An Infectious Disease and Innate Immunity Model

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Recently, the zebrafish was established as a model for infection and immunity (Davis et al. 2002; Menudier et al. 1996; Neely et al. 2002; Phelan et al. 2005b; Pressley et al. 2005; Prouty et al. 2003; van der Sar et al. 2003, 2006). The zebrafish is particularly useful because each point in its development can be easily exploited to learn important information about the immune system. During the first four days of development, the zebrafish exhibits no adaptive immunity markers (Traver et al. 2003). Four days post-fertilization, ragl and rag2 expression is noted (Willett et al. 1997), and zebrafish begin to develop the T and B cells necessary to mount adaptive immune responses (Danilova and Steiner 2002; Danilova et al. 2004). It has been shown that, while some adaptive immunity markers are present early in the developing larvae, the zebrafish requires 4-6 weeks to achieve a fully functional adaptive immune response (Lam et al. 2004). With the development of viral and bacterial infection models (Davis et al. 2002; Menudier et al. 1996; Neely et al. 2002; Phelan et al. 2005b; Pressley et al. 2005; Prouty et al. 2003; van der Sar et al. 2003), it is now possible to study innate immune responses exclusively in these first weeks of development and thereby examine the role of innate immunity without the complications of the adaptive immune response.

3.3.1 Bacterial Models

Several bacterial models of infection for zebrafish have been described and will prove useful in the study of zebrafish immunity (Davis et al. 2002; Menudier et al. 1996; Neely et al. 2002; Pressley et al. 2005; Prouty et al. 2003; van der Sar et al. 2003). For example, our laboratory established an effective, bacterial immersion infection model using Edwardsiella tarda, a Gram-negative rod (Pressley et al. 2005). Acute infection of both embryos and adults was noted through histopathology and cumulative percent mortalities. Additionally, upregulation of transcripts for the proinflammatory cytokines IL-1ß and TNF-a was observed. Infection studies with strains of Streptococcus (Neely et al. 2002), Mycobacterium (Davis et al. 2002; Prouty et al. 2003), Salmonella (van der Sar et al. 2003), and Listeria (Menudier et al. 1996) have also been reported, but these infection schemes are limited to injection rather than immersion.

3.3.2 Viral Models

Our laboratory was also the first to demonstrate that zebrafish at varying stages of development were susceptible to lethal infection upon immersion challenge by snakehead rhabdovirus (SHRV), and that such infections could elicit potent antiviral responses throughout development, as measured by zebrafish type I IFN and Mx transcript levels (Phelan et al. 2005b). Other laboratories have shown that zebrafish can be infected with infectious hematopoietic necrosis virus (IHNV), infectious pancreatic necrosis virus (IPNV), and spring viremia of carp virus (SVCV; LaPatra et al. 2000; Sanders et al. 2003). Each of these infection models was limited to adult fishes. Unlike the SHRV model, infection of developing zebrafish from embryonic through juvenile stages was not described. IHNV and IPNV were able to replicate within the zebrafish, but these fish exhibited no mortalities (LaPatra et al. 2000). SVCV was shown to induce pathology consistent with viral infection in zebrafish adults, but these infections occurred at temperatures between 15 °C and 20 °C, well below the optimal temperature for maintaining zebrafish (28 °C; Sanders et al. 2003). As a result, zebrafish needed to be acclimated to lower temperatures and infections took longer to occur.

The establishment of infectious disease models in zebrafish has made it possible to assay mechanisms of host defense. Zebrafish homologs of mammalian TLRs and their pathway components have been identified by in silico analysis, and many have been partially cloned (Jault et al. 2004; Meijer et al. 2004; Phelan et al. 2005a). Phylogenetic analyses infer strong conservation amongst TLRs and their pathway components, from fishes to mammals (Iliev et al. 2005; Roach et al. 2005). Very little, however, has been done to characterize their function. Our laboratory characterized full-length zebrafish TLR3, IRAK4, and TRAF6 orthologs and assayed the effects of infection on their expression at different stages of development (Phelan et al. 2005a). All of the genes were upregulated in response to infection by E. tarda, but only TLR3 and TRAF6 expression were activated upon SHRV infection. The results demonstrated that a robust TLR-mediated antibacterial and antiviral response could be triggered upon infection. These findings were bolstered by a recent investigation into the role of zebrafish MyD88 in mediating response to infection. A MO-mediated gene knockdown of MyD88 was shown to disrupt clearance of Salmonella enterica serovar Typhimurium Ra bacteria (van der Sar et al. 2006), demonstrating an important role for MyD88-dependent signaling in zebrafish.

Homologs for a variety of mammalian cytokines have been identified in zebrafish, and some have begun to be characterized. These include IL-1b (Pressley et al. 2005), TNF-a (Praveen et al. 2006a; Pressley et al. 2005), and type I IFN (Altmann et al. 2003; Robertsen 2006), as have been described, as well as IL-10 (Zhang et al. 2005), IL-11 (Huising et al. 2005), IL-15 (Bei et al. 2006), IL-22 (Igawa et al. 2006), IL-26 (Igawa et al. 2006) and IFN-y (Igawa et al. 2006; Robertsen 2006). In addition, a variety of chemokines have been identified (Baoprasertkul et al. 2005) and, based upon an extensive genome analysis, up to 46 CC chemokines in zebrafish may exist (Peatman and Liu 2006). In other fishes, homologs for lymphotoxin-P (Kono et al. 2006), granulocyte colony-stimulating factors (Santos et al. 2006), and IL-18 (Huising et al. 2004) have been identified.

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How To Bolster Your Immune System

How To Bolster Your Immune System

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