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Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 9, Number 2, February 2008
Contents
Modulators of the Innate Immune Response
Guest Editor: Suzanne S. Bohlson
Editorial Pp. 101
Role of C-Type Lectins in Mycobacterial Infections
Pp. 102-112
J.B. Torrelles, A.K. Azad, L.N. Henning, T.K. Carlson and
L.S. Schlesinger
[Abstract]
Directing an Appropriate Immune Response: The
Role of Defense Collagens and other Soluble Pattern Recognition
Molecules Pp. 113-122
D.A. Fraser and A.J. Tenner
[Abstract]
The Pattern Recognition Receptor Dectin-1: From
Fungi to Mycobacteria Pp. 123-129
J.S. Schorey and C. Lawrence
[Abstract]
CD93 and Related Family Members: Their Role in
Innate Immunity Pp. 130-138
M.C. Greenlee, S.A. Sullivan and S.S. Bohlson
[Abstract]
Collagen Receptor Integrins: Rising to the Challenge
Pp. 139-149
K.D. McCall-Culbreath and M.M. Zutter
[Abstract]
Molecular Mechanisms of Host-Pathogen Interactions
and their Potential for the Discovery of New Drug Targets
Pp. 150-157
V. Briken
[Abstract]
Properdin and Complement Activation: A Fresh Perspective
Pp. 158-164
D.E. Hourcade
[Abstract]
The Host Complement System and Arbovirus Pathogenesis
Pp. 165-172
T.E. Morrison and M.T. Heise
[Abstract]
Abstracts
[Back to top]
Editorial
More than 120 years have passed since Dr. Ilya Ilyich Metchnikoff’s
first description of phagocytosis, originating from his observation
that mobile cells from starfish larvae migrated to and surrounded
foreign material (thorns from a tangerine tree in this case).
His pioneering work formed the foundation for the discipline
of innate immunity, now regarded not only as the first line
of host defense, but also the instructor of the adaptive immune
response, and regulator of tissue repair and homeostasis.
The innate immune system was considered to be a “nonspecific”
host defense system when viewed in contrast to the exquisite
specificity provided by the billions of monoclonal lymphocyte
receptors of the adaptive immune system. However, this view
of the innate immune system has been revised with the identification
of Toll like receptors (TLR), cytosolic nucleotide binding
and oligomerization domain (NOD)-like receptors, and other
pattern recognition receptors (PRR), either soluble or expressed
on the surface of phagocytic cells, that recognize conserved
molecular patterns on microorganisms and dead/dying (apoptotic)
cells. In addition, cooperation among pattern recognition
receptors and other specialized receptors (e.g. integrins)
forms a macromolecular signaling complex that allows a phagocyte
to specifically recognize a target particle and respond appropriately;
an initial step in the generation of an immune response.
In this issue of Current Drug Targets, eight review articles
focus on modulators of innate immunity, specifically the receptors
and pathways involved in the particle recognition phase by
the phagocyte. They address complement, adhesion molecules
and non-TLR PRR in innate immunity. Because TLR and NOD-like
receptors have been the focus of numerous recent comprehensive
reviews, this issue explores alternative pathways and receptors
that enable the innate immune system to fine-tune the host
response. Specific drug targets and therapies related to inflammation,
host defense and autoimmunity are identified and emphasized.
The first five articles of this issue focus on receptors (soluble
and membrane bound) that modulate innate immunity. In the
first article, Torrelles and colleagues (pages 102-112) describe
cell-associated C-type lectin PRRs and soluble collectins
in the innate immune response to mycobacteria, a pathogen
that exploits the phagocytic cell, residing within host macrophages.
Fraser and Tenner (pages 113-122) then focus specifically
on the soluble PRR with particular emphasis on defense collagens
(including collectins) in the regulation of phagocytosis and
cytokine synthesis. Lawrence and Schorey (pages 123-129) follow
with a review on Dectin-1, a membrane bound non-TLR PRR which
can recognize specific pathogens and form a cooperative signaling
complex with TLR. Next Greenlee and colleagues (page 130-138)
describe a novel family of C-type-lectin-like domain-containing
surface glycoproteins involved in innate immunity and phagocytosis.
Further examples of specific receptors involved in modulation
of innate immunity continue on pages (139-149) where McCall-Culbreath
and Zutter describe the role of β1
integrins in host defense and autoimmunity. Briken (pages
150-157) then explores specific drug targets relevant to host-pathogen
interactions, focusing on the modulins, bacterial proteins
and lipids involved in manipulation of host cells. The final
two reviews focus on the complement system, an arm of the
innate immune system that leads to opsonization of pathogens
for phagocytosis, cell recruitment during inflammation, and
direct lysis of pathogens. First Hourcade (pages 158-164)
describes a novel complement activation pathway and then Morrison
and Heise (pages 165-172) address the role of the complement
system in response to arbovirus infection.
With the advances in genomics and proteomics seen over the
last decade that have identified the critical genes and gene
products in the immune system, it now falls to investigators
to elucidate the relationships between these products and
how together they form the system that recognizes the environment
and responds appropriately. A philosophically inclined colleague
of mine once suggested that the most interesting things in
the universe were invisible. Perhaps this statement could
apply to the still undefined (or invisible) relationships
and cooperation among proteins and pathways that lead to effective
immunity -- the elimination of dangerous non-self and clearance
of dead or dying old self. As these molecular relationships
become visible through research, we are led to ever more questions
about the invisible, and that is precisely why we will continue
to develop novel strategies and increasingly effective therapies
to promote human health.
Suzanne S. Bohlson
Indiana University School of Medicine-South Bend
123 Raclin Carmichael Hall
1234 Notre Dame Avenue
South Bend, IN 46617
USA
E-mail: Bohlson.2@nd.edu
[Back to top]
Role of C-Type Lectins in Mycobacterial Infections
J.B. Torrelles, A.K. Azad, L.N. Henning, T.K. Carlson and
L.S. Schlesinger
Worldwide clinical cases due to multi drug- and extensively
drug-resistant strains of Mycobacterium tuberculosis (M.tb)
are increasing making the need for new therapies more critical
than ever. A major obstacle for designing new drugs to treat
mycobacterial infections is our limited knowledge of the interface
between the bacillus (especially M.tb) and its host.
The pulmonary innate immune system plays a key role in the
recognition of microbes entering via the respiratory
route. Although the specificity of this system is broad and
based on the recognition of pathogen-associated molecular
patterns (PAMPs), it is uniquely regulated to limit inflammation
and thereby prevent damage to the gas-exchanging alveoli.
Pulmonary surfactant proteins A and D (SP-A and SP–D)
are collagenous, soluble, C-type (Ca2+
-dependent) lectins (named collectins) of the
lung innate immune system that are secreted into the alveoli
by resident type II alveolar epithelial cells and distal bronchiolar
Clara cells. The related collectin in serum, mannose-binding
lectin/protein (MBL or MBP), provides first-line defense against
several microbes. Phagocytes represent the first cellular
defense in the alveoli and their surface is rich in C-type
lectin pattern recognition receptors (PRRs), including the
mannose receptor (MR), dendritic cell–specific ICAM-3-grabbing
nonintegrin (DC-SIGN) and DC-associated C-type lectin-1 (Dectin-1).
This review will discuss the important roles of the cell-associated
C-type lectin PRRs and soluble collectins in the innate immune
response to mycobacterial infections, and will present the
current state of knowledge regarding the potential uses of
these C-type lectins in therapy against infections, focusing
on M.tb.
[Back to top]
Directing an Appropriate Immune Response: The Role of Defense
Collagens and other Soluble Pattern Recognition Molecules
D.A. Fraser and A.J. Tenner
Defense collagens and other soluble pattern recognition
receptors contain the ability to recognize and bind molecular
patterns associated with pathogens (PAMPs) or apoptotic cells
(ACAMPs) and signal appropriate effector-function responses.
PAMP recognition by defense collagens C1q, MBL and ficolins
leads to rapid containment of infection via complement
activation. However, in the absence of danger, such as during
the clearance of apoptotic cells, defense collagens such as
C1q, MBL, ficolins, SP-A, SP-D and even adiponectin have all
been shown to facilitate enhanced phagocytosis and modulate
induction of cytokines towards an anti-inflammatory profile.
In this way, cellular debris can be removed without provoking
an inflammatory immune response which may be important in
the prevention of autoimmunity and/or resolving inflammation.
Indeed, deficiencies and/or knock-out mouse studies have highlighted
critical roles for soluble pattern recognition receptors in
the clearance of apoptotic bodies and protection from autoimmune
diseases along with mediating protection from specific infections.
Understanding the mechanisms involved in defense collagen
and other soluble pattern recognition receptor modulation
of the immune response may provide important novel insights
into therapeutic targets for infectious and/or autoimmune
diseases and additionally may identify avenues for more effective
vaccine design.
[Back to top]
The Pattern Recognition Receptor Dectin-1: From Fungi to Mycobacteria
J.S. Schorey and C. Lawrence
The ability of the innate immune system to quickly recognize
and respond to an invading pathogen is essential for controlling
the infection. For this purpose, cells of the immune system
express receptors which recognize evolutionarily conserved
structures expressed by various pathogens but absent from
host cells. In this review we focus on the non-classical C-type
lectin receptors including Dectin-1 whose role has been extensively
characterized in the recognition and response to fungal pathogens.
Dectin-1 is a type II transmembrane protein which binds β
-1,3 and β
-1,6 glucans. It is expressed on most cells of the innate
immune system and has been implicated in phagocytosis as well
as killing of fungi by macrophages, neutrophils and dendritic
cells. The Dectin-1 cytoplasmic tail contains an immunoreceptor
tyrosine based activation motif (ITAM) that signals in part
through the spleen tyrosine kinase and in collaboration with
Toll-like receptors. Although the main research focus has
been on Dectin-1’s role as a fungal and yeast pathogen
recognition receptor, more recent studies suggest that Dectin-1
may have a broader function in pathogen recognition including
a role in directing a macrophage response to mycobacterial
infections.
[Back to top]
CD93 and Related Family Members: Their Role in Innate Immunity
M.C. Greenlee, S.A. Sullivan and S.S. Bohlson
CD93 belongs to a newly described family of transmembrane
glycoproteins which also includes endosialin and thrombomodulin.
These cell surface proteins are grouped into a family based
on similar ectodomain architecture consisting of a C-type
lectin-like domain, a series of EGF-like repeats and a highly
glycosylated mucin-like domain. However, recent studies suggest
overlapping functions in the regulation of processes involving
innate immunity and inflammation. CD93 regulates phagocytosis
of apoptotic cells in vivo, a function critical to
development, tissue repair and maintenance of tissue homeostasis.
In addition, in vitro studies have demonstrated a
role for CD93 in phagocytosis of antibody and complement opsonized
particles and also in leukocyte and endothelial cell adhesion.
Analysis of CD93 expression on endothelial cells in the developing
mouse embryo correlates with the remodeling of blood vessels
suggesting a role for CD93 in regulating angiogenesis, a process
tightly linked to acute and chronic inflammation and also
required for tumor metastasis. Endosialin has been characterized
as a tumor specific antigen and functions in angiogenesis.
Thrombomodulin is best characterized as a natural anticoagulant;
however, more recent reports have illuminated the importance
of thrombomodulin in the regulation of inflammation. This
review discusses similarities and differences in the family
members, and focuses on known and speculated functions in
regulation of innate immunity.
[Back to top]
Collagen Receptor Integrins: Rising to the Challenge
K.D. McCall-Culbreath and M.M. Zutter
Integrins are α
β
heterodimeric receptors that connect the extracellular environment
with intracellular signaling events. Integrins are important
for normal development and function, but are also involved
in the pathogenesis of diseases including cancer, autoimmunity
and heart disease. We will review the present data on a family
of integrins, the collagen receptors that include the α1β1,
α2β1,
α10β1
and α11β1
integrins. We will describe the knowledge gained from genetic
deletion of each integrin in animal models. Mice lacking any
single collagen receptor display no overt defect. However,
studies using the
α1β1
and α2β1
integrin-deficient mice indicate that these receptors play
an important role in innate immunity, inflammation and autoimmunity.
Finally, we will elucidate the interesting and sometimes overlapping
roles for α1β1
and α2β1
integrins in disease and will propose potential stategies
to therapeutically target these receptors to alleviate or
treat disease.
[Back to top]
Molecular Mechanisms of Host-Pathogen Interactions and their
Potential for the Discovery of New Drug Targets
V. Briken
Vaccines and chemotherapy have undeniably been the discoveries
in the field of biomedical research that have exerted the
biggest impact on the improvement of public health. Nevertheless,
the development of bacterial resistance to antibiotics has
co-evolved over time with the discovery of new drugs. This
entails the necessity for continuous research on new anti-infectious
agents.The current review highlights recent discoveries in
the molecular mechanisms of specific host pathogen interactions
and their potential for drug discovery. The focus is on facultative
and obligate intracellular pathogens (Mycobacterium, Chlamydia
and Legionella) and their manipulation of host cells
in regard to inhibition of phagosome maturation and cell death.
Furthermore, the composition and role of the SecA2 and the
ESX-1 secretion pathways in bacterial virulence and manipulation
of infected host cells is discussed. The central hypothesis
proposed in this review is that the characterization of bacterial
proteins and lipids involved in host cell manipulation (modulins)
will provide an abundance of new drug targets. One advantage
of targeting such bacterial modulins for drug development
is that these anti-modulin drugs will not disrupt the beneficial
host microflora and therefore have fewer side effects
[Back to top]
Properdin and Complement Activation: A Fresh Perspective
D.E. Hourcade
The C3 convertases are the major proteases of the complement
cascade and are assembled at the site of complement activation
via several different pathways. Properdin’s
functional role in stabilizing the alternative pathway convertase
has been long established; however, new evidence demonstrates
that properdin can also bind to certain microbial surfaces,
and provide a platform for de novo convertase assembly.
Therefore, properdin participates in two distinct mechanisms
for complement activation: the alternative pathway and a properdin-directed
pathway. Previous work had implicated the alternative pathway
in the initiation and/or progression of several autoimmune
diseases and in the host defense against certain bacterial
pathogens. Those conclusions were based on evidence that cannot
distinguish effects of the alternative pathway from effects
of the properdin-directed pathway. With the identification
of the new role for properdin in C3 convertase assembly there
became a pressing need to reassess the mechanisms of complement
activation, determine the specific role of properdin in each
of these pathways, and explore the new therapeutic avenues
that could arise.
[Back to top]
The Host Complement System and Arbovirus Pathogenesis
T.E. Morrison and M.T. Heise
Arthropod-borne viruses (arboviruses) are a significant
cause of human diseases worldwide. Interactions between these
viruses and the innate immune system play a major role in
determining the outcome of disease. The complement system
is particularly important in this process as activation of
complement can contribute to both host defense as well as
injury to host tissues. This review focuses on the increasing
evidence that the complement system plays key roles in both
protective and pathologic outcomes of arbovirus infection.
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