cox N, Hughes JM, LeDuc JW, Bellini WJ, Anderson
LJ, SARS Working Group.
N Engl J Med. 2003 May 15; 348(20):1953-66.
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[Science. 2003]
Marra MA, Jones SJ, Astell CR, Holt RA, Brooks-Wilson A, Butterfield
YS, Khattra J, Asano JK, Barber SA, Chan SY, Cloutier A, Coughlin
SM, Freeman D, Girn N, Griffith OL, Leach SR, Mayo M, McDonald H,
Montgomery SB, Pandoh PK, Petrescu AS, Robertson AG, Schein JE,
Siddiqui A, Smailus DE, Stott JM, Yang GS, Plummer F, Andonov A,
Artsob H, Bastien N, Bernard K, Booth TF, Bowness D, Czub M, Drebot
M, Fernando L, Flick R, Garbutt M, Gray M, Grolla A, Jones S,
Feldmann H, Meyers A, Kabani A, Li Y, Normand S, Stroher U, Tipples
GA, Tyler S, Vogrig R, Ward D, Watson B, Brunham RC, Krajden M,
Petric M, Skowronski DM, Upton C, Roper RL
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respiratory syndrome.
[Science. 2003]
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Peñaranda S, Bankamp B, Maher K, Chen MH, Tong S, Tamin A, Lowe L,
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Ksiazek TG, Rollin PE, Sanchez A, Liffick S, Holloway B, Limor J,
McCaustland K, Olsen-Rasmussen M, Fouchier R, Günther S, Osterhaus
AD, Drosten C, Pallansch MA, Anderson LJ, Bellini WJ
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[J Gen Virol. 2003]
Ng ML, Tan SH, See EE, Ooi EE, Ling AE
J Gen Virol. 2003 Dec; 84(Pt 12):3291-3303.
* Angiotensin-converting enzyme 2 is a functional receptor for the
SARS coronavirus.
[Nature. 2003]
Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran
M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M
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of severe acute respiratory syndrome coronavirus.
[Biochem Biophys Res
Commun. 2005]
Bergeron E, Vincent MJ, Wickham L, Hamelin J, Basak A, Nichol ST,
Chrétien M, Seidah NG
Biochem Biophys Res Commun. 2005 Jan 21; 326(3):554-63.
* Silencing SARS-CoV Spike protein expression in cultured cells by RNA
interference. [FEBS
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Zhang Y, Li T, Fu L, Yu C, Li Y, Xu X, Wang Y, Ning H, Zhang S, Chen
W, Babiuk LA, Chang Z
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* Prior infection and passive transfer of neutralizing antibody
prevent replication of severe acute respiratory syndrome coronavirus
in the respiratory tract of mice.
[J Virol. 2004]
Subbarao K, McAuliffe J, Vogel L, Fahle G, Fischer S, Tatti K,
Packard M, Shieh WJ, Zaki S, Murphy B
J Virol. 2004 Apr; 78(7):3572-7.
* A DNA vaccine induces SARS coronavirus neutralization and protective
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Yang ZY, Kong WP, Huang Y, Roberts A, Murphy BR, Subbarao K, Nabel GJ
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* Severe acute respiratory syndrome coronavirus spike protein
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[Proc Natl Acad Sci U
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Subbarao K, Moss B
Proc Natl Acad Sci U S A. 2004 Apr 27; 101(17):6641-6.
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by interferon- alpha.
[J Infect Dis. 2004]
Ströher U, DiCaro A, Li Y, Strong JE, Aoki F, Plummer F, Jones SM,
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J Infect Dis. 2004 Apr 1; 189(7):1164-7.
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coronavirus by a human mAb to S1 protein that blocks receptor
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Natl Acad Sci U S A. 2004]
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Tallarico AS, Olurinde M, Choe H, Anderson LJ, Bellini WJ, Farzan M,
Marasco WA
Proc Natl Acad Sci U S A. 2004 Feb 24; 101(8):2536-41.
* Review Effects of chloroquine on viral infections: an old drug
against today's diseases?
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Lancet Infect Dis. 2003 Nov; 3(11):722-7.
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Ng ML, Tan SH, See EE, Ooi EE, Ling AE
J Med Virol. 2003 Nov; 71(3):323-31.
[PubMed ] [Ref list <#B16>]
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coronavirus (SARS-CoV) spike glycoprotein-mediated viral entry.
Simmons G, Reeves JD, Rennekamp AJ, Amberg SM, Piefer AJ, Bates P
Proc Natl Acad Sci U S A. 2004 Mar 23; 101(12):4240-5.
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pH-dependent entry of severe acute respiratory syndrome coronavirus is
mediated by the spike glycoprotein and enhanced by dendritic cell
transfer through DC-SIGN.
Yang ZY, Huang Y, Ganesh L, Leung K, Kong WP, Schwartz O, Subbarao K,
Nabel GJ
J Virol. 2004 Jun; 78(11):5642-50.
[PubMed ] [Ref list <#B18>]
A human homolog of angiotensin-converting enzyme. Cloning and functional
expression as a captopril-insensitive carboxypeptidase.
Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ
J Biol Chem. 2000 Oct 27; 275(43):33238-43.
[PubMed ] [Ref list <#B19>]
Synthesis and characterization of a native, oligomeric form of
recombinant severe acute respiratory syndrome coronavirus spike
glycoprotein.
Song HC, Seo MY, Stadler K, Yoo BJ, Choo QL, Coates SR, Uematsu Y,
Harada T, Greer CE, Polo JM, Pileri P, Eickmann M, Rappuoli R, Abrignani
S, Houghton M, Han JH
J Virol. 2004 Oct; 78(19):10328-35.
[PubMed ] [Ref list <#B20>]
In vitro inhibition of severe acute respiratory syndrome coronavirus by
chloroquine.
Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M
Biochem Biophys Res Commun. 2004 Oct 8; 323(1):264-8.
[PubMed ] [Ref list <#B21>]
Chloroquine and ammonium chloride prevent terminal glycosylation of
immunoglobulins in plasma cells without affecting secretion.
Thorens B, Vassalli P
Nature. 1986 Jun 5-11; 321(6070):618-20.
[PubMed ] [Ref list <#B22>]
Inhibition of vesicular stomatitis virus glycoprotein expression by
chloroquine.
Dille BJ, Johnson TC
J Gen Virol. 1982 Sep; 62 (Pt 1)():91-103.
[PubMed ] [Ref list <#B23>]
Inhibition of human immunodeficiency virus infectivity by chloroquine.
Tsai WP, Nara PL, Kung HF, Oroszlan S
AIDS Res Hum Retroviruses. 1990 Apr; 6(4):481-9.
[PubMed ] [Ref list <#B24>]
Anti-HIV effects of chloroquine: inhibition of viral particle
glycosylation and synergism with protease inhibitors.
Savarino A, Lucia MB, Rastrelli E, Rutella S, Golotta C, Morra E,
Tamburrini E, Perno CF, Boelaert JR, Sperber K, Cauda R
J Acquir Immune Defic Syndr. 2004 Mar 1; 35(3):223-32.
[PubMed ] [Ref list <#B25>]
Review Clinical pharmacokinetics and metabolism of chloroquine. Focus on
recent advancements.
Ducharme J, Farinotti R
Clin Pharmacokinet. 1996 Oct; 31(4):257-74.
[PubMed ] [Ref list <#B26>]
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