Current Drug Targets - Volume 9, Issue 2, 2008

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 hostpathogen 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.

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.

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.

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 nonclassical 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.

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.

Integrins are αβ 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 αα11β1 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.

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.

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.

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.