The mucosal immune system of fish: The evolution of tolerating commensals while fighting pathogens
Graphical abstract
Introduction
Most infections start at or affect the mucosal epithelia of animals. Mucosal surfaces face many antigens while living in harmony with commensal microorganisms, known conjunctionally as microbiota. Over the last few years, the literature has been filled with many studies on how the microbiota shapes the host and its immune system [1], [2], [3]. Commensal colonization brings many physiological, metabolic and immunological benefits to the host. Some specific examples include harvesting of nutrients from food, providing essential vitamins and producing biofilms that block pathogen entrance [4]. The mucosal immune system of vertebrates comprises a unique array of innate and adaptive immune cells and molecules that act in concert to protect the host against pathogens (Fig. 1). At the same time, the mucosal immune system has evolved to permit the colonization of mucosal surfaces with complex and diverse microbial communities [4], [5]. For example by developing lymphocytes with high specificity and memory capacities, the vertebrate mucosal immune system is capable of remembering commensals and pathogens. In a parallel way, commensals have evolved decreasing its pathogenicity in order to inhabit the advantageous and nutritious mucosal surfaces, like the gut, without being eliminated [4]. This represents an intricate example of co-evolution that scientists are slowly beginning to unravel.
Both pathogens and commensals share “microbe-associated molecular patterns” (MAMPs) recognized by the pattern recognition receptors (PRRs) of the immune system. This means that the immune system cannot distinguish, for instance, if the lipid A core binding motif of LPS that interacts with TLR4, in fact originates from a commensal or a pathogen [6]. Therefore, permitting commensal colonization requires precise homeostatic regulatory mechanisms from the host's immune system. Commensals may nevertheless become harmful if homeostasis is breached and they access the host's internal milieu [4].
Fish live in aquatic environments, which are an ideal medium for microorganism growth compared to air. These conditions may pose additional challenges to the mucosal immune system of aquatic vertebrates versus their terrestrial counterparts. As a consequence, some of the principles of mammalian mucosal immunity may not be necessarily applicable to aquatic vertebrates. In teleosts, the gut, the skin and the gills are the main mucosal surfaces and immune barriers. Lower vertebrates, like cartilaginous and teleost fish, are the oldest animals with an adaptive immune system based on antibodies, B cells and T cells [7]. Additionally, teleost fish are the most primitive vertebrates where dedicated antibodies specific to mucosal surfaces have been characterized [8]. These large and multifunctional surfaces represent the sites where the innate and adaptive immune systems first had to cooperate during the evolution of vertebrates to allow “good” while avoiding “bad” microorganisms.
As described later in this review, the gut, skin and gills of fish, despite having some functional and structural differences, all share many characteristics with type I mucosal surfaces of mammals [9] (Fig. 1). Mammalian type I mucosal surfaces are represented by the intestine, the respiratory tract and the uterus, and they exert physiological functions in a similar way to those of teleost mucosal surfaces. Type I mucosal surfaces contain mucus-secreting cells generally arranged in a simple one-layered epithelium. Teleost mucosal surfaces also contain mucus-producing cells arranged in a simple columnar epithelium in the gut [10], one to four layers of cuboidal or squamous epithelial cells in the gills [11], and a stratified squamous epithelium in the skin [12]. In mammalian mucosal surfaces the main immunoglobulin is IgA, which is mostly produced by plasma cells present in the gut lamina propria. In a similar way, the teleost IgA homologue, IgT/IgZ, has a preponderant role in gut mucosal immunity [8]. Additionally, in mammals Igs are exported across epithelial barriers into the lumen via the polymeric immunoglobulin receptor (pIgR) expressed by epithelial cells. The pIgR is also expressed in the gut [8] and skin [13] of teleosts and it is responsible for the transport of IgM and IgT across mucosal barriers. Further, many other immunological elements of the adaptive and innate immune system, like the presence of T cells, macrophages, mast cells, dendritic cells and the coordinated expression of cytokines, are common to mucosal surfaces of mammals and teleost fish as illustrated in Fig. 1. Thus, the study of fish mucosal immunity is not only exciting because of its interest to aquaculture researchers and evolutionary biologists but also because it offers a unique model to study unresolved aspects of mucosal immunity in mammals.
This review emphasizes the importance of investigating the mucosal immune system of teleosts and highlights the most recent advances (both basic and applied) in the field. Furthermore, the parallelisms and differences with the mammalian mucosal immune system and predictions on future discoveries in this research area are described. Finally, mucosal immunotherapy approaches, like probiotics and vaccines, which may help improving not only the mucosal, but also the overall immune response of fish, are discussed.
Section snippets
Innate immunity at teleost mucosal surfaces
The innate components of the immune system are the first barrier that the microorganisms have to confront in their contact with the host. Thereby these components are abundant at mucosal surfaces and their interaction with commensals is highly regulated to avoid hyper reaction. In this section, the humoral and cellular innate components present at mucosal surfaces of teleosts are reviewed and compared to their mammalian homologues.
Adaptive immunity at teleost mucosal surfaces
Adaptive immunity first emerged when the earlier vertebrates (agnathans) appeared approximately 500 million years ago. One of the current evolutionary hypotheses is that adaptive immunity may have been driven mainly by the microbial colonization of mucosal surfaces [4], [80]. In this section the presence and roles of immunoglobulins (Igs), and B and T lymphocytes in mucosal surfaces of teleost fish are discussed in the context of commensals and pathogens.
Exploiting mucosal immunity for immunotherapy
The control and eradication of mucosal pathogens requires targeted immunotherapies that specifically protect local mucosal sites. Several new mucosal delivery approaches are being developed and optimized for use in mammals. The aquaculture industry will benefit from these technological advances by exploiting the strengths of the fish mucosal immune system.
Concluding remarks
The mucosal immune system of vertebrates is one of the most sophisticated examples of evolution found in nature. During vertebrate evolution, increasingly complex body structures implied higher metabolic rates and created an evolutionary pressure for new metabolic abilities. Vertebrates thus may have allowed commensals to colonize their mucosa for the benefits of new genetic material rather than coding for those new metabolic abilities themselves [133]. The metabolome is therefore defined as
Acknowledgments
This work was supported by the National Science Foundation (NSF-MCB-0719599 to J.O.S.), National Institutes of Health (R01GM085207-01 to J.O.S.) and CETI COBRE grant (P20GM103452 to I.S.).
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