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Infection and Immunity, March 2000, p. 1271-1275, Vol. 68, No. 3
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Iron Acquisition from Pseudomonas
aeruginosa Siderophores by Human Phagocytes: an Additional
Mechanism of Host Defense through Iron Sequestration?
Bradley E.
Britigan,1,2,*
George T.
Rasmussen,1,2
Oyebode
Olakanmi,1,2 and
Charles D.
Cox3
Medical and Research Service, Veterans
Administration Medical Center, Iowa City, Iowa
52246,1 and Departments of Internal
Medicine2 and
Microbiology,3 The University of Iowa
College of Medicine, Iowa City, Iowa 52242
Received 15 September 1999/Returned for modification 8 November
1999/Accepted 6 December 1999
 |
ABSTRACT |
Chelation of iron to iron-binding proteins is a strategy of host
defense. Some pathogens counter this via the secretion of low-molecular-weight iron-chelating agents (siderophores). Human phagocytes possess a high-capacity mechanism for iron acquisition from
low-molecular-weight iron chelates. Efficient acquisition and
sequestration of iron bound to bacterial siderophores by host phagocytes could provide a secondary mechanism to limit microbial access to iron. In the present work we report that human neutrophils, macrophages, and myeloid cell lines can acquire iron from the two
Pseudomonas aeruginosa siderophores. Analogous to iron
acquisition from other low-molecular-weight chelates, iron acquisition
from the siderophores is ATP independent, induced by multivalent
cationic metals, and unaffected by inhibitors of endocytosis and
pinocytosis. In vivo, this process could serve as an additional
mechanism of host defense to limit iron availability to invading
siderophore-producing microbes.
| |
INTRODUCTION |
Iron is critical to the growth and
metabolism of nearly all living organisms, prokaryotic and eukaryotic.
Limiting the concentration of free extracellular iron is a strategy of
host defense against pathogenic microorganisms that is practiced by
many animal species (4, 9, 12, 22). Humans accomplish this
by binding extracellular iron to the iron-chelating proteins
transferrin and lactoferrin (4, 9, 12, 22). Although there
are some exceptions (5), most bacteria are unable to
directly utilize iron bound to either of these two human proteins. As a
means of acquiring iron under such conditions, many bacterial pathogens
secrete highly efficient low-molecular-weight iron chelating agents,
termed siderophores (17, 18). These agents compete for and
bind available iron. These siderophore-iron complexes are recognized by
the bacteria, which then internalize the iron.
The ability to produce siderophores has been linked to the pathogenic
potential of many bacterial species including Pseudomonas aeruginosa, Escherichia coli, Vibrio
vulnificus, and Vibrio cholerae (11, 13, 14,
23). Siderophore production compromises the effectiveness of the
iron limitation approach to host defense. The host could decrease the
access of the organism to iron if host inflammatory cells could
efficiently acquire and sequester iron chelated to the same
siderophores. Once internalized by these cells, such iron would no
longer be accessible to the organism.
We have previously demonstrated that human phagocytes and myeloid cell
lines possess an inducible high-capacity mechanism for iron acquisition
from a variety of low-molecular-weight iron-chelating agents (19,
20). This system has the following features: (i) its activity is
induced by a variety of multivalent cationic metals; (ii) it is
unaffected when the cells are depleted of ATP or when receptor-mediated
endocytosis is inhibited with dihydrocytochalasin B; and (iii) its
efficiency is chelate specific (19, 20). Based on these
findings, we hypothesized that this phagocyte-associated iron
acquisition system could potentially serve as a host defense mechanism
against siderophore-producing microbes by allowing these cells to
compete with the bacterial pathogen for siderophore-bound iron. To test
this hypothesis, we assessed the ability of human phagocytic cells and
myeloid cell lines to acquire iron bound to the P. aeruginosa-derived siderophores pyoverdin and pyochelin, as
well as the mechanism responsible.
| |
MATERIALS AND METHODS |
Purification and iron loading of P. aeruginosa
siderophores.
Pyoverdin and pyochelin were purified to uniformity
from the growth media of P. aeruginosa strain PA01 (ATCC
15692) using previously described methods (6, 8). For iron
acquisition studies, pyochelin and pyoverdin were loaded with
59Fe by incubating each siderophore with
59FeCl3 such that sufficient 59Fe
was available to load 40% of the siderophore. This was based on the
Fe-siderophore binding stoichiometry of 1:2 and 1:1 for pyochelin and
pyoverdin, respectively (6, 8). [14C]pyoverdin
and [35S]pyochelin were generated using previously
described techniques (2). Briefly, PAO1 bacteria were grown
to early stationary phase (absorbance at 600 nm, 0.6) in 1% Casamino
Acids (CAA) medium, harvested, washed, and resuspended at 2.4 × 1010 CFU/ml in 20 ml of 5 mM phosphate buffer (pH 7.5)
containing 1 mM MgSO4. Concentrated CAA was added to make
the resuspension culture 0.25% CAA, and either 0.5 µCi of
[14C]ornithine (for pyoverdin) or 0.5 µCi of
35SO42
(for pyochelin) was added
to label the siderophores. Reaction cultures were incubated with
shaking at 250 rpm at 37°C for 2 h. Bacteria were removed by
centrifugation, and the supernatants were subjected to siderophore
purification by standard methods (6, 7). The purity of
pyochelin (2) and pyoverdin (7) was analyzed by
high-performance liquid chromatography. The yield of purified
[35S]pyochelin was analyzed by measurement of the
absorbance at 350 nm (7), and the yield of purified
[14C]pyoverdin was assayed by fluorescence emission at
460 nm when solutions were excited at 400 nm (6). The levels
of radioactivity in the two samples were analyzed by liquid
scintillation counting. Radiolabeled pyoverdin or pyochelin was then
loaded with "cold" iron by the method described above for pyochelin
and pyoverdin, except that 57FeCl3 was used.
Human phagocytes.
Human neutrophils and mononuclear
phagocytes were separated from other components of the peripheral
venous blood of normal human donors by a previously established method
(3). Briefly, erythrocytes were removed from heparinized
blood by dextran sedimentation. Leukocytes were separated into
neutrophils and mononuclear cells by centrifugation through a
Ficoll-Hypaque gradient. Neutrophils were washed in Hanks' balanced
salt solution (HBSS) and then kept on ice until used on the same day.
Monocytes and lymphocytes were maintained in in vitro culture for 5 days in Teflon flasks (RPMI 1680 plus 20% autologous serum) to allow
the monocytes to differentiate into monocyte-derived macrophages (MDM)
(10). MDM were then separatedfrom lymphocytes based on their
adherence to plastic over this period in culture. Prior to their use in
iron acquisition assays, MDM were mobilized into solution by being
placed on ice (4°C) for 1 h and then gently scraped as
previously described (19). This low-temperature scraping
leads to negligible cell injury as determined by the measurement of
release of intracellular lactate dehydrogenase (19).
HL-60 and U937 cells.
The human promyelocytic HL-60 and
promonocytic U937 cell lines were cultivated in RPMI 1640 (University
of Iowa Cancer Center, Iowa City, Iowa) plus 10% fetal calf serum and
2 mM glutamine as previously described (19). Prior to use in
iron acquisition assays, the cells were washed three times and
suspended at the desired concentration in HBSS.
Cellular 59Fe acquisition.
Cellular iron
acquisition from pyochelin and pyoverdin was measured by a previously
described method (20). Briefly, cells were suspended in HBSS
(5 × 106/ml) and placed in 96-well plates (100 µl/well). After equilibration at 37°C under 5% CO2,
the desired 59Fe chelate was added at a concentration of
740 nM 59Fe. At defined time points, the cell suspension
was centrifuged (500 × g for 5 min at 4°C) and the
pellet was washed three times. The amount of 59Fe
associated with the cell pellet was then determined with a gamma
counter. In each experiment, the 59Fe chelate was added to
some wells which contained only HBSS but no cells, to control for
possible 59Fe binding to the plate or formation of
non-cell-associated iron aggregates which could cosediment with the
cell pellet. These values, which generally are <0.05% of the added
counts per minute (cpm), were subtracted from those of the
corresponding cell-containing samples at each time point to assess
cell-specific 59Fe acquisition. In some cases, cells were
pretreated with Ga(NO3)3 or other reagents
prior to addition of 59Fe, as detailed in Results.
For measurements of the stability of iron association with the cells,
cells which had been incubated for defined periods in the presence of
the desired 59Fe chelate were washed three times in HBSS
and resuspended in HBSS lacking 59Fe. At defined time
points, the cells were separated from the HBSS supernatant by
centrifugation (500 × g for 5 min at 4°C) and the
pellet was washed an additional three times. The amount of
59Fe associated with the cell pellet, as well as the amount
in the initial supernatant, was then determined with the gamma counter. In some experiments, iron chelators such as pyochelin, pyoverdin, or
nitrilotriacetic acid (NTA) were added to the medium in an attempt to
enhance the removal of 59Fe from the cells.
Statistical analyses.
Results obtained under different
experimental conditions were compared by Student's paired t
test when independent variables were being assessed or by analysis of
variance when analyses of trends were being determined. In each case,
results were considered significant at P < 0.05.
| |
RESULTS |
Acquisition of iron from P. aeruginosa siderophores by
phagocytic cells.
When incubated with
[59Fe]pyoverdin or [59Fe]pyochelin,
neutrophils, MDM, and HL-60 cells each exhibited a similar capacity to acquire 59Fe from these two P. aeruginosa
siderophores over time (Fig. 1). A single
experiment in which U937 cells were used yielded similar results (data
not shown). Analogous to the iron acquisition we had previously
observed from other low-molecular-weight chelates by these cells
(19, 20), preincubating the cells with 1 mM Ga(NO3)3 for 30 min resulted in a dramatic
increase in the magnitude of 59Fe acquired from either
pyochelin or pyoverdin (Fig. 1). Overall iron acquisition from both
siderophores occurred more rapidly with the cell lines than with either
neutrophils or macrophages when they were pretreated with
Ga(NO3)3. Cellular iron acquisition from both
pyoverdin and pyochelin appears to be dissociated from acquisition of
the siderophores themselves. No cellular uptake of either
[35S]ferripyochelin or [14C]ferripyoverdin
could be detected under the conditions which led to detectable iron
acquisition (data not shown).
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FIG. 1.
Acquisition of iron from pyoverdin or pyochelin by
phagocytes and other myeloid cells. Shown are the mean and standard
error of the mean (n = 3) concentrations of iron
acquired from pyoverdin or pyochelin by neutrophils (A), macrophages
(B), and HL-60 cells (C) in the absence ( ) or presence ( ) of
preincubation of the cells with 1 mM Ga(NO3)3
for pyoverdin and in the absence ( ) or presence ( ) of
preincubation of the cells with 1 mM Ga(NO3)3
for pyochelin. Each cell type examined exhibited the ability to acquire
iron from each bacterial siderophore and a marked enhancement of iron
acquisition with gallium pretreatment.
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For the above process to be of biological significance, the iron
acquired from pyoverdin and pyochelin must be stably associated
with
the cells. As shown in Fig.
2 and
3, regardless of whether
the cells
are preincubated with Ga(NO
3)
3, more than 65%
of the
iron acquired from pyoverdin or pyochelin by HL-60 cells
remained
cell associated over a subsequent 4-h incubation in HBSS to
which
no exogenous iron was added. Addition of either apo-pyochelin
or
apo-pyoverdin to the cell suspension also failed to remove
most of the
iron from the cells, regardless of whether it had
initially been
acquired from pyochelin or pyoverdin (Fig.
2).
These data indicate that once cell
associated, iron acquired from
the siderophore is not readily released
into the extracellular
space and therefore would be unavailable to the
microbe.
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FIG. 2.
Stability of cell-associated iron after acquisition from
pyoverdin or pyochelin. (A and B) Control (A) and
Ga(NO3)3-pretreated (B) HL-60 cells were
incubated with [59Fe]pyoverdin for 1 h and then were
repetitively washed and resuspended in buffer alone () or buffer
containing 300 µM apo-pyoverdin () or 100 µM apo-pyochelin
(). Cell-associated 59Fe was then determined over time.
(C and D) control (C) and Ga(NO3)3-pretreated
(D) HL-60 cells were incubated with [59Fe]pyochelin for
1 h and then repetitively washed and resuspended in buffer alone
() or buffer containing 300 µM apo-pyoverdin () or 100 µM
apo-pyochelin (). The cell-associated 59Fe concentration
was then determined over time. Curves shown are representative of three
separate experiments for each condition.
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|
Mechanism of myeloid cell iron acquisition from pyoverdin and
pyochelin.
The above findings are consistent with iron acquisition
from pyoverdin and pyochelin occurring via the inducible
endocytosis-independent mechanism of iron acquisition we have recently
described for myeloid cells (19, 20). To provide additional
evidence in support of this hypothesis, we used the HL-60 cell line to
assess if key features previously identified for this iron acquisition
mechanism also apply to iron acquisition from pyoverdin and pyochelin.
As shown in Fig.
3, treatment of HL-60
cells with 1 mM NaCN and 50 mM 2-deoxyglucose, which decreases the ATP
levels in HL-60
cells to less than 2% of control levels
(
20), had no effect
on the subsequent ability of the cells
to acquire iron from either
pyoverdin or pyochelin. The lack of effect
of NaCN and 2-deoxyglucose
is a feature which distinguishes the iron
acquisition mechanism
we have described from endocytosis or pinocytosis
(
15,
16,
21).
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FIG. 3.
Effect of ATP depletion on iron acquisition from
pyochelin and pyoverdin by HL-60 cells. Control HL-60 cells (solid
bars) or cells which had been pretreated with 1 mM NaCN and 50 mM
2-deoxyglucose (cross-hatched bars) were then incubated with
Ga(NO3)3 and suspended in the presence of
[59Fe]pyoverdin or [59Fe]pyochelin. After
60 min of incubation, cell-associated 59Fe was determined.
No difference (P > 0.05) in cell acquisition of
59Fe was observed from either pyoverdin or pyochelin as a
consequence of treatment of the cells with the metabolic inhibitors.
Results shown are mean and standard error of the mean (n = 3) concentrations of cell-associated iron from experiments
performed in duplicate.
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|
The rate of this form of iron acquisition by human myeloid cells also
is induced by a variety of multivalent cationic metals
as well as a
variety of iron chelates (
19,
20). In contrast,
divalent
metals have been previously shown to have little effect
(
19,
20). Consistent with these findings, salts of Al
3+,
La
3+, Ga
3+, and Gd
3+, markedly
increase
59Fe acquisition from both pyoverdin and pyochelin
by HL-60 cells
(Fig.
4). Iron
acquisition following cellular exposure to FeCl
3 also
increased over that of the control but did not quite reach
statistical
significance (Fig.
4). In contrast to our previous
observations with
HL-60 acquisition of iron from other low-molecular-weight
iron chelates
(
19,
20), Cu
2+, Cd
2+, and
Zn
2+ enhanced the acquisition of iron from both pyochelin
and pyoverdin
(Fig.
5). Mn
2+
had no effect (Fig.
5). Also in contrast to our observations
with other
iron chelates capable of having their iron acquired
by HL-60 cells
(
20), neither ferripyochelin (up to 100 µM) nor
ferripyoverdin (up to 300 µM) induced the rate of HL-60 acquisition
of
59Fe complexed to the ferric iron chelator NTA (Fig.
6).
In fact,
preincubation with ferripyoverdin appears to decrease iron
acquisition
from NTA by HL-60 cells (Fig.
6). As expected
(
20), preincubation
of the cells with either
Ga(NO
3)
3 or FeNTA enhanced the ability
of the
cells to acquire Fe from NTA (Fig.
6).
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FIG. 4.
Effect of trivalent metals on iron acquisition from
pyoverdin (A) and pyochelin (B) by HL-60 cells. Shown is the mean and
standard error of the mean (n = 3) concentration of
cell-associated 59Fe following a 60-min incubation, in the
presence of [59Fe]pyoverdin (A) or
[59Fe]pyochelin (B), of control HL-60 cells or cells
which had been preincubated with 1 mM trivalent metal (indicated on the
x axis). *, P < 0.05 relative to control.
Specific P values relative to control for are as follows:
A1, P < 0.02; Fe, P < 0.07; Ga,
P < 0.002; Gd, P < 0.01; and La,
P < 0.02 (A) and A1, P < 0.02; Fe,
P < 0.06; Ga, P < 0.04; Gd,
P < 0.04; and La, P < 0.02 (B).
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FIG. 5.
Effect of divalent metals on iron acquisition from
pyoverdin (A) and pyochelin (B) by HL-60 cells. Shown is the mean and
standard error of the mean (n = 3) concentration of
cell-associated 59Fe following a 60-min incubation, in the
presence of [59Fe]pyoverdin (A) or
[59Fe]pyochelin (B), of control HL-60 cells and cells
which had been preincubated with 1 mM divalent metal (indicated on the
x axis). Experiments utilizing the trivalent metal Ga were
performed as a positive control and are included as a point of
reference. *, P < 0.05 relative to control. Specific
P values relative to control are as follows: Ga,
P < 0.05; Cd, P < 0.02; Cu,
P < 0.003; Mn, P < 0.2; and Zn,
P < 0.05 (A) and Ga, P < 0.0007; Cd,
P < 0.003; Cu, P < 0.00005; Mn,
P < 0.9; and Zn, P < 0.0007 (B).
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FIG. 6.
Effect of ferrisiderophores on of HL-60 iron acquisition
from NTA. Shown is the mean and standard error of the mean
(n = 4) concentration of cell-associated
59Fe following incubation at the defined time points, in
the presence of [59Fe]NTA, of HL-60 cells which had first
been preincubated with buffer only (), 300 µM ferripyoverdin
(), 100 µM ferripyochelin ( ), 100 µM
Ga(NO3)3 (), or 100 µM FeNTA (, single
experiment) for 30 min prior to the addition of
[59Fe]NTA.
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| |
DISCUSSION |
Limiting extracellular iron availability has been regarded as an
important mechanism of human host defense against microbial pathogens,
essentially all of which require iron for optimal growth and metabolism
(4, 9, 12, 22). Most investigations have focused on the role
of iron chelation by the extracellular host iron-binding proteins
transferrin and lactoferrin in achieving this process (4, 9, 12,
22). However, many bacterial pathogens produce siderophores,
whose affinity for iron is in the range of lactoferrin and transferrin,
effectively negating this iron limitation strategy of the host
(17, 18).
In the present work we present data which indicate that human
phagocytic cells (neutrophils and macrophages) as well as myeloid cell
lines (HL-60 and U937) are capable of acquiring iron from the two
siderophores produced by the major human pathogen P. aeruginosa. These data are consistent with the possibility that
iron acquisition from bacterial siderophores by phagocytes at sites of
infection serves as an additional mechanism for the host to limit iron
availability for invading microbes. To our knowledge, this possibility
has not been previously proposed.
The mechanism whereby phagocytes and myeloid cells acquire iron
from pyoverdin and pyochelin exhibits many of the same characteristics as the mechanism of transferrin-independent iron acquisition from a
variety of low-molecular-weight chelating agents we recently detailed
in these cell types (19, 20). It is ATP independent, highly
inducible by multivalent cationic metals, and unaffected by inhibitors
of endocytosis and pinocytosis. In contrast to our earlier experience
with this means of cellular iron acquisition, several divalent metals
(Cu, Cd, and Zn) also exhibit the ability to enhance the magnitude of
iron acquisition from both pyochelin and pyoverdin. Since the mechanism
whereby these metals enhance cellular iron acquisition from
low-molecular-weight chelating agents is unknown, it is difficult to
speculate why divalent metals alter the rate of iron acquisition from
the bacterial siderophores but not other low-molecular-weight
iron-chelating agents. Nevertheless, since we were unable to detect the
uptake of the siderophores themselves, the mechanism probably involves
separation of the iron from the siderophore at the cell surface.
The lack of an identifiable buffer or growth medium in which both
myeloid cells and P. aeruginosa remain viable and functional precludes the ability to directly test to what extent host phagocytes can disrupt the siderophore-dependent growth of P. aeruginosa. However, in vitro P. aeruginosa requires
approximately 7 to 29 µM pyochelin or pyoverdin for rapid growth in
the presence of inhibitory levels of transferrin (1).
Preliminary data from our laboratory indicate that HL-60 cells have the
capacity to acquire at least 50 nmol of iron from pyochelin or
pyoverdin per 106 cells over 30 min. Since concentrations
of phagocytes can approach 105/µl at sites of infection,
the potential for competition between P. aeruginosa bacteria
and phagocytic cells for siderophore-bound iron seems quite plausible.
Although one could extrapolate the data reported herein as evidence for
a generalized potential of phagocytic cells to disrupt iron metabolism
of all siderophore-producing microbes, this would be premature and may
be incorrect. We have previously shown that the magnitude of
transferrin-independent iron acquisition is chelate specific
(19). Interestingly, myeloid cell iron acquisition from
deferoxamine, a siderophore produced by Streptomyces
pilosus, is quite low (19). Most bacterial siderophores
fall into one of two classes, phenol-catechol type or hydroxymate acid
type (17, 18). Pyoverdin is a member of the hydroxymate
class of siderophores, and thus it might be expected that myeloid cells would be able to acquire iron to a similar extent from other members of
this class such as the Escherichia coli siderophore
aerobactin. In contrast, pyochelin is a unique compound with no clear
relationship to other siderophores (8). Additional work is
needed to define the spectrum of microbial siderophores from which
human phagocytic cells can remove iron. Unfortunately, most microbial
siderophores are not available from commercial sources.
In summary, we have obtained data which demonstrate the ability of
human phagocytes and myeloid cell lines to efficiently acquire iron
from both of the siderophores produced by P. aeruginosa. These data are consistent with the possibility that such events in vivo
serve as an additional mechanism of host defense to limit iron
availability to invading siderophore-producing microbes. Further
studies to assess the extent to which this observation extends to other
microbes and the role of the process in vivo are indicated.
| |
ACKNOWLEDGMENTS |
This work was supported in part by the National Institutes of
Health (AI28412) and the Department of Veterans Affairs Research Service through a Merit Review Award. It was performed during the
tenure of B. E. Britigan as an Established Investigator of the
American Heart Association.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Medicine, The University of Iowa, 200 Hawkins Dr., SW54 GH, Iowa City, IA 52242. Phone: (319) 356-3674. Fax: (319) 356-4600. E-mail: bradley-britigan{at}uiowa.edu.
Editor:
E. I. Tuomanen
| |
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Infection and Immunity, March 2000, p. 1271-1275, Vol. 68, No. 3
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
