Local Inflammation Exacerbates the Severity of Staphylococcus aureus Skin Infection
Staphylococcus aureus is the leading cause of skin infections. In a mouse model of S. aureus skin infection, we found that lesion size did not correlate with bacterial burden. Athymic nude mice had smaller skin lesions that contained lower levels of myeloperoxidase, IL-17A, and CXCL1, compared with wild type mice, although there was no difference in bacterial burden. T cell deficiency did not explain the difference in lesion size, because TCR βδ (-/-) mice did not have smaller lesions, and adoptive transfer of congenic T cells into athymic nude mice prior to infection did not alter lesion size. The differences observed were specific to the skin, because mortality in a pneumonia model was not different between wild type and athymic nude mice. Thus, the clinical severity of S. aureus skin infection is driven by the inflammatory response to the bacteria, rather than bacterial burden, in a T cell independent manner.
Local Inflammation Exacerbates the Severity of
Staphylococcus aureus Skin Infection
Christopher P. Montgomery
, Melvin D. Daniels
, Fan Zhao
, Brad Spellberg
, Anita S. Chong
, Robert S.
1 Department of Pediatrics, University of Chicago, Chicago, Illinois, United States of America, 2 Department of Surgery, University of Chicago, Chicago, Illinois,
United States of America, 3 Division of General Internal Medicine, Los Angeles Biomedical Research Institute at Harbor-University of California at Los Angeles
Medical Center, Torrance, California, United States of America
Staphylococcus aureus is the leading cause of skin infections. In a mouse model of S. aureus skin infection, we
found that lesion size did not correlate with bacterial burden. Athymic nude mice had smaller skin lesions that
contained lower levels of myeloperoxidase, IL-17A, and CXCL1, compared with wild type mice, although there was
no difference in bacterial burden. T cell deficiency did not explain the difference in lesion size, because TCR βδ (-/-)
mice did not have smaller lesions, and adoptive transfer of congenic T cells into athymic nude mice prior to infection
did not alter lesion size. The differences observed were specific to the skin, because mortality in a pneumonia model
was not different between wild type and athymic nude mice. Thus, the clinical severity of S. aureus skin infection is
driven by the inflammatory response to the bacteria, rather than bacterial burden, in a T cell independent manner.
Citation: Montgomery CP, Daniels MD, Zhao F, Spellberg B, Chong AS, et al. (2013) Local Inflammation Exacerbates the Severity of Staphylococcus
aureus Skin Infection. PLoS ONE 8(7): e69508. doi:10.1371/journal.pone.0069508
Editor: Michael Otto, National Institutes of Health, United States of America
Received April 18, 2013; Accepted June 10, 2013; Published July 5, 2013
Copyright: © 2013 Montgomery 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 the National Institute of Child Health and Human Development [Pediatric Critical Care Scholar Development
Program HD047349 to CPM]; the National Institute of Allergy and Infectious Diseases [AI076596 to CPM, AI072630 to MDD and ASC, AI081719 to BS,
AI97113 to ASC, and AI040481 to RSD]; the National Institute of Arthritis and Musculoskeletal and Skin Diseases [AR059414 to RSD]; and the National
Heart, Lung, and Blood Institute [T32 HL07605 to MDD]. The funders had no role in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.
Competing interests: BS reports receiving grant and contract support from Cubist, Pfizer, and Bristol Myers Squibb; serving as a consultant for Glaxo
Smith Kline, Pfizer, Meiji, Adenium, Cardeas, and aRigen; and receiving honoraria from Cubist. RSD reports serving as a paid consultant for Pfizer and
receiving a research grant from Pfizer. CPM, MDD, FZ, and ASC have no conflicts of interest to declare. This does not alter the authors' adherence to all
the PLOS ONE policies on sharing data and materials.
* E-mail: firstname.lastname@example.org
Staphylococcus aureus is the leading cause of skin and soft
tissue infections (SSTI) in the United States . The burden of
disease from S. aureus SSTI, particularly those caused by
methicillin-resistant isolates (MRSA) is extremely high
(reviewed in 2. The highly virulent genetic background USA300
(designated by pulsed-field gel electrophoresis pattern) has
emerged as the leading cause of community-associated MRSA
(CA-MRSA) infections, including SSTI, in the United States
[2,3]. Increasing resistance to antimicrobial therapy among S.
aureus isolates highlights the shortage of effective
antimicrobials to treat these infections. Therefore, in addition to
standard local therapies (i.e. incision and drainage), there is a
need to identify other methods of treatment and prevention.
Development of novel immune-based therapeutic strategies
against S. aureus SSTI has been hampered by an incomplete
understanding of the pathogenesis of these infections,
particularly with regard to the host response. The microbial
contributions to virulence have been well described. For
example, the S. aureus global regulators agr and sae are
necessary for the full virulence of USA300 isolates [4–7]. The
staphylococcal α-hemolysin (Hla), by virtue of interacting with
its cellular receptor, ADAM10, promotes S. aureus SSTI by
disrupting epithelial integrity . Phenol soluble modulins are
also important in the pathogenesis of S. aureus skin infections
[7,9]. However, despite such advances in the understanding of
the microbial determinants of virulence, the host factors that
play a role in defense against these infections and the factors
that determine the size of skin lesions are less well defined.
Considerable insight has been gained by understanding that
certain patients are highly susceptible to S. aureus skin
infections. For example, those with defects in neutrophil
function are at increased risk for pyogenic infections caused by
S. aureus. One example of such a defect is chronic
granulomatous disease, in which the neutrophil oxidative burst
is impaired [10,11]. It has also been observed that patients with
specific T cell immunodeficiencies have an increased incidence
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of S. aureus SSTI. For example, patients with HIV infection and
low CD4 counts have higher rates of S. aureus SSTI (reviewed
in 12. In addition, patients with Hyper IgE syndrome, an
immunodeficiency in which differentiation and function of Th17
lymphocytes are impaired, are highly susceptible to S. aureus
SSTI . Two lines of experimental evidence have supported
the notion that IL-17 responses are important in defense
against these infections. First, mice that are deficient in IL-17A
and F (but not either separately) develop spontaneous S.
aureus cutaneous infections . Second, mice that are
deficient in the IL-17 receptor or innate-like γδ T cells are highly
susceptible to S. aureus skin infection, an effect that is
reversed with the administration of recombinant IL-17 .
Therefore, innate immunity and T cell responses are each
important in defense against S. aureus SSTI. Because they
have defects in T lymphocytes and innate immunity (by virtue
of abnormal skin structure), athymic nude mice could be a
valuable tool to better understand the contributions of each to
host defense against these infections [16,17]. We hypothesized
that athymic nude mice would have altered susceptibility to S.
aureus SSTI on the basis of altered innate immunity and T cell
deficiency. Elucidation of the mechanisms of altered
susceptibility would provide insight into innate defenses against
S. aureus SSTI.
All animal experiments were approved by the Institutional
Animal Care and Use Committee at the University of Chicago
(protocol # 71694) and were performed in strict accordance
with the Guide for the Use and Care of Laboratory Animals of
the National Institutes of Health.
S. aureus isolates and growth
S. aureus isolate SF8300 is a USA300 MRSA isolate
provided by Henry Chambers (University of California, San
Francisco). The virulence of SF8300 in a mouse model of skin
infection has been described . For preparation of the
inoculum, the bacteria were subcultured onto tryptic soy agar
(TSA) and incubated at 37°C overnight. The following evening,
one colony was inoculated into tryptic soy broth (TSB) and
incubated overnight at 37°C, with shaking (250 rpm). On the
morning of inoculation, the overnight culture was diluted 1:100
in fresh TSB and grown until the mid-exponential phase
(approximately 3 hours). The bacteria were washed twice and
resuspended in sterile phosphate buffered saline (PBS) at a
concentration of 1.5 x 10
CFU/50 µl (skin infection) or 1.3 x
CFU/20 µl (pneumonia).
Balb/c wild-type and athymic nude female mice were
purchased from Taconic. C57Bl/6j wild type, athymic nude, and
TCR βδ (-/-) female mice, that lack both αβ and γδ T cells,
were purchased from Jackson Laboratories. All mice were
infected at 6–8 weeks of age.
Mouse models of
S. aureus skin infection and
Our mouse models of S. aureus skin infection and
necrotizing pneumonia have been described . Briefly, on
the day of inoculation, the mice were sedated with ketamine
and xylazine. For skin infection, the flanks of the sedated mice
were shaved with clippers when necessary and cleansed with
an ethanol solution. Skin infection was induced by
subcutaneous inoculation of 50 µl of the bacterial suspension.
For pneumonia, the sedated mice were intranasally inoculated
with 20 µl of S. aureus. For both models, mice were returned to
their cages and observed to awaken. All mice had free access
to food and water throughout the duration of the experiments.
For the skin infection model, animals were observed daily and
skin lesion size was measured using digital photography and a
standardized measurement (Adobe Photoshop).
Bacterial recovery and cytokine quantification in skin
Three days after inoculation, the mice were euthanized by
inhalation. Skin lesions were excised under sterile
conditions. The lesions were homogenized using a rotor-stator
homogenizer and aliquots were removed for bacterial
quantification and assessment of cytokine levels. For bacterial
quantification, serial dilutions of aliquots were performed in
sterile PBS and plated on mannitol salt agar. Enumeration of
colonies was performed 24 hours later. For determination of
cytokine levels, lesion homogenates were centrifuged and the
supernatants were removed. ELISA was performed to assess
the levels of IL-17A and CXCL-1 (R&D Systems). The amount
of myeloperoxidase (MPO) in the lesions was quantified in
order to estimate the neutrophil activity (Hycult Biotech).
T cell isolation and adoptive transfer
One day prior to inoculation, naïve Balb/c mice were
sacrificed and the spleens were harvested. T cells were
isolated using the Pan T Cell Isolation Kit II (Miltenyi Biotech),
according to the manufacturer’s recommendations. T cells (8
million/mouse) were adoptively transferred into naïve athymic
nude mice by retroorbital injection (200 µl/mouse). Control
nude mice received 200 µl of sterile PBS. The mice were
allowed to recover and were infected with S. aureus the
Data were analyzed using GraphPad Prism. Student’s t test
or one-way ANOVA with Newman-Keuls post-test were used to
compare lesion size, cytokine levels, and bacterial CFU
between the groups. Correlation between lesion size and
bacterial burden was assessed by Pearson’s correlation.
Mortality rates were compared using Fisher’s exact test. p<0.05
was considered significant.
S. aureus skin infection resulted in smaller skin lesions
in athymic nude mice
Cutaneous infection with S. aureus of athymic nude mice
from the Balb/c background resulted in significantly smaller
S. aureus Infection
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lesions (mean maximum area of dermonecrosis 24 ± 5 mm
compared with wild type mice (129 ± 8 mm
) (p<0.001) (Figure
1A). These differences persisted for nearly two weeks, and
lesions resolved more quickly in athymic nude mice, compared
with wild type mice. Smaller lesions were also observed in
athymic nude mice from the C57Bl/6 background (mean
maximum area of dermonecrosis 48 ± 12 mm
), compared with
wild type mice (136 ± 13 mm
) (p<0.001) (Figure 1B). Other
than differences in size, the gross appearance of the lesions
was similar between the groups (Figure 1C).
Athymic nude mice had attenuated local inflammatory
responses but no difference in bacterial burden in the
In order to better understand the factors that might be
important in determining the size of skin lesions in the mouse
model, wild type (Balb/c) and athymic nude mice were
sacrificed 3 days after infection with S. aureus USA300.
Consistent with the data presented above, athymic nude mice
had significantly smaller lesions compared with wild type mice
(p<0.001) (Figure 2A). Despite this, the number of bacteria
recovered from the skin lesions was not significantly different
between the mouse strains (p=0.2) (Figure 2B). Interestingly,
lesion size was not correlated with bacterial burden in wild type
=0.1; p=0.3) or athymic nude mice (r
=0.1; p=0.3) (Figure
2C). This raised the possibility that the inflammatory response
was more important in determining lesion severity, as assessed
by lesion size, than bacterial burden in the lesions.
The levels of MPO, a measure of neutrophil activity, as well
as the proinflammatory neutrophil chemokines IL-17A and
CXCL-1, were measured in the lesions. Not surprisingly, IL-17A
was not detected in the lesions of athymic nude mice, since
IL-17A is predominantly a T lymphocyte derived cytokine
(Figure 2D). The levels of CXCL-1 (Figure 2E) and MPO
(Figure 2F) were also significantly lower in the skin lesions of
athymic nude mice, compared with wild-type mice (p<0.01).
Therefore, the smaller lesions observed after experimental
inoculation of athymic nude mice were associated with lower
levels of chemokines and less inflammation, but were not
associated with decreased bacterial burden. Moreover, lesion
size was not correlated with bacterial burden in either wild type
or athymic nude mice. These data support the notion that the
local inflammatory response is a key determinant of lesion size.
Figure 1. Athymic nude mice had smaller lesions after cutaneous infection with S. aureus. (A) Athymic nude mice from the
Balb/c background had smaller lesions, compared wild type Balb/c mice, after infection with S. aureus. (B) Athymic nude mice from
the C57Bl/6 background had smaller lesions, compared with wild type C57Bl/6 mice, after infection with S. aureus. (C) Photographs
of representative lesions from wild type and athymic nude mice from the Balb/c background. Bars represent 10 mm. Data are
presented as mean ± SEM. * indicates p<0.01. N=8 mice/group.
Inflammation and S. aureus Infection
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T lymphocyte deficiency did not mediate the smaller
skin lesions observed after infection of athymic nude
mice with S. aureus
We hypothesized that the abrogated inflammatory response
and smaller skin lesions observed in athymic nude mice would
be explained by T cell deficiency. In order to assess this, the
severity (i.e. lesion size) of S. aureus skin infection was
compared between wild type C57Bl/6j and congenic TCR βδ
(-/-) mice. Interestingly, there was no significant difference in
lesion size between C57Bl/6j (mean maximum area of
dermonecrosis 95 ± 17 mm
) and TCR βδ (-/-) mice (103 ± 22
) (p=0.8) (Figure 3A), suggesting that T cell deficiency
alone did not alter lesion size in this model.
To further test whether T cell deficiency contributed to the
smaller lesions observed in athymic nude mice, congenic wild
type T lymphocytes (or PBS as a control) were adoptively
transferred to naïve athymic nude mice prior to infection with S.
aureus. Consistent with prior observations, athymic nude mice
that received PBS prior to infection had significantly smaller
lesions (mean maximum area of dermonecrosis 69 ± 7 mm
compared with wild type Balb/c mice (135 ± 6 mm
(Figure 3B,C). Transfer of naïve T lymphocytes prior to
infection resulted in lesion size (91 ± 11 mm
) that was not
significantly different compared with PBS-treated athymic nude
mice (p=0.11) but were significantly smaller compared with wild
type mice (p<0.001). These data further supported the notion
that T cell deficiency did not mediate the altered lesion severity
observed in athymic nude mice.
To determine if the diminished severity of skin infection in
athymic nude mice was specific to the skin or was a systemic
phenomenon, a mouse model of S. aureus necrotizing
pneumonia was used . The mortality rate of mice infected
with S. aureus via intranasal inoculation was not significantly
different between athymic nude (63%) and wild type mice
(50%) (p=0.5) (Figure 3D). Thus, the diminished inflammatory
response and severity of S. aureus infection was specific to the
skin, and was not a generalized phenomenon at other sites.
In a clinically relevant model of S. aureus SSTI, we found
that the bacterial burden in the skin lesions was not correlated
with clinical severity (i.e. lesion size). The smaller lesions
observed in athymic nude mice contained lower levels of the
proinflammatory cytokines CXCL1 and IL-17A, and had
diminished neutrophil activity, as assessed by MPO levels.
Surprisingly, despite smaller lesions and less inflammation in
the athymic nude mice, there was no difference in the number
of bacteria recovered from the lesions between wild type and
athymic nude mice. The abrogated severity was not explained
by T cell deficiency, as TCR βδ (-/-) mice did not have altered
lesion size, and adoptive transfer of T cells into athymic nude
mice had no effect on lesion size. Furthermore, athymic nude
Figure 2. Athymic nude mice had less inflammation but no difference in bacterial recovery from skin lesions. Wild type
and athymic nude mice from the Balb/c background (n=10 mice/group) were sacrificed 3 days after inoculation with S. aureus.
Athymic nude mice had smaller skin lesions (A) but no difference in bacterial burden in the lesions (B), compared with wild type
mice. (C) The lesion size was not correlated with bacterial burden in wild type or athymic nude mice. The skin lesions of athymic
nude mice had lower levels of IL-17A (D), CXCL1 (E), and myeloperoxidase (F), compared with wild type mice. Data are presented
as mean ± SEM.
Inflammation and S. aureus Infection
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mice did not have altered susceptibility to S. aureus
We used athymic nude mice as a tool to better understand
the innate immune response to S. aureus SSTI. We were
surprised to find that athymic nude mice were less susceptible
to S. aureus SSTI compared with wild-type mice, as they were
found to be highly susceptible to S. aureus bacteremia . We
hypothesized that the relative resistance of athymic nude mice
to S. aureus cutaneous infection was due to T cell deficiency. A
role for T cells in defense against S. aureus SSTI is supported
by clinical observations that specific T cell deficiency
predisposes to S. aureus SSTI [12,13]. However, we found that
TCR βδ (-/-) mice, that lack both αβ and γδ T cells, did not
have smaller lesions, compared with wild type mice.
Furthermore, adoptive transfer of T cells into athymic nude
mice did not alter the lesion size. Thus, the smaller lesions
observed in athymic nude mice were not due to T cell
deficiency. Rather, local inflammatory responses in the skin
determined the severity of S. aureus SSTI. Collectively, these
results confirm that the mechanisms of defense against S.
aureus SSTI, necrotizing pneumonia, and bacteremia differ.
Because athymic nude mice retain some γδ T cells that
develop outside the thymus , it was tempting to speculate
that their relative resistance to S. aureus SSTI was due to the
presence of γδ T cells producing IL-17A and the absence of αβ
T cells in the skin. Indeed, this notion is supported by the fact
that γδ T cell derived IL-17A is necessary for defense against
S. aureus skin infection . However, we found that athymic
nude mice had smaller lesions despite the lack of detectable
IL-17A, arguing against this possibility.
Although athymic nude mice are immunodeficient, they have
been reported to be resistant to certain pathogens. For
example, Bacillus anthracis skin infection was less severe in
athymic nude mice, an effect that was hypothesized to be due
to heightened local innate immunity manifested as a superficial
neutrophilic response . This may be true in those
circumstances. However, we found lower levels of the
proinflammatory cytokines CXCL1 and IL-17A, as well as lower
levels of MPO, a marker of neutrophil activity, suggesting that
inflammation was less severe in the skin lesions of athymic
nude mice. These results thus argue against this explaining the
differences we observed after S. aureus skin infection.
Figure 3. Local factors, rather than systemic immunodeficiency, mediated the smaller skin lesions in athymic nude
mice. (A) There was no difference in lesion size between C57Bl/6j (wild type) and TCR βδ (-/-) mice after infection with S. aureus
(n=5-10 mice/group). Data are presented as mean ± SEM. (B) T cell deficiency did not explain the smaller lesions observed in
athymic nude mice, as adoptive transfer of T cells into naïve Balb/c athymic nude mice prior to infection with S. aureus did not result
in altered lesion size (n=8 mice/group). Data are presented as mean ± SEM. * indicates p<0.01 compared with wild type mice. (C)
Photographs of representative lesions from wild type mice and from nude mice that received PBS or adoptive transfer of T cells
prior to infection with S. aureus. The black bars indicate 10 mm. (D) There was no difference in the mortality rate of athymic nude or
wild type Balb/c mice in a mouse model of S. aureus necrotizing pneumonia (n=8 mice/group).
Inflammation and S. aureus Infection
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We were also surprised to find that, despite the smaller
lesions, there was no difference in the number of bacteria
recovered from the lesions of wild type and athymic nude mice
at 3 days post-infection. This suggests that bacterial burden
may not be the primary driver of lesion severity, and argues
that lesion severity may be due, at least in part, to the
associated inflammatory response. In support of this idea, we
found no correlation between lesion size and bacterial burden
in either wild type or athymic nude mice.
These findings are consistent with the Damage Framework
Model of Casadevall and Pirofski, which underscores that
severity of infection is often driven by the inflammatory
response to the invading pathogen as much or more as by the
direct effects of the pathogen itself . A similar phenomenon
was described during Acinetobacter baumannii bactermia,
during which there was no correlation between bacterial burden
and severity of resulting sepsis . These results inform the
increasing recognition the novel preventative and therapeutic
strategies for infections could be developed by targeting the
host response to the pathogen rather than by attempting to kill
the pathogen directly . Future studies are needed to
address whether manipulation of the inflammatory response in
our model of S. aureus SSTI will alter lesion severity.
In summary, we found that S. aureus skin lesion size was
driven by the local inflammatory response to the organism
rather than by bacterial burden in wild type and athymic nude
mice. Athymic nude mice were relatively resistant to S. aureus
skin infection, as assessed by decreased lesion size and a
diminished inflammatory response. This effect was not
mediated by T cells and was not associated with altered
immunity against experimental S. aureus pneumonia,
suggesting that the local inflammatory response in the skin is a
primary driver of lesion severity in S. aureus SSTI.
Conceived and designed the experiments: CPM MDD BS ASC
RSD. Performed the experiments: CPM MDD FZ. Analyzed the
data: CPM MDD FZ BS ASC RSD. Contributed reagents/
materials/analysis tools: CPM BS ASC RSD. Wrote the
manuscript: CPM BS ASC RSD.
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