Embed Size (px)
Citation preview
ImmunoparasitologyPhillip Scott
Author’s address
Phillip Scott,Department of Pathobiology, School of Veter-
inary Medicine, University of Pennsylvania,
Philadelphia, PA, USA.
Correspondence to:
Phillip ScottDepartment of Pathobiology
School of Veterinary Medicine
3800 Spruce Street
Philadelphia, PA 19104, USA
Fax: þ1 215 573 7023
E-mail: [email protected]
Mosmann et al. (1) reported that CD4þ T-cell clones could be
divided into two subsets based on the cytokines they pro-
duced. Understanding these subsets, termed T-helper 1
(Th1) and Th2, and more broadly defining the role of cyto-
kines in protection and immunopathology have been the basis
for much of the research in the field of immunoparasitology
over the last 18 years. Murine models of parasitic diseases,
such as leishmaniasis and trichuriasis, provided the oppor-
tunity to determine how Th1 and Th2 cells differentiate and
regulate each other in an in vivo context. Studies with both
protozoan parasites and tissue-dwelling helminths helped
elucidate the cells and cytokines that shape the adaptive
immune response, and studies with gastrointestinal nematodes
explored the poorly understood immune system of the gut. In
this volume, many of those contributions are highlighted.
Taken together, they point out how the field of immuno-
parasitology has contributed to our understanding of the
immune response. While it is hoped that this information
will lead to better treatments and vaccines for parasitic
diseases, on this front there has been only limited success;
there are no vaccines for any of the major human parasitic
diseases. However, several contributions in this volume
address this issue and describe how immunologic memory
functions in parasitic diseases – information that will be useful
for developing successful vaccines.
After the initial discovery that interleukin-12 (IL-12) and
IL-4 promoted Th1 and Th2 responses respectively, a series of
questions were raised (2). How and when are these cytokines
produced after infection? What cells produce IL-12 and IL-4,
and where are these cells located? What parasite molecules
activate cells to produce these cytokines? What interactions
with the host lead to preferential development of Th1
responses after some infections (e.g. Toxoplasma) and Th2
responses after others (e.g. many of the helminths), and why
are some parasites able to induce both responses – either at
different stages of the infection (e.g. Schistosoma mansoni, malaria) or
Immunological Reviews 2004Vol. 201: 5–8Printed in Denmark. All rights reserved
Copyright � Blackwell Munksgaard 2004
Immunological Reviews0105-2896
5
in different inbred strains of mice (e.g. Leishmania, Trichuris)? What
are the effector mechanisms involved in protection against
gastrointestinal nematodes? Some of these questions remain
unanswered, but the focus of the last several years on early
host–pathogen interactions has provided information that has
significantly increased our understanding in this area.
In this volume, several laboratories report on the interac-
tions between protozoa and the signaling pathways associated
with innate immune responses. Protozoa promote a Th1
response through interactions with the innate immune system,
presumably utilizing signaling pathways employed by other
pathogens. Gazzinelli, Sher, Langhorne, and their colleagues
describe the parasite molecules from Trypanosoma cruzi, African
trypanosomiasis, Toxoplasma gondii, Leishmania, and malaria that
can promote the activation of the innate immune system.
Many of these molecules contain glycosylphosphatidylinosital
anchors that appear to function as pathogen-associated mole-
cular patterns (PAMPs) and thus activate Toll/IL-1 receptor-
signaling pathways, although for several of these molecules, it
has been difficult to assign a specific Toll-like receptor (TLR)
to their function. In addition to the role that TLRs play in
parasite activation of cells, other pathways also contribute to
cell activation. For example, in Toxoplasma, a parasite cyclophi-
lin was described that binds to CCR5 and induces IL-12 pro-
duction. Because the nuclear factor-k B (NF-kB) family of
transcription factors is central to the development of both
innate and adaptive immune responses, it is important to
define how these different NF-kB transcription factors func-
tion in parasitic diseases. In this volume, Hunter and cowork-
ers review what is known about NF-kB in the development of
immunity to Toxoplasma, Leishmania, and Trichuris.
The factors contributing to the development of Th2
responses following infection with helminths are less well
defined. In this volume, contributions from the laboratories
of Gause, Grencis, and Maizels address this issue. Owing to the
association of TLRs and Th1 responses, it may not be surpris-
ing that no parasite TLR ligands capable of stimulating Th2
responses have been defined. However, that does not mean
that helminths do not express TLR ligands. Thus, Trichuris muris
stimulates the Toll pathway, but rather than initiating a pro-
tective response, such activation is associated with suscept-
ibility. This leaves open the question of how helminths
provoke such a dominant Th2 response. Some suggest that
the preferential development of Th2 responses is associated
with the release of helminth proteases (Maizels et al.), while
others report that helminth antigens that have no proteolytic
activity can still promote Th2 responses (Gause et al.). Clearly,
there are likely to be multiple pathways involved, and the
studies reported here provide an extensive overview of this
field.
One approach to defining the factors promoting T-helper
cell development is to study dendritic cells (DCs), as these cells
initiate immune responses. As described above, protozoa may
utilize Toll/IL-1 receptor-signaling pathways, as well as other
pathways, to stimulate DCs and promote a Th1 response. As
discussed by Langhorne and colleagues, the nature of the
interactions between DCs and the blood stages of malaria
will dictate the nature of the immune response that develops.
These observations with protozoan parasites raise the question
of how helminths influence DC function and whether hel-
minths actively promote a Th2 response by stimulating DCs
in a particular way. One of the most studied parasitic hel-
minths is Schistosoma mansoni, in which the role of DCs has been
extensively investigated. Schistosomiasis is associated with an
early Th1 response that switches to a dominant Th2 response
over time. This switch occurs when egg laying begins, and in
this volume, Pearce et al. describe how egg antigens influence
DC function, such that they promote Th2 responses. Import-
antly, it appears that once DCs are exposed to egg antigens,
they can promote a Th2 response by themselves, highlighting
the critical role of DCs in shaping the nature of the immune
response in this infection. Nutman and colleagues, in their
studies with filariasis, further highlight the complexity of
parasite–DC interactions. The complex filarial life cycle leads
to the presence of different parasite stages interacting with DCs
in different locations and potentially leading to different out-
comes. Notably, live microfilaria were found to induce DC
apoptosis, although the mechanism involved is not yet
defined, while exposure of human Langerhans’ cells to third
stage larvae leads to DC migration but not upregulation of
markers associated with activation.
One of the unique areas of research in the field of immuno-
parasitology is the identification of effector pathways asso-
ciated with protection to gastrointestinal helminths, and the
contributions by Finkelman, Grencis, and Maizels discuss these
pathways. When one considers that there are more than 3.5
billion people infected with these organisms, it is astonishing
that the final effector mechanism(s) involved in controlling
these parasites is still poorly understood. Nevertheless, there is
a consensus emerging that while infection with gut nematodes
induces many effector mechanisms, only some of them are
effective against a particular species. The effector mechanisms
involved in controlling tissue-dwelling helminths are also an
area of controversy; in this volume, Wynn, Stadecker, Dessein,
and their coworkers address the relative contributions of
the Th1 and Th2 immune response to protection and
Scott � Immunoparasitology
6 Immunological Reviews 201/2004
immunopathology associated with schistosomiasis. What is
clear is that an appropriate balance in the Th1/Th2 ratio
is critical in controlling immunopathology, and how that is
achieved is an area of intensive investigation.
The importance of regulating host effector mechanisms may
stem from the fact that in contrast to many bacterial and viral
infections, most parasitic diseases are chronic, thus putting
pressure on the host to modulate effector responses that if
continued would be immunopathologic. In fact, parasitic dis-
ease is frequently not the result of the absence of immunity
but rather is due to the continued presence of an ineffective
immune response. This immunopathology may be a disadvan-
tage not only for the host but also for the parasite; thus, there
are many strategies employed by parasites to modulate
immune effector mechanisms. Some occur quite early after
infection. For example, in this volume, Denkers et al. describe
how Toxoplasma blocks both the NF-kB and the mitogen-
activated protein kinase pathways – critical signaling pathways
promoting proinflammatory responses. Interestingly, Toxo-
plasma may also block the CCR5-dependent pathway for IL-12
production (described above) by releasing a parasite product
related to lipoxin, an arachidonic acid metabolite that down-
regulates CCR5.
As Th1 and Th2 cells cross-regulate each other via suppres-
sive cytokines, much of the focus on regulation has been on
these cells and the cross-regulatory cytokines they produce.
However, many other regulatory mechanisms exist. For exam-
ple, as described by Wynn et al. in this volume, a decoy IL-13
receptor is critical for controlling the egg-induced granuloma-
tous response associated with S. mansoni. Furthermore, chronic
disease may not always be the result of cross-regulation by
Th1 and Th2 cells. Thus, in this volume, McMahon-Pratt and
Alexander describe the immune responses associated with the
chronic disease observed following infection with L. mexicana
and L. donovani parasites. In contrast to L. major infections, the
inability to resolve an infection with these organisms is not
due to a dominant Th2 response, suggesting that other
mechanisms suppress the development of protective Th1
responses. How this suppression occurs is actively being pur-
sued by several laboratories.
A particularly exciting area of immunoregulation is defining
the role of T-regulatory (Treg) cells in modulating the
immune responses to parasites. Treg cells were initially
described as cells that control autoimmunity, but we now
know that they also play a critical role in modulating immune
responses induced by infection (3). In this volume, an article
from the laboratory of Sacks describes the important role Treg
cells play in leishmaniasis. Interestingly, it appears that the
presence of Treg cells is required to maintain persistent para-
sites after resolution of disease. This finding is of particular
note, because in the absence of persistent parasites, a large part
of the immunity associated with resolving a primary infection
with Leishmania was lost. While the initial focus has been on the
ability of Treg cell to suppress Th1 responses, Maizels and
colleagues describe the potential role of Treg cells in modulat-
ing Th2 responses associated with helminth infections. Thus,
in a mouse model of filariasis, depletion of Treg cells led to
heightened Th2 effector activity and clearance of a large per-
centage of the worms. These results raise the obvious next
question of how Treg cells are activated during infection;
levels of Treg cells do appear to fluctuate during infection,
but how this occurs is unknown. An interesting observation
reported by Kaye et al. is that stromal cells taken from L.
donovani-infected mice promote the development of DCs that
may contribute to Treg-cell development or expansion. Many
unanswered questions about these cells exist, and studies in
models of parasitic diseases are likely to help answer some of
these questions.
Despite the significant advances we have made in our under-
standing of the immune responses that occur following para-
sitic infections, no vaccine for any of these major human
diseases is currently in use. The difficulties in the development
of a successful vaccine include defining protective antigens,
determining what is the most appropriate effector mechanism
to elicit, determining what adjuvants to use, and understand-
ing the basic immunology associated with memory-cell devel-
opment and maintenance. The development of a vaccine for
human malaria, which causes more than two million deaths a
year, has been a high priority for many years. Nevertheless, no
vaccine has been forthcoming. In this issue, Good et al.
describe the challenges associated with the development of a
malaria vaccine and suggest that a successful approach may not
depend on immunity that mimics natural immunity. How-
ever, this discussion does not mean that after natural infec-
tions, malaria is unable to induce some level of immunity, and
in this volume, Riley and colleagues provide an important
analysis of the memory responses that are associated with
malaria infection. Understanding the limitations of naturally
induced memory will be critical in forging a new approach to
vaccine development.
The final three articles focus on understanding how early
effector responses and subsequent memory responses develop
during parasitic infections. The development of efficacious
vaccines remains a challenge for the field of parasitology,
and one of the problems may be that so little is understood
about the generation of memory cells, particularly memory
Scott � Immunoparasitology
Immunological Reviews 201/2004 7
T cells. Recently, several laboratories have characterized the
memory T cells arising following bacterial or viral infections,
which has provided a better understanding of memory T cells
(4). These studies and others indicate that subpopulations of
memory T cells exhibit distinct functions and migration pat-
terns. However, as parasitic infections are frequently chronic,
the factors involved in the development and maintenance of
memory T cells may differ from acute bacterial or viral infec-
tions where sterile immunity is achieved. In this volume,
articles from the laboratories of Zavala and Tarleton define
the generation and maintenance of effector and memory
CD8þ T cells during infection with Plasmodium and T. cruzi,
respectively. Both of these studies utilize T-cell receptor trans-
genic mice to monitor the in vivo activation and expansion of T
cells after infection, permitting a sophisticated analysis of the
factors involved in both T-cell effector function and memory
T-cell development. For example, in T. cruzi, the capacity of
CD8þ T cells to provide protection was completely dependent
upon their ability to make interferon-g, and in malaria the
ability of CD4þ T cells to promote CD8þ T-cell responses was
shown to depend upon IL-4 production. Finally, we describe
how CD4þ Th1 cells develop and are maintained as memory
CD4þ T cells during infection with Leishmania major. These
studies indicate that infection-induced resistance to L. major is
mediated by both an effector T-cell population, maintained
due to the persistence of parasites following resolution of
disease, and a central memory T-cell population that does
not require persistent parasites.
The work described in this volume provides an up-to-date
picture of where the field is at present; from these studies, one
can predict what the future directions are for immunopara-
sitology. Clearly much more information on the PAMPs and
other parasite factors that induce both Th1 and Th2 responses
is required; this information may aid in designing immuno-
therapies. Gastrointestinal nematodes remain a huge burden
on humankind, and better understanding of mucosal immune
responses will be a focus of much research. Regulation of
immunity is a hallmark of parasitic infection, and future stud-
ies are likely to focus on a better understanding of how Treg
cells develop and function in a number of parasitic diseases.
Finally, we ended this volume with chapters addressing how
memory T cells develop; this area will also be one of continued
extensive research, which hopefully will not only broaden our
understanding of immunologic memory but also provide
information useful in the design of the much needed vaccines
for parasites.
References
1. Mosmann TR, Cherwinski H, Bond MW,
Giedlin MA, Coffman RL. Two types of
murine helper T cell clone. I. Definition
according to profiles of lymphokine activities
and secreted proteins. J Immunol
1986;136:2348–2357.
2. Murphy KM, Reiner SL. The lineage decisions
of helper T cells. Nat Rev Immunol
2002;2:933–944.
3. Hori S, Takahashi T, Sakaguchi S. Control of
autoimmunity by naturally arising regulatory
CD4þ T cells. Adv Immunol 2003;81:331–371.
4. Sallusto F, Geginat J, Lanzavecchia A. Central
memory and effector memory T cell subsets:
function, generation, and maintenance. Annu
Rev Immunol 2004;22:745–763.
Scott � Immunoparasitology
8 Immunological Reviews 201/2004
