Fish immunity: the potential impact on vaccine development and performance

Authors


Correspondence: C J Secombes, Scottish Fish Immunology Research Centre, University of Aberdeen, Aberdeen AB24 2TZ, Scotland, UK. E-mail: c.secombes@abdn.ac.uk

The recent years have witnessed a vast increase in our knowledge of the immune system of fish (Lieschke & Trede 2009). We now know of families of immune molecules that have been expanded in fish relative to other vertebrates, as seen with the tripartite motif family proteins (Van der Aa, Levraud, Yahmi, Lauret, Briolat, Herbomel, Benmansour & Boudinot 2009), and that in some cases, completely novel immune genes are present, which include, among others, the novel immunoglobulin-like transcripts (Østergaard, Martin, Wang, Stet & Secombes 2009) and novel immune-type receptors (Yoder 2009). Nevertheless, at a basic level, the teleost immune system appears to operate in a manner that would be familiar to a mammalian immunologist, and many of the key molecules needed for control have been discovered and include a large number of cytokines that act as paracrine signals and cell surface-associated receptor–ligand systems that mediate co-stimulatory effects (Gong, Xiang & Shao 2009; Secombes, Zou & Bird 2009; Sugamata, Suetake, Kikuchi & Suzuki 2009). As predicted from early immunization/vaccination studies (Ellis 1988; Midtlyng 2005), fish clearly possess an adaptive immune response that can be primed by prior exposure to foreign molecules, as occurs during an infection or vaccination. Such fish may be immune upon re-exposure to the same molecules from a pathogen, if the correct type of immune response was triggered initially, and hence the reason for reference to specific immunity and immunological memory. These are features apparently absent from invertebrate immune systems, or at least not mediated by the same molecular mechanisms. So, does this new knowledge help to develop better means to control fish diseases and improve fish health, particularly in relation to aquaculture?

There are many fish diseases known today for which no efficacious vaccines exist, and the use of low-efficacy vaccines may actually reduce profitability (Thorarinsson & Powell 2006). In the case of parasite vaccines, very few have been developed successfully for any organism and so it seems likely that there will be no quick fix regardless of our state of knowledge of the host–parasite interactions in different species. However, as genomes are sequenced and virulence mechanisms are established, there may be some future hope. A case in point is research into oomycetes such as Saprolegnia (Phillips, Anderson, Robertson, Secombes & Van West 2008). Sequencing of expressed genes from this organism has already hinted at targets for immune intervention (Robertson, Anderson, Phillips, Secombes, Diéguez-Uribeondo & Van West 2009), and when the genome sequence has been finalized later this year, may give the complete picture and allow protracted but logistically possible ways to screen for vaccine targets. In the case of bacterial and viral diseases for which it has also proven difficult to develop effective vaccines, as with ISAV (Mikalsen, Sindre, Torgersen & Rimstad 2005), which is currently a major issue for salmon farming in Chile (Kibenge, Godoy, Wang, Kibenge, Gherardelli, Mansilla, Lisperger, Jarpa, Larroquete, Avendano, Lara & Gallardo 2009; Mardones, Perez & Carpenter 2009), then part of the problem may be that the manner in which the vaccine is delivered is inappropriate or that it has triggered the ‘wrong’ type of immune response. Here, the recent advances in fish immunology can help. Study of the key immunoregulatory molecules in different disease states can identify the protective mechanisms needed for disease resistance, and hence the pathways that need to be triggered by vaccination. This can now be done using functional genomics approaches, such as microarray analysis or deep sequencing (Caipang, Brinchmann & Viswanath 2009; Van der Sar, Spaink, Zakrzewska, Bitter & Meijer 2009), which allow broad coverage of the host response and, with time, will become closer to the complete coverage of all expressed genes within a host. Subsequent screening of pilot vaccines to determine whether they can induce suitable immune responses may help speed up the development of those that are the most effective, and eventually in silico approaches may even be developed to help. An example of how this could work has been shown recently in haddock (Melanogrammus aeglefinus), where, after vaccination and challenge with Vibrio anguillarum, a correlation was seen between protection and interleukin-22 expression in the gills (Corripio-Miyar, Zou, Richmond & Secombes 2009). Interleukin-22 is a molecule known in mammals to initiate and activate pathways leading to protection against extracellular bacterial pathogens, particularly at mucosal surfaces (Dubin & Kolls 2008), and recently, the gills of fish have been shown to contain an interesting and novel intraepithelial lymphoid tissue (Haugarvoll, Bjerkas, Nowak, Hordvik & Koppang 2008) that may be a place where specific antimicrobial responses are initiated.

It is also possible that the inclusion of these immunoregulatory molecules in fish vaccines will have value in driving the immune response in a particular direction. There is a large body of literature on this in relation to farm animal and human vaccine development (Charerntantanakul 2009; Kayamuro, Abe, Yoshioka, Katayama, Nomura, Yoshida, Yamashita, Yoshikawa, Kawai, Mayumi, Hiroi, Itoh, Nagano, Kamada, Tsunoda & Tsutsumi 2009; Tan, Wang, Shang & Yang 2009), but studies in fish are only just beginning since the discovery of many of the molecules has occurred in the last few years. With the advent of DNA vaccines (Einer-Jensen, Delgado, Lorenzen, Bovo, Evensen, Lapatra & Lorenzen 2009; Lorenzen, Einer-Jensen, Rasmussen, Kjaer, Collet, Secombes & Lorenzen 2009), it has become relatively simple to incorporate such molecules as molecular adjuvants into the constructs, to test their effectiveness. Although it remains to be seen as to how widespread the use of DNA vaccines for fish will become, at least for screening purposes, to identify the molecules with the best adjuvant properties for particular vaccines, this would seem an ideal approach and one that could subsequently allow the encoded proteins to be made and used in conventional vaccines.

Hence, the future is rosy in terms of the number of new molecules that can now be monitored as markers of fish vaccine efficacy or tested as novel adjuvants to boost the immune response and ensure that appropriate and protective responses are elicited. Clearly, this will take time to investigate and it may be that combinations of some of these molecules prove to be the most successful. Nevertheless, it seems likely that some of these advances in elucidating the immune molecules present in fish and determining how they function will impact on vaccine development and help deliver a new generation of vaccines against diseases for which there are few treatments currently.

Acknowledgments

Thanks are due to Drs Pieter van West and Steve Bird, University of Aberdeen, for comments on this paper.

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