Parasitic Infection Improves Survival from Septic
Peritonitis by Enhancing Mast Cell Responses to Bacteria
Rachel E. Sutherland, Xiang Xu, Sophia S. Kim, Eric J. Seeley, George H. Caughey, Paul J. Wolters*
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America
Mammals are serially infected with a variety of microorganisms, including bacteria and parasites. Each infection reprograms
the immune system’s responses to re-exposure and potentially alters responses to first-time infection by different
microorganisms. To examine whether infection with a metazoan parasite modulates host responses to subsequent bacterial
infection, mice were infected with the hookworm-like intestinal nematode Nippostrongylus brasiliensis, followed in 2–4 weeks
by peritoneal injection of the pathogenic bacterium Klebsiella pneumoniae. Survival from Klebsiella peritonitis two weeks after
parasite infection was better in Nippostrongylus-infected animals than in unparasitized mice, with Nippostrongylus-infected
mice having fewer peritoneal bacteria,more neutrophils,andhigherlevels of protective interleukin6. The improvedsurvivalof
Nippostrongylus-infected mice depends on IL-4 because the survival benefit is lost in mice lacking IL-4. Because mast cells
protect mice from Klebsiella peritonitis, we examined responses in mast cell-deficient KitW-sh/KitW-shmice, in which parasitosis
failed to improve survival from Klebsiella peritonitis. However, adoptive transfer of cultured mast cells to KitW-sh/KitW-shmice
restored survival benefits of parasitosis. These results show thatrecent infectionwithNippostrongylus brasiliensis protects mice
from Klebsiella peritonitis by modulating mast cell contributions to host defense, and suggest more generally that parasitosis
can yield survival advantages to a bacterially infected host.
Citation: Sutherland RE, Xu X, Kim SS, Seeley EJ, Caughey GH, et al. (2011) Parasitic Infection Improves Survival from Septic Peritonitis by Enhancing Mast Cell
Responses to Bacteria in Mice. PLoS ONE 6(11): e27564. doi:10.1371/journal.pone.0027564
Editor: Rory Edward Morty, University of Giessen Lung Center, Germany
Received June 21, 2010; Accepted October 19, 2011; Published November 16, 2011
Copyright: ? 2011 Sutherland et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by National Institutes of Health (NIH) grants HL024136 (GHC) and HL075026 (PJW). The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: firstname.lastname@example.org
Despite availability of antibiotics, more than 100,000 deaths are
attributable to sepsis every year, making it the fifth leading cause of
death in the United States . Septic patients succumb to
mediators of the innate immune response to infection . These
mediators recruit and activate inflammatory cells that control the
infection. However, when in excess, these mediators promote
sepsis-associated life-threatening pathologies, including clotting
activation, hypotension, lung injury, and multi-organ failure.
Conversely, a number of cells (e.g., macrophages and mast cells)
and mediators (e.g., TNF-a and IL-6) improve host survival
following severe bacterial infections. These cells and mediators
protect the host in a variety of ways, including enhancing
clearance of the infecting microorganism or limiting the extent
of inflammation. The ability to mount an inflammatory response
sufficient to clear infection while minimizing toxicity to host tissues
is a key determinant of survival during sepsis.
Symbiosis describes the relationship between organisms of
different species. When the relationship benefits both organisms it
is mutualistic and when it benefits just one organism, it is parasitic.
Typically, intestinal worms such as nematodes are classified as
parasites because they provide no apparent benefit to the host,
while causing diarrhea and anemia and consuming nutrients
required for growth and reproduction . However, benefits of
parasites may be context-dependent and less obvious than their
drawbacks. The studies in the present work explore the hypotheses
that intestinal parasites, which alter host defenses by provoking
strong immune responses, provide a previously unrecognized
benefit by altering immune responses such that the likelihood of
surviving severe bacterial infection and sepsis is enhanced.
Materials and Methods
All chemicals were from Sigma (St. Louis, MO) unless otherwise
C57BL/6 and IL-4
Labs (Bar Harbor, ME). Mast cell-deficient C57BL/6 KitW-sh/
KitW-shmice (Wsh mice)  were provided originally by Peter
Besmer (Memorial Sloan-Kettering Institute, New York, NY). All
mice used in these experiments are in a C57BL/6 background.
The experimental procedures were performed in 8–12 week-old
mice and were approved by the UCSF Committee on Animal
2/2mice were purchased from Jackson
Nippostrongylus brasiliensis infection of mice
Using previously described methods , mice were infected by
injecting 500 N. brasiliensis larvae suspended in 200 ml of PBS
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subcutaneously at the base of the tail of each mouse via a 27-gauge
Induction of Klebsiella pneumoniae septic peritonitis in
Klebsiella pneumoniae bacteria (strain 43816, serotype 2, American
Type Culture Collection, Manassas, VA) were resuspended in
5 mL of Nutrient Broth (Difco) and cultured overnight at 37uC.
100 ml of this suspension was added to 50 mL of Nutrient Broth
and grown for 3–4 h to log phase when colony-forming units
(CFU) were determined by OD600readings and confirmed by
culture. Septic peritonitis was generated in mice by i.p. injection of
150 CFU suspended in 200 ml of PBS. After recovery from
anesthesia, mice were monitored three times daily. Moribund mice
were euthanized by CO2inhalation and cervical dislocation.
Mast cell culture from bone marrow
Mouse bone marrow-derived cultured mast cells (BMCMC)
were differentiated from femoral bone marrow by culture in
medium supplemented with recombinant mouse IL-3 and stem
cell factor(rmSCF; Peprotech, Rocky Hill, NJ) as described .
Cells were used after 5 weeks in culture, at which time they
consisted of .95% mast cells (as identified by metachromatic
granules in cells stained with toluidine blue). BMCMC from
levels of active tryptase, and expression of FceRIa and CD117,
indicating that they mature similarly when cultured in the
presence of IL-3 and SCF.
2/2bone marrow showed similar granular morphology,
Adoptive transfer of mast cells into KitW-sh/KitW-shmice
To reconstitute intraperitoneal mast cells, 46106BMCMC
suspended in 500 ml of sterile PBS were injected i.p into 5-week
mice. Reconstituted mice were used in
experiments after allowing 5 weeks for mast cells to differentiate
within the peritoneum [7,8]. This method selectively reconstitutes
mast cells in peritoneum and mesentery to levels similar to those in
wild type C57BL/6 mice. In additional experiments, mice were
rapidly reconstituted to ensure that the phenotype of mast cells
studied in vivo matched the in vitro phenotype. In these
experiments, 1.256105BMCMC suspended in 500 ml of sterile
PBS were injected i.p. into 5-week old KitW-sh/KitW-shmice, which
were studied within 24 h of injection.
Quantification of cellular response to infection
To recover intraperitoneal inflammatory cells, anesthetized
mice were euthanized and the abdominal skin cleansed with 70%
ethanol. 4 mL of sterile 0.9% NaCl were then instilled into the
peritoneum. The abdomen was massaged gently for 1 min then
opened with sterile scissors to reclaim lavage fluid, which was
centrifuged at 500 g for 4 min at 4uC and the supernatant saved
for cytokine analysis. Cell pellets were resuspended in red cell lysis
buffer (Sigma) for 10 min, re-centrifuged, and the cell pellet
resuspended in PBS. Cell numbers were counted with a
hemocytometer and cells differentiated in cytospun preparations
stained with Diff-Quik (American Scientific Products, McGaw
Quantification of bacterial CFU
10 ml of peritoneal lavage fluid were diluted serially in sterile
0.9% NaCl. 10 ml of each dilution were aseptically plated and
cultured at 37uC on nutrient agar for non-fastidious microorgan-
ism plates. After 24 h, the numbers of bacterial colonies were
Cytokine concentrations were measured in lung and peritoneal
lavage fluid using ELISA kits: MIP-2 (R&D systems, Minneapolis,
MN), KC (R&D systems), TNF-a (eBioscience, San Diego, CA),
IL-6 (R&D Systems), and IFN-c (eBioscience) according to the
Survival curves were analyzed using the log-rank (mantel-cox)
test. ANOVA followed by two-tailed t testing was used to compare
markers of organ dysfunction, bacterial CFU, and mean cytokine
concentration. Calculations were performed using Statview 5.0.1
software (SAS Institute Inc., Cary, NC) and graphpad PRISM
software (GraphPad, La Jolla, CA). Significance was assigned to P
Parasitosis improves survival following subsequent
While investigating the role of mast cells in modulating survival
during septic peritonitis, we noted that control mice had better
survival while our mouse colony was inadvertently infected with
pinworm. This observation prompted us to hypothesize that
parasitosis protects against subsequent bacterial infection. To
examine this hypothesis, N. brasiliensis-infected mice (henceforth
termed Nippo mice) wereinfected i.p. with K. pneumoniae 2 weeks later
(after worm expulsion) to induce septic peritonitis. Remarkably,
survival following K. pneumoniae-mediated septic peritonitis in Nippo
mice was significantly better than in unparasitized control mice
(Fig. 1A). Interestingly, the survival advantage was no longer
present in mice infected with Klebsiella 4 weeks after N. brasiliensis
infection (Fig. 1 B), suggesting that the protective mechanism does
not involve a permanent change in adaptive immunity.
Figure 1. N. brasiliensis infection protects from death from K.
pneumoniae-mediated septic peritonitis. C57BL/6 mice (WT) or
C57BL/6 mice infected with N. brasiliensis (A) 2 or (B) 4 weeks earlier
(Nippo mice) were injected with 150 CFU of K. pneumoniae i.p. and
survival was monitored. Mice infected with N. brasiliensis 2 but not 4
weeks before bacterial infection are more likely to survive septic
peritonitis than unparasitized control mice. (n=25 mice/group,
Parasitosis and Sepsis
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Recent parasitosis enhances peritoneal clearance of
To probe mechanisms by which N. brasiliensis infection protects
mice from subsequent septic peritonitis, endpoints known to affect
sepsis survival, including bacterial clearance, degree and type of
cellular inflammation, and levels inflammatory cytokines, were
assessed at intervals after infection. The results show that
peritoneal CFU of K. pneumoniae are markedly diminished 4 and
24 h after inoculation in Nippo versus unparasitized mice (Fig. 2),
suggesting that improved survival may be due to enhanced
peritoneal clearance of bacteria.
Recent parasitosis enhances peritoneal recruitment of
neutrophils in response to bacteria
To decipher the mechanism by which N. brasiliensis enhances K.
pneumoniae clearance, peritoneal inflammatory cells were quantified
in Nippo mice at baseline and 4 and 24 h after K. pneumoniae
infection. At baseline, there was no difference in the number or
types of peritoneal leukocytes in Nippo versus unparasitized mice.
However, Nippo mice had significantly more neutrophils 4 h after
inoculation with K. pneumoniae (Fig. 3). By 24 h after inoculation,
this difference in neutrophils is no longer present and there is a
slight predominance of monocytes in Nippo mice, possibly related
to fewer bacteria (Fig. 2). These results indicate that prior
infection with N. brasiliensis enhances local neutrophil recruitment
during peritoneal K. pneumoniae infection and that this early
recruitment likely enhances bacterial clearance and survival.
Il-6 release increases in Nippo mice after K. pneumoniae
To investigate whether differences in cytokine expression
explain enhanced bacterial clearance in Nippo mice, intraperito-
neal levels of three cytokines that regulate the host response to
bacterial infections (TNF-a, IL-6, and IL-1ß) were compared at
baseline and 4 and 24 h after K. pneumoniae infection in Nippo and
unparasitized mice. Baseline levels of these cytokines were similar
in Nippo and unparasitized mice (Fig. 4), indicating that diffe-
rences in baseline production of key cytokines that mediate innate
immune responses to bacterial infection do not explain the
differences in bacterial clearance. Although peritoneal levels of
TNF-a and IL-1ß did not differ 4 or 24 h after K. pneumoniae
infection, levels of IL-6 at 4 h were significantly higher in Nippo
mice (Fig. 4). IL-6 enhances neutrophil killing of K. pneumoniae in
the peritoneum within the first hours of inoculation . This
suggests that the higher intraperitoneal levels of IL-6 early after
K. pneumoniae infection may contribute to enhanced bacterial
clearance and higher likelihood of surviving infection.
Improved survival of Nippo mice is mast cell-dependent
Because two endpoints (i.e., numbers of locally recruited
neutrophils and levels of intraperitoneal IL-6) that could influence
survival from bacterial peritonitis are mast-cell dependent in some
disease models [10,11,12,13], we examined whether mast cells
mediate the observed survival advantage in Nippo mice. To test this
possibility, mast cell-deficient Wsh mice and Wsh mice infected 2
weeks earlier with N. brasiliensis (Wsh-Nippo mice) were subjected to
K. pneumoniae septic peritonitis. In contrast to the survival
advantage noted in wild type mice, there was no difference in
survival between Wsh and Wsh-Nippo mice (Fig. 5A), suggest that
mast cells may be essential for the survival advantage. To
determine whether this protective effect is due to mast cells
specifically, survival from K. pneumoniae peritonitis was compared in
N. brasiliensis-infected and unparasitized Wsh mice in which
peritoneal mast cells were selectively reconstituted by injection of
BMCMC from wild type mice [14,15]. As shown in Fig. 5B, mast
cell reconstitution in Wsh mice recovered the survival advantage
conferred by prior parasitosis. Because Wsh mice clear N.
brasiliensis worms normally (Fig. 5C), worm retention does not
explain the lack of a survival advantage in Wsh-Nippo mice. Similar
to wild type Nippo mice, mast cell-reconstituted Wsh-Nippo mice
had higher levels of IL-6 in peritoneal lavage fluid compared to
mast cell-reconstituted Wsh control mice 4 h after infection with
Klebsiella (124 vs. 65.4 pg/mL). These findings suggest that the
survival advantage enjoyed by wild type Nippo mice is mast cell-
IL-4 favorably alters mast cell responses to sepsis
Th2 cytokines are major mediators of the immune response to
N. brasiliensis infection . To examine whether Th2 cytokines
could contribute to the survival advantage enjoyed by Nippo mice,
we focused on IL-4, a Th2 cytokine released during N. brasiliensis
infection that is not required for worm expulsion . To test
whether IL-4 contributes to the survival advantage, survival of
parasitized and unparasitized wild type and IL-42/2mice was
compared in the Klebsiella septic peritonitis model. In these
experiments, survival of unparasitized IL-42/2and parasitized
IL-42/2mice was similar to each other (Fig. 6A), suggesting that
the survival advantage in wild type Nippo mice is IL-4-dependent.
To test whether IL-4 alters mast cell responses to Klebsiella
infection and sepsis, Wsh mice were reconstituted with BMCMC
cultured for 1 week in the absence (Wsh+WT) or presence of
50 ng/mL IL-4 (Wsh+WT+IL-4). 10 week-old mice were
reconstituted by i.p. injection of 125,000 mast cells, then infected
i.p. 24 h later with K. pneumoniae. As shown in Fig. 6B, Wsh mice
reconstituted with IL-4-conditioned mast cells are more likely to
survive peritonitis than Wsh mice reconstituted with unconditioned
To explore mechanisms by which IL-4-conditioned mast cells
enhance survival from septic peritonitis, peritoneal inflammatory
cell profiles in Wsh+WT and Wsh+WT+IL-4 mice were compared
at baseline and 4 h after i.p. injection of Klebsiella. Uninfected
Wsh+WT and Wsh+WT+IL-4 mice did not differ in total
differential cell counts, indicating that IL-4 conditioning of
BMCMC does not influence the baseline profile of peritoneal
inflammatory cells (Fig. 6C). In contrast, Wsh+WT+IL-4 mice
recruited significantly more neutrophils than Wsh+WT controls
4 h after Klebsiella infection, as also observed in wild type Nippo
mice (Fig. 3), suggesting that IL-4 conditioning of mast cells in
vivo contributes to the survival advantage in Nippo mice.
Figure 2. Peritoneal clearance of K. pneumoniae is enhanced in
mice previously infected with N. brasiliensis. C57BL/6 (WT) and
C57BL/56 mice infected 2 weeks earlier with N. brasiliensis (Nippo Mice)
were injected i.p. with 150 CFU of K. pneumoniae. Dilutions of
peritoneal lavage fluid obtained 4 (A) and 24 h (B) after K. pneumoniae
injection were cultured on agar plates and bacterial colonies were
counted. (n=7–9 mice/group, *P,0.05).
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To examine whether IL-4 conditioning of mast cells can
contribute to the observed increased levels of IL-6 in Nippo mice,
IL-6 production was measured in BMCMC conditioned for one
week with IL-4 followed by 24 h of incubation with heat-killed K.
pneumoniae. As shown in Fig. 6D, IL-4-conditioned mast cells
produce significantly more IL-6 than unconditioned mast cells
following stimulation with K. pneumoniae, consistent with a role for
IL-4 in priming mast cells to respond to the presence of bacteria in
vivo by producing IL-6.
This study reports that prior infection of mice with parasitic
worms can improve survival during subsequent septic peritonitis.
In this model, a recent history of parasitosis with the hookworm-
like nematode N. brasiliensis improves survival by enhancing
clearance of K. pneumoniae bacteria infecting the peritoneum. The
worms appear to accomplish this by provoking production of Th2
cytokines, such as IL-4, which primes mast cells to enhance their
innate responses to bacteria. These suggest that intestinal worm
infections may be mutually beneficial to the host by protecting
them from subsequent bacterial infection.
The immune system is in a constant state of flux controlled in
large part by the infectious organisms it encounters. These
exposures educate the immune system such that it will clear
repeat infections by the same microorganism and thereby limit
potential harm to the host. More recent data has shown that an
infection by one microorganism can provide heterologous
protection from an unrelated organism [17,18,19,20]. For
example, latent herpesvirus infection improves survival from
subsequent Listeria monocytogenes infection by increasing Listeria
clearance . Similarly, inhalation of Haemophilus influenzae
extracts improves survival from subsequent infections, including
Streptococcus pneumoniae, Klebsiella pneumoniae, Aspergillus fumigatus, and
influenza A [18,19,20]. Collectively, these studies show that prior
exposure to infectious agents or extracts of them can favorably
modulate the immune response to subsequent heterologous
The present study reports parasitic infection with N. brasiliensis
favorably alter the immune response to a heterologous intraper-
Figure 3. Peritoneal neutrophil recruitment is enhanced in parasitized mice following K. pneumoniae infection. C57BL/6 (WT) and
C57BL/6 mice infected 2 weeks earlier with N. brasiliensis (Nippo mice) were euthanized at baseline (A), 4 h (B) and 24 h (C) after i.p. injection of
150 CFU of K. pneumoniae and inflammatory cells were recovered by peritoneal lavage. Total cells were counted using a hemocytometer and
differential cell counts were determined on cytospun cells stained with Diff-Quik. (n=7–9 mice/group, **P,0.01, ***P,0.001 for Nippo compared to
unparasitized control mice).
Figure 4. IL-6 is elevated in Nippo mice. Levels of (A) TNF-a, (B) IL-6, and (C) IL-1b were measured by ELISA in peritoneal lavage fluid from WT or
Nippo mice at baseline, 4 and 24 h after i.p. injection of 150 CFU of K. pneumoniae. (n=7–9 mice/time point, *P,0.05 for Nippo mice compared to
unparasitized control mice).
Parasitosis and Sepsis
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itoneal infection with the bacterium K. pneumoniae. The data show
that mice previously infected with N. brasiliensis have more
neutrophil recruitment and higher intraperitoneal IL-6 levels
early after K. pneumoniae infection. These exaggerated immune
responses are associated with improved bacterial clearance and
host survival . Although an explanation for the enhanced
neutrophil recruitment remains undefined, possibilities include
activation of innate immune cells, such as mast cells, by products
made by N. brasiliensis or by mediators produced in response to the
N. brasiliensis infection. This study reports IL-4 as a candidate
mediator produced in response to the N. brasiliensis infection that
can augment mast cell responses to subsequent K. pneumoniae
Prior work has established that mast cells play an essential role
in regulating the immune response to severe bacterial infections
and sepsis [7,11] by secreting of TNF-a and tryptase, which
promote recruitment of neutrophils to sites of infection  ,
and IL-6, which potentiates neutrophil killing of bacteria [10,12].
The finding that Nippo mice have higher intraperitoneal IL-6 levels
4 h after infection and that IL-4-conditioned mast cells generate
more IL-6 is consistent with the idea that mast cells are a source of
the higher IL-6 levels in Nippo mice. Determining whether mast
cells are a source of IL-6 under these conditions, or other cells
contribute will require further study. In prior work, we reported
that increased intraperitoneal levels of IL-6 improve survival of
higher intraperitoneal IL-6 levels underscores the beneficial effects
of locally produced IL-6 and suggests that increasing peritoneal
IL-6 early in the course of infection benefits the host independent
of its cellular source.
The observed mast cell dependence of the survival advantage
of parasitized mice with bacterial peritonitis suggests that
N. brasiliensis infection changes mast cell behavior and that mast
cell responses to bacterial infection are not static. This is consistent
with reports that mast cell numbers and phenotypes change during
parasitic infections [5,22,23]. In addition, this study provides
the first evidence that the phenotypic change produced by
N. brasiliensis infection in vivo or by conditioning with IL-4 in
vitro protects mice from death from K. pneumoniae-mediated septic
peritonitis. These findings suggest that augmenting mast cell
2/2mice . The finding that Nippo mice have
Figure 5. Improved survival of Nippo mice is mediated by mast
cells. (A) Mast cell-deficient KitW-sh/KitW-shmice (Wsh, n=25) or Wsh
mice infected with N. brasiliensis 2 weeks earlier (Wsh+Nippo mice,
n=24) were injected with 150 CFU of K. pneumoniae i.p. and survival
was monitored. (B) pmc-WT (25 mice) and pmc-WT mice infected with
N. brasiliensis 2 weeks earlier (pmc-WT-Nippo Mice, 25 mice), were
injected with 150 CFU of K. pneumoniae i.p. and survival monitored
(*P,0.012). (C) Expulsion of N. brasiliensis is normal in KitW-sh/KitW-sh
mice. WT and KitW-sh/KitW-shmice (n=5/group) were infected with 500
N. brasiliensis larvae and intestinal worm burden assessed 7 and 14 d
Figure 6. IL-4 favorably alters mast cell responses to sepsis. (A)
IL-4+/+mice (WT), IL-4+/+mice infected with N. brasiliensis 2 weeks
earlier (Nippo mice), IL-42/2mice, or IL-42/2mice infected with N.
brasiliensis 2 weeks earlier (IL-42/2+Nippo) were injected with 150 CFU
of K. pneumoniae i.p and survival was monitored. (n=35 mice/group,
*P=0.02 comparing WT vs. Nippo mice and P=0.13 comparing IL-42/2
injection of 125,000 WT BMCMC (Wsh+WT) or BMCMC preconditioned
for 7 d with 50 ng/mL IL-4 (Wsh+WT+IL4). 24 h later, mice were injected
with 150 CFU of K. pneumoniae i.p. Mice reconstituted with BMCMC
conditioned with IL-4 were more likely to survive than controls (n=35
mice/group). (C) IL-4 enhances mast cell-dependent neutrophil
recruitment during K. pneumoniae septic peritonitis. Wsh+WT and
Wsh+IL4 mice were injected with 150 CFU of K. pneumoniae i.p.
Inflammatory cells in peritoneum of uninfected Wsh-WT (black bar) or
Wsh-IL-4 (white bar) and infected Wsh-WT (Wsh-WT-kleb, hatched bar)
and infected Wsh-IL-4 (Wsh-IL-4-kleb, boxed bar) mice 4 h after
infection with Klebsiella. (*P,0.05 Wsh-WT vs. Wsh-WT (kleb) neut,
and **P,0.01 Wsh-IL4-kleb vs. Wsh-WT-kleb neuts). (D) IL-4 conditioned
mast cells produced greater amounts of IL-6. BMCMC cultured for 7 d in
the absence (cont) or presence of 50 ng/mL IL-4 (IL-4) were stimulated
with heat-killed K. pneumoniae and the amount of IL-6 released into the
culture media quantified by ELISA. (**P,0.01).
2/2+Nippo). (B) Wsh mice (Wsh) were reconstituted by i.p.
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responses to bacteria could be therapeutic in severe bacterial
infections and sepsis.
Although not required for worm expulsion, IL-4 is a major
mediator of the host response to N. brasiliensis infection . The
improved survival of Nippo mice appears to depend on IL-4
because the survival benefit is lost in mice lacking this cytokine
(Fig. 6). Although IL-4-conditioned BMCMC are not pheno-
copies of peritoneal MC in Nippo mice, the result that mast cell-
deficient Wsh mice reconstituted with IL-4-conditioned mast cells
have better survival and elevated intraperitoneal IL-6 levels
following K. pneumoniae peritonitis suggests that conditioning of
peritoneal mast cells by endogenously generated IL-4 in Nippo
mice could contribute to the survival benefit. The biochemical
explanation for how IL-4 increases mast cell IL-6 production
remains undefined. Because the heat-killed Klebsiella was used as a
stimulus, we suspect IL-4 is influencing there TLR signaling.
Overall these findings are consistent with prior observations that
over-expression of IL-4 improves survival in mice with sepsis and
Pseudomonas pneumonia [25,26]. Similarly, IL-4 stimulates
production of the antimicrobial peptide LL37 in mast cells
, showing that IL-4 can provoke a change in mast cells that
could enhance bacterial clearance. Determining how IL-4
enhances mast cell responses in Nippo mice and whether other
Th2 cytokines similarly contribute to the protection requires
Classically, parasite-host interactions are recognized to benefit
the parasite and harm the host. This perspective has changed as it
has become apparent that some parasites may provide a benefit to
their host . For example, trypanosomes synthesize vitamin B6
and therefore can provide a source of the vitamin to infected
rodents living in environments low in vitamin B6 . The present
study reports a novel way in which metazoan parasites may benefit
their host: namely, by protecting them from a subsequent life-
threatening bacterial infection. Because a live rodent is required
for the life cycle of N. brasiliensis, the survival benefit may mutually
benefit the parasite by ensuring that the host survives and is
available for the parasite to complete its life cycle. Thus, in the
context of severe bacterial infection, N. brasiliensis infection is
mutually beneficial rather than parasitic. Whether similar
mutually beneficial parasite-host interactions occur in infected
humans remains to be examined.
In summary, the data presented here establish that prior
infection with a hookworm-like intestinal parasite can improve
survival from a severe Gram-negative bacterial infection. The
survival benefit depends on mast cells and IL-4 and is associated
with augmented neutrophil recruitment, secretion of IL-6 and
accelerated bacterial clearance. The results suggest that host
infection with metazoan parasites can be mutually beneficial and
may reinforce co-evolution of parasite and host by protecting the
host from death from bacterial infection.
The authors thank the lab of UCSF’s Dr. Richard Locksley for providing
the original stock of N. Brasiliensis.
Conceived and designed the experiments: GHC PJW. Performed the
experiments: RES XX SSK EJS PJW. Analyzed the data: RES SSK XX
EJS GHC PJW. Contributed reagents/materials/analysis tools: GHC
PJW. Wrote the paper: RES SSK XX EJS GHC PJW.
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