PMC:1271393 / 2060-9406 JSONTXT

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The interaction of the human host with a wide variety of pathogens has been accompanied by genetic adaptations to spatially and temporally fluctuating selective pressures imposed by the infectious agents. Numerous studies have sought the genetic imprint of natural selection imposed by pathogen pressures in human genes involved in immune response or, more generally, in host-pathogen interactions (Vallender and Lahn 2004). For example, natural selection has acted on such genes as MHC, β-globin, G6PD, IL-2, IL-4, TNFSF5, the Duffy blood group genes, and CCR5 (Ohta 1991; Hughes et al. 1994; Flint et al. 1998; Hamblin and Di Rienzo 2000; Tishkoff et al. 2001; Bamshad et al. 2002; Sabeti et al. 2002; Verrelli et al. 2002). However, little is known about genetic variation of genes involved in direct recognition of pathogens, or pathogens' products, and virtually no studies have investigated the extent to which pathogens have exerted selective pressures on the innate immune system.\nThe phylogenetically ancient innate immune system governs the initial detection of pathogens and stimulates the first line of host defense (Medzhitov and Janeway 1998a, 2000, 2002; Janeway and Medzhitov 2002). Recognition of pathogens is mediated by phagocytic cells through germline-encoded receptors, known as “pattern recognition receptors,” which detect pathogen-associated molecular patterns that are characteristic products of microbial physiology (Kimbrell and Beutler 2001; Janeway and Medzhitov 2002). This initial interaction is then translated into a set of endogenous signals that ultimately lead to the induction of the adaptive immune response (Medzhitov and Janeway 1998b).\nIn recent years, the C-type lectin receptors have received much attention in the area of innate immunology, the results of which were novel functional insights into the primary interface between host and pathogens (Medzhitov 2001; Cook et al. 2003; Fujita et al. 2004; Geijtenbeek et al. 2004; McGreal et al. 2004). In this context, two prototypic members of the C-type lectin–receptor family are particularly interesting, since they can act as both cell-adhesion receptors and pathogen-recognition receptors. These lectins include CD209 (DCSIGN: dendritic cell–specific ICAM-3 grabbing nonintegrin [MIM 604672]) and its close relative CD209L (L-SIGN: liver/lymph node–specific ICAM-3 grabbing nonintegrin [MIM 605872]) (Curtis et al. 1992; Geijtenbeek et al. 2000b, 2004; Soilleux et al. 2000; Pohlmann et al. 2001). These lectin-coding genes are located on chromosome 19p13.2-3, within an ∼26-kb segment, and result from a duplication of an ancestral gene (Bashirova et al. 2003; Soilleux 2003). An additional characteristic of both CD209 and CD209L is the presence of a neck region, primarily made up of seven highly conserved 23-aa repeats, that separates the carbohydrate-recognition domain involved in pathogen binding from the transmembrane region. This neck region presents high nucleotide identity between repeats, both within each molecule and between CD209 and CD209L. It has been shown that this region plays a crucial role in the oligomerization and support of the carbohydrate-recognition domain; therefore, it influences the pathogen-binding properties of these two receptors (Soilleux et al. 2000, 2003; Feinberg et al. 2005). In regard to expression profiles, CD209 is expressed primarily on phagocytic cells, such as dendritic cells and macrophages, whereas CD209L expression is restricted to endothelial cells in liver and lymph nodes (Bashirova et al. 2001; Soilleux et al. 2001, 2002). As pathogen-recognition receptors, the two lectins have been shown to recognize a vast range of microbes, some of which are of major public health importance (Geijtenbeek et al. 2004). Indeed, CD209 captures bacteria such as Mycobacterium tuberculosis, Helicobacter pylori, and certain Klebsiela pneumonia strains; viruses such as HIV-1, Ebola virus, cytomegalovirus, hepatitis C virus, Dengue virus, and SARS-coronavirus; and parasites like Leishmania pifanoi and Schistosoma mansoni (Geijtenbeek et al. 2000a, 2003; Alvarez et al. 2002; Colmenares et al. 2002; Halary et al. 2002; Appelmelk et al. 2003; Lozach et al. 2003; Tailleux et al. 2003; Tassaneetrithep et al. 2003; Bergman et al. 2004; Marzi et al. 2004). With regard to CD209L, studies to date have shown an interaction with a variety of viruses, including HIV, hepatitis C, Ebola, and coronavirus, as well as with the parasite Schistosoma mansoni (Bashirova et al. 2001; Alvarez et al. 2002; Gardner et al. 2003; Jeffers et al. 2004; Van Liempt et al. 2004). In this context, the efficiency of the two lectins in pathogen recognition and subsequent processing may have important consequences for the quality of host immune responses and consequent pathogen control and/or clearance.\nAn important step forward in the understanding of human adaptation to pathogens and control of infectious diseases includes the description of quality and quantity of genetic variation in genes involved in host recognition of infectious agents. Given the direct interaction of CD209 and CD209L with a large variety of pathogens, the CD209/CD209L genomic region provides an excellent model system to illustrate the extent to which pathogens have exerted selective pressures on host immunity genes. An additional feature that makes these genes highly interesting in evolutionary studies is that they are likely to have been influenced by similar genomic forces (recombination, mutation rates, etc.) because of their close physical proximity (∼15 kb), high nucleotide (73%) and amino acid (77%) identity, and identical exon-intron organization (Soilleux 2003) (fig. 1 ). In addition, it has been proposed that gene duplication of immunity genes is a molecular strategy developed by the host to enlarge its defense potential (Ohno 1970; Trowsdale and Parham 2004). A number of immune-system gene families have evolved, by gene duplication followed by natural selection, to provide responses to a wider range of pathogens, with welldocumented examples in immunoglobulin and MHC genes (Hughes et al. 1994; Ota et al. 2000). In this context, duplicated genes in cis, like CD209 and CD209L, may have undergone differential selective pressures to enlarge the defense role of these lectins. To address these complex issues, we performed a sequence-based survey of the entire CD209/CD209L region in a panel of individuals of different ethnic origins. Here, we report evidence showing that these two closely related innate immunity genes have gone through completely different evolutionary processes that are reflected in their current patterns of diversity. In addition, our study provides novel insights into how pathogens have shaped the patterns of variability of immunity genes resulting from gene duplication.\nFigure 1 Scaled diagram of the CD209/CD209L genomic region. Sequenced regions are represented in gray. For CD209, we sequenced a total of 5,500 bp per chromosome, and, for CD209L, 5,391 bp per chromosome. The neck region corresponding to exon 4 and composed of seven coding repeats is also shown."}