temperature, because all lower-lying energy
levels are already occupied and thus fur-
ther occupation is forbidden. For a mea-
surement of position correlations, the
antisymmetry of the wave function results
in an apparent antibunching, where fer-
mions seem to avoid each other. Bosons,
in contrast, experience an increase in the
probability of reaching a state already occu-
pied by other bosons. That is, bosons tend
to bunch together. For small systems of par-
ticles, the consequences of quantum statis-
tics were exploited in fermionic (4) as well
as bosonic (5) systems. Preiss et al. observe
this effect of bunching in the position cor-
relations of two identical atoms undergoing
a quantum walk.
Surprisingly, although this behavior due
to quantum statistics seems to be funda-
mentally fixed, interactions between parti-
cles can in fact turn bosonic bunching into
fermionic antibunching and vice versa. This
has been seen, for example, by association
of two fermionic atoms to a bosonic mol-
ecule that can undergo Bose-Einstein con-
densation (6), or pairing of fermions in a
many-body system showing superfluid be-
havior similar to Cooper pairs in a super-
conductor (7). Preiss et al. go the other way:
By increasing repulsive interaction more
and more, the bosonic atoms under investi-
gation start to mimic the behavior of weakly
interacting fermions, as was observed in
one-dimensional Bose gases in the so-called
Tonks-Girardeau regime (8, 9). With their
superb position resolution, Preiss et al. can
track the crossover from the quantum sta-
tistics–dominated bosonic bunching to the
interaction-dominated antibunching, again
extracting position correlations of two at-
oms doing a quantum walk.
The system presented by Preiss et al. al-
lows the study of the interplay of all these
aforementioned aspects in a rather simple,
paradigmatic system comprising all these
effects: two identical, interacting atoms.
Beyond the illustration of quantum physics,
their system can serve as a basic building
block for a bottom-up approach to engi-
neering of complex quantum states atom by
atom. ■
REFERENCES
1. P. M. Preiss et al., Science 347, 1229 (2015).
2. M. Ben Dahan, E. Peik, J. Reichel, Y. Castin, C. Salomon,
Phys. Rev. Lett. 76, 4508 (1996).
3. M. Karski et al., Science 325, 174 (2009).
4. A. N. Wenz et al., Science 342, 457 (2013).
5. A. M. Kaufman et al., Science 345, 306 (2014).
6. M. Greiner, C. A. Regal, D. S. Jin, Nature 426, 537 (2003).
7. M. W. Zwierlein, J. R. Abo-Shaeer, A. Schirotzek, C. H.
Schunck, W. Ketterle, Nature 435, 1047 (2005).
8. T. Kinoshita, T. Wenger, D. S. Weiss, Science 305, 1125
(2004).
9. B. Paredes et al., Nature 429, 277 (2004).
10.1126/science.aaa6885
SCIENCE sciencemag.org
IMMUNOLOGY
Getting sepsis therapy right
Is decreasing inflammation or increasing the host immune
response the better approach?
By Richard S. Hotchkiss1
and Edward R. Sherwood2
S
epsis—a complication of infection—is
a factor in at least a third of all hos-
pital deaths—a sobering statistic (1).
Patients with sepsis frequently pres-
ent with fever, shock, and multior-
gan failure. Because of this dramatic
clinical scenario, investigators have gener-
ally assumed that sepsis mortality is due
to unbridled inflammation (2). Research
in animal models, in which administration
of the cytokines tumor necrosis factor–α
(TNF-α) and interleukin-1 (IL-1) reproduced
many features of sepsis, supported that as-
sertion. Yet, over 40 clinical trials of agents
that block cytokines, pathogen recognition,
or inflammation-signaling pathways have
universally failed (3, 4). However, on page
1260 of this issue, Weber et al. (5) show that
blocking a cytokine—specifically, IL-3—can
indeed be protective against sepsis.
IL-3 is a pleiotropic cytokine that induces
proliferation, differentiation, and enhanced
function of a broad range of hemopoietic
cells (blood cells derived from the bone
marrow). Using a mouse abdominal sep-
sis model, Weber et al. identified IL-3 as a
critical driving force of sepsis. The authors
observed that the cytokine caused prolif-
eration and mobilization of myeloid cells
that generated excessive proinflammatory
cytokines, thereby fueling systemic inflam-
mation, organ injury, and death. Blocking
IL-3 (by treating wild-type mice with an an-
tibody that blocks the receptor for IL-3 or
using IL-3–deficient mice) prevented sepsis-
induced increases in the number of circulat-
ing neutrophils and inflammatory monocytes
and decreased the amount of circulating
inflammatory cytokines, thus ameliorating
organ injury and improving survival. Ad-
ditionally, the authors showed a correlation
between mortality in septic patients and el-
evated blood IL-3 concentrations.
The findings of Weber et al. are mecha-
nistically analogous to that of another study
in which intravenous injection of mesen-
chymal stem cells (also known as bone
marrow stromal cells) into a mouse model
of sepsis led to reprogramming of immune
cells toward a less inflammatory phenotype,
thereby decreasing organ injury and mortal-
ity (6). In this scenario, mesenchymal stem
Published by AAAS
cells released factors that reprogrammed
monocytes and macrophages; the down-
stream effect was to prevent a damaging,
unrestrained immune response. Thus, IL-3
blockade and mesenchymal stem cell–based
therapy represent potential approaches for
sepsis treatment because of their ability to
broadly reshape early immune responses
from a proinflammatory, damaging reaction
Downloaded from http://science.sciencemag.org/ on August 10, 2016
to a more balanced and effective one.
However, a few cautionary caveats should
be considered before adopting this ap-
proach. A phase II clinical trial of granulo-
cyte-macrophage colony-stimulating factor
(GM-CSF), a cytokine that increases produc-
tion, maturation, and function of monocytes,
macrophages, and neutrophils, thereby
mimicking selected properties of IL-3, was
efficacious in treating sepsis and, indeed, a
large multicenter trial of GM-CSF in sepsis
is under way (7). This is contrary to the find-
ings of Weber et al. that blocking IL-3 can
“Which approach to sepsis…
is correct? …there are several
clues…”
ameliorate sepsis. Two other highly prom-
ising agents that are likely to enter clinical
trials in sepsis are IL-7 (which promotes
CD4+ and CD8+ T lymphocyte proliferation
and maturation) and an antibody to pro-
grammed death–ligand 1 [(PD-L1), an immu-
nosuppressive protein] (8, 9). Both IL-7 and
anti-PD-L1 antibody are immunostimulatory
agents that reverse key immunologic defects
in lymphocytes and monocytes from septic
patients ex vivo and are highly effective in
multiple animal models of sepsis (9). Emerg-
ing evidence shows correlations between
lymphopenia (decrease in lymphocytes)
and impaired leukocyte functions with late
mortality in patients with sepsis (8, 9). Thus,
there is rationale for using approaches that
selectively enhance antimicrobial immunity
during sepsis.
1
Department of Anesthesiology, Medicine, and Surgery,
Washington University School of Medicine, St. Louis,
MO, USA. 2Department of Anesthesiology and Pathology,
Microbiology and Immunology. Vanderbilt University School
of Medicine, Nashville, TN, USA. E-mail: hotch@wustl.edu;
edward.r.sherwood@vanderbilt.edu
13 MARCH 2015 • VOL 347 ISSUE 6227 1201
INSIGHTS | P E R S P E C T I V E S
Immunoinfammatory response in sepsis
Excessive
infammation
anti-IL-3, mesenchymal stem cells
Balanced
Impaired
Microbial assault immunity
Therapy
Enhance immunity:
(IL-7, GM-CSF,
anti-PD-L1, IFN-γ)
Inflammatory response to sepsis. Potential immune
therapies can modulate immune responses that provoke
excessive inflammation or enhance immunity if there
is an impaired immune response to microbial infection.
IFN-γ, interferon-γ.
Which approach to sepsis—decreasing ex-
cessive inflammation versus boosting host
immunity—is correct? The answer to this
question is critical and there are several clues
(see the figure). Immunologic status is highly
dependent on the age and general health
of the individual. Although young, previ-
ously healthy individuals acquire virulent
infections, early inflammatory deaths are
becoming less common in developed coun-
tries because of improved surveillance and
advances in supportive care. In the United
States, 75% of the deaths in sepsis occur in
patients over the age of 65 (10). The immune
system in the elderly is substantially impaired
and renders them susceptible to infection.
Patients with major comorbidities, including
chronic renal and liver failure, also are im-
munosuppressed, rendering them more vul-
nerable to developing and dying from sepsis.
Thus, the patient populations that represent
the highest proportion of sepsis deaths are
likely to require therapy that augments im-
munity. By contrast, the number of sepsis
patients with overwhelming inflammation,
who may benefit from therapies that reduce
early hyper-release of proinflammatory cyto-
kines (“cytokine storm”), is declining.
Another caveat affecting treatment se-
lection is timing (11). Patients rapidly tran-
sition from the initial cytokine storm to a
predominant immunosuppressed state as
sepsis persists. This shift to an immuno-
suppressed state occurs for many reasons,
1202 13 MARCH 2015 • VOL 347 ISSUE 6227
Therapy
Modulate immune response:
Pathogens
eliminated
Exhausted
immune
response Pathogen
not contained
Pathogen Develop secondary
contained
including massive sepsis-induced death
of immune cells, development of T cell ex-
haustion, and generation of T regulatory
and myeloid-derived suppressor cells. A
postmortem study of intensive care unit
patients, in which spleens and lungs were
harvested rapidly after death, showed that
compared to patients dying of causes other
than sepsis, immune effector cells from sep-
tic patients were massively depleted (12).
Most of the sepsis deaths occurred after a
prolonged course in the intensive care unit.
This protracted septic course is difficult to
reproduce in animal models. For example,
animal sepsis mortality reported by Weber
et al. generally occurred within 24 to 48
hours after sepsis onset (during the hyper-
inflammatory phase) and is therefore not
reflective of most clinical deaths in sepsis.
Recent studies provide compelling evi-
dence for this immunologic evolution. In
patients admitted with sepsis, “late” positive
blood and tissue cultures were detected in
~28% of patients, and over half of these in-
fections were due to fungi or weakly virulent
bacteria considered to be “opportunistic”
pathogens (13). In addition, use of latent viral
reactivation as a surrogate marker of loss of
immunocompetence (14) showed that over
42% of septic patients had reactivation of two
or more viruses. The amount of viral reacti-
vation in septic patients was comparable to
that occurring in organ transplant patients
on immunosuppressive therapy, further evi-
dence of the remarkable degree of impaired
immunity in patients with sepsis.
So, how should sepsis be treated? The cor-
nerstone of sepsis therapy remains drainage
and/or removal of the infected site, fluid re-
suscitation, and rapid antibiotic administra-
Published by AAAS
Late death
(smoldering infammation)
Early death
(organ injury)
Survival
Death
(from primary infection)
Downloaded from http://science.sciencemag.org/ on August 10, 2016
Late death
infection (from secondary
infection)
tion. Although anti-inflammatory therapies,
such as blocking IL-3, may be beneficial in se-
lected patients, history has not been kind to
such approaches. It may be that restorative
immunotherapy, in which adjuvants that
stimulate host immunity would be the cen-
terpiece for response modification, offers the
most promise. To guide sepsis immunother-
apy, new methods to determine the health
of the various components of a patient’s im-
mune system are being developed and may
direct the application of targeted immune-
adjuvant therapies in the future (15). ■
RE FERENCES AND NOTES
1. V. Liu et al., JAMA 312, 90 (2014).
2. R. S. Hotchkiss, I. E. Karl, N. Engl. J. Med. 348, 138 (2003).
3. J. Cohen et al., Lancet Infect. Dis. 12, 503 (2012).
4. D. C. Angus, JAMA 306, 2614 (2011).
5. G. F. Weber et al., Science 347, 1260 (2015).
6. K. Németh et al., Nat. Med. 15, 42 (2009).
7. C. Meisel et al., Am. J. Respir. Crit. Care Med. 180, 640
(2009).
8. R. S. Hotchkiss et al., Lancet Infect. Dis. 13, 260 (2013).
9. F. Venet et al., J. Immunol. 189, 10 (2012).
10. G. S. Martin, D. M. Mannino, M. Moss, Crit. Care Med. 34, 15
(2006).
11. J. Leentjens et al., Am. J. Respir. Crit. Care Med. 187, 1287
(2013).
12. J. S. Boomer et al., JAMA 306, 2594 (2011).
13. G. P. Otto et al., Crit. Care 15, R183 (2011).
14. A. H. Walton et al., PLOS ONE 9, e98819 (2014).
15. J. L. Vincent, L. Teixeira, Am. J. Respir. Crit. Care Med. 190,
1081 (2014).
ILLUSTRATION: ADAPTED BY P. HUEY/SCIENCE
ACKNOWL EDGMENTS
R.S.H. has been on the advisory boards of Bristol-Myers Squibb
(BMS), GlaxoSmithKline (GSK), and Merck, on immunotherapy
for sepsis (he speaks on the topics of IL-7, anti-PD-1, anti-PD-L1,
IL-15, IFN-γ, and GM-CSF). He is a paid consultant to BMS, GSK,
Merck, and MedImmune on immunotherapy for sepsis. He
collaborates with Revimmune on a trial of IL-7 in sepsis and with
BMS on a trial of anti-PD-L1 in sepsis. He receives funding from
BMS and MedImmune for studies with anti-PD-1 and anti-PD-L1
and from GSK to test immunomodulators in sepsis.
10.1126/science.aaa8334
sciencemag.org SCIENCE
 Getting sepsis therapy right
Richard S. Hotchkiss and Edward R. Sherwood (March 12, 2015)
Science 347 (6227), 1201-1202. [doi: 10.1126/science.aaa8334]

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