Abstract
Shrimp, being an invertebrate, lack a vertebrate-like adaptive immune system. However, an efficient innate immune system, consisting of physical barriers and cellular and humoral components, exists in shrimp. The innate immunity is activated by the recognition of different microbial cellular components (pathogen-associated molecular patterns, PAMPs) by the host-associated pattern recognition receptors (PRRs), which triggers different signalling pathways and subsequently leads to different cellular and humoral immune responses. Cellular defence involves various processes (phagocytosis, encapsulation, nodule formation, coagulation, apoptosis etc.) directly mediated by haemocytes. However, humoral components include activation of different cascade systems and release of molecules accumulated within the haemocytes (prophenoloxidase (proPO) activating system, antioxidant system, agglutinins, protease-inhibitors, anti-microbial peptides, phosphatase, lysozyme etc.). Apart from this, RNA interference (RNAi), microRNA and complement system have been found to play crucial roles in the protective immunity in shrimp. Moreover, existence of immunological memory and adaptive immunity in shrimp has been suggested, and molecules such as Down syndrome cell adhesion molecules (Dscam), fibrinogen-related proteins (FREPs) and hemolin have been reported to be involved in this. The existence of adaptive immunity in shrimp suggests the possibility of vaccinating shrimp against specific pathogens.
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1 Introduction
Farming of penaeid shrimp represents one of the most economically important sectors of the rapidly growing aquaculture food production system worldwide. However, sustainable production has been hampered by the emergence of various diseases of infectious (opportunistic and obligate pathogens) and non-infectious (stressful farm conditions) origin resulting in considerable economic losses in many countries [1, 2]. Further, no effective control strategies are available to deal with the infectious disease outbreaks in shrimp farming owing to the limited understanding of the host–pathogen interaction. The susceptibility/resistance of shrimp to invading pathogens is greatly influenced by the immune status of the host and, therefore, understanding shrimp immune system is of utmost importance in designing the strategies for the control and management of diseases in shrimp aquaculture. There has been significant advancement in the understanding of the immune mechanisms of crustaceans, as large repertoire of receptors, signalling pathways and defence mechanisms have been elucidated in the past several years. Crustacean immunology, especially the study of shrimp immune system, has gained prominence not only because of the commercial importance of some of the species but also from the standpoint of being invertebrates which occupy a diverse ecological niche and face a diverse pathogen challenge. Immune mechanism of an animal involves recognition of non-self-molecules, and consists of a series of coordinated events mediated by various cells and molecules that may be specific or non-specific in function, which ultimately aids in resisting the invasion of pathogens.
2 Nature of Immune Responses
The fundamental attribute of immune system is its capacity to recognize and respond to no-self. Traditionally, immune mechanisms have been categorized into two, innate and adaptive. According to Medzhitov [3], the major distinction between innate and adaptive immunity is in the types of receptors used in the recognition of pathogens. Further, in the general features, there are many differences between these two arms of the immune system. According to Kvell et al. [4], innate immunity is considered to be natural, non-specific, non-anticipatory and non-clonal but germ-line encoded. Adaptive immunity, on the other hand, is specific, anticipatory, clonal and somatic. It is generally considered that invertebrates possess only innate immunity and vertebrates have innate and adaptive defence mechanisms. Shrimp, being invertebrates, do not possess a vertebrate-like adaptive immune response; however, they have well-developed innate defence mechanisms. Though the innate defence is non-specific, it provides a highly effective defence response against invading pathogens [5, 6]. Nevertheless, there are compelling evidences which show that shrimp possess a specific or quasi-specific immune defence [7] and many adaptive immune molecules in the immune repertoire [8,9,10,11,12,13,14,15]. The innate defence mechanisms in shrimp consist of physical barriers, cellular and humoral components which work in a coordinated way to deal with all invading pathogens [16]. Cellular responses include phagocytosis, encapsulation, nodule formation etc. and are mediated directly by haemocytes. However, prophenoloxidase (proPO) activating system, agglutinins, protease-inhibitors, anti-microbial peptides, phosphatase, lysozyme etc. are the major components of the humoral responses [16,17,18,19,20].
2.1 Physical/Structural Barriers
In shrimp, a hard cuticular exoskeleton provides the physical barrier to the easy entry of microbes into the body. The structure also possesses anti-microbial humoral factors such as polyphenoloxidase and this physical and chemical barrier provides the primary defence against invading pathogens. The cuticle consists of different layers: an outermost epicuticle, followed by inner exocuticle and endocuticle (Fig. 1). The waxy epicuticle is devoid of the polysaccharide, chitin, whereas the sclerotized exo- and endocuticle contain variable levels of chitin and calcium-containing minerals. Below the cuticular layers lies the underlying epidermis and beneath which the basement membrane. The tegumental glands located beneath the epidermis helps in the phenolic tanning of the cuticle by producing polyphenoloxidase. Cuticle covers not only the entire outer body surface of the animal including gills but also the anterior and posterior portions of the gastrointestinal tract [21]. However, the cuticular lining of gills and gut is very thin compared to that of the cuticular lining of the external surface. Moreover, the gastrointestinal tract is equipped to digest the pathogens through the gut enzymes and acids. These features protect the intestinal epithelium from direct access to pathogens that can enter via oral route [22]. The disease-causing agents that need to get entry to the underlying tissues have to penetrate these physical and chemical barriers. However, it is possible that pathogens can break the first line of defence in the event of a physical damage to the overlying structures and/or during moulting when the cuticular structures are vulnerable.
Histological section showing cuticular layers of penaeid shrimp. (a) cuticular lining of the outer exoskeleton; (b) cuticular lining of the gastrointestinal tract. Cu cuticular layers, Ep epidermal layer, Tg tegumental gland
2.2 Cellular and Humoral Immune Responses
Shrimp innate immune system possesses both cellular and humoral components that are activated upon pathogen challenge. The immune activation in response to pathogens involves release of soluble molecules and cellular and humoral components mediated by haemocytes [23]. As mentioned, constituents of the cellular immune responses include all the reactions that are controlled directly by haemocytes such as phagocytosis, encapsulation, nodule formation etc. Humoral components, on the other hand, include cell-free components of the haemolymph. These include a variety of molecules and cascades such as proPO activating system, clotting cascade agglutinins, protease-inhibitors, anti-microbial peptides, phosphatase, lysozyme, reactive oxygen and nitrogen intermediates etc. [16,17,18,19,20, 23]. Though there is a clear categorization of the components such as cellular and humoral, it is evident that these responses overlap and the two components are interdependent and work in synergy to protect the animal from pathogen challenge (Fig. 2).
Components of shrimp immune system
2.2.1 Cellular Immune Response
Once the invading pathogen escapes the primary barrier, it gets entry into the body cavity (haemocoel) where it will be responded by circulating blood cells and fixed cells in gills, lymphoid organ or hepatopancreas. Unlike vertebrates, crustaceans possess an ‘incompletely closed’ or ‘partly open’ circulatory system [24] characterized by blood vessels and channels which permeate various tissues. The circulating blood cells in crustaceans (as they circulate in the haemocoel) are called as haemocytes and are mainly responsible for cellular immunity and play a crucial role in defence against microbial invasion. The haemocytes comprise of three main types: hyaline cells, semi-granular cells (SGCs) and granular cells (GCs); and this classification is mainly based on the cell size, nuclear/cytoplasmic (N/C) ratio and the number of intracellular granules (GCs) [24, 25]. Hyaline/agranular cells (5–15% of the circulating haemocytes), as the name implies, are without or with very limited number of granules in the cytoplasm. These are the smallest among the three types of haemocytes and with the highest N/C ratios. The major role of these cells involves clotting, encapsulation and phagocytosis [21, 26]. Semigranulocytes are the most abundant haemocytes (75%), which possess many small granules and are responsible for phagocytosis, nodule formation, encapsulation, proPO activation and clotting [21, 26, 27]. SGCs also possess peroxinectin, one of the cell adhesion proteins [28]. The GCs contain large number of granules possessing a low nucleus-to-cytoplasm ratio and comprises of 10–20% of the total haemocytes [29]. Immune functions of GCs include nodule formation, encapsulation, proPO activation, clotting and production of anti-microbial peptides (AMPs) [21, 29]. Usually, microbial encapsulation is followed by melanization due to proPO which is stored in an inactive form within the granules of the GCs. Apart from proPO, GCs harbour AMPs, protease inhibitors and cell adhesion/degranulating factor called peroxinectin [24].
2.2.1.1 Phagocytosis
In all animal phyla, phagocytosis is considered as the fundamental process for the removal of microorganisms or other small particles (both biotic and abiotic). Phagocytosis in crustaceans is primarily carried out by haemocytes (phagocytes) [16] and the process involves recognition and binding of endogenous foreign materials or pathogen surface receptors on the phagocytic cells (Fig. 3). This is followed by their uptake and engulfment into the cell and subsequent formation of a digestive vacuole called the phagosome. This process initiates a signalling cascade that results in the formation of phagolysosome by fusion of phagosome with lysosomes. Subsequently, several degradative enzymes are released into the phagolysosome and reactive oxygen intermediates (ROIs) are produced, which destroy the engulfed particles [30, 31]. This process, termed as respiratory burst, results in the formation of various ROIs such as superoxide anion (O2−), hydrogen peroxide (H2O2), hydroxyl radicals (OH−) and singlet oxygen (1O2). In crustaceans, phagocytes can be found free in the haemocoel and/or associated with the vascular system of organs such as lymphoid organ, hepatopancreas, gills etc. [32]. The phagocytic process is regulated by many components including pattern recognition receptors (PRRs) [33, 34] such as lectins, scavenger receptors, immunoglobulin-related protein and fibrinogen-related protein [35, 36].
Diagrammatic representation of phagocytosis, encapsulation and nodule formation
2.2.1.2 Encapsulation
When the size of pathogen such as fungal spores, helminths etc. is too large which cannot be phagocytosed by a single cell, several haemocytes cooperate and adhere together to form a capsule around the foreign particles so that the particles can be blocked from getting into circulation. This process is called encapsulation and is a significant cellular immune defence mechanism in invertebrates against pathogens [37] (Fig. 3). Encapsulation is a coordinated response involving multiple cells to eliminate foreign particles which cannot be phagocytosed or cannot be destroyed by humoral factors [38]. Encapsulation involves adherence of several haemocytes to each other and across the surface of intruding particles with the help of adhesion molecules, forming multi-layered cellular sheaths [39]. The cell adhesion molecule peroxinectin plays an important role in enhancing the encapsulation process [28]. A typical capsule is characterized by 5–30 compact layers of haemocytes without intercellular spaces [38]. Some of the humoral substances are responsible for the final destruction of the encapsulated material. Encapsulation can result in significant decline in the number of circulating haemocytes; however, the haemocyte number gets restored to the normal levels in few days [40].
2.2.1.3 Nodulation
Nodule formation occurs when the numbers of microorganisms are more than what can be removed by phagocytosis. Similar to encapsulation, the function of nodule formation is to wall off invading microbes and microparasites. However, nodule formation and encapsulation are different in which nodule formation involves the entrapment of aggregated microorganisms by haemocyte cluster whereas encapsulation involves the formation of multi-layered haemocyte capsule around larger eukaryotic parasites (Fig. 3). Nodulation process is activated either through induction or enhanced expression of cell adhesion molecules such as peroxinectins and integrins [37]. The microbes entrapped in the nodule are immediately eliminated from circulation, which could be noticed in the gills and in sinuses between the hepatopancreatic tubules. Encapsulation and nodulation activate proPO activity and melanization, production of free radicals and AMPs, and subsequently result in the destruction of the microbes [16]. These processes also play vital roles in the sclerotization and wound healing process [41].
2.2.1.4 Apoptosis
Apoptosis is an evolutionarily conserved form of programmed cell death carried out by specialized cellular machinery [42]. Apoptosis performs different functions such as removal of unwanted or potentially harmful cells, besides playing critical role in development [43]. The apoptotic events are carried out by a family of cysteine proteases called caspases. During viral infection, apoptosis is regulated as a critical innate cellular response to limit the replication of virus and prevent the spread of infection in the host [44]. Apoptosis plays an important role in anti-viral response in shrimp, as many apoptosis-related genes such as caspases, inhibitor of apoptosis protein (IAP), apoptosis inducing factor (AIF) etc. have been identified from shrimp [45,46,47,48]. Various caspases have been identified in shrimp and the caspases characterized from Penaeus vannamei are designated as initiator or effector caspases on the basis of their domain structure and their localization in cytoplasm near the membrane or within the nucleus [47]. Further, apoptosis-mediated thwarting of virus multiplication has been recorded in shrimp against WSSV and Taura syndrome virus [49, 50]. Role of caspase as the key effector of apoptosis has also been investigated in shrimp (Marsupenaeus japonicus) and was shown that silencing of Pjcaspase gene resulted in the inhibition of WSSV-induced apoptosis resulting in increased viral copy [45]. However, knocking down of cap-3, a homolog of human caspase-3 in P. vannamei showed contrasting results when challenged with low and high dose of WSSV leading to the observation that in WSSV-challenged shrimp apoptosis may increase mortality rather than decrease [51]. On the other hand, many viruses, including WSSV, possess genes such as anti-apoptotic proteins (AAP-1) that can suppress or delay apoptosis so that sufficient quantities of viral progeny are produced. Consequently, delay in apoptosis helps in spreading the viral progeny from infected to uninfected cells of the host [43, 52, 53].
2.2.1.5 Haemolymph Coagulation or Clotting
Clotting/coagulation, mediated by cellular and humoral components, is an integral part of the invertebrate immune system. Clotting prevents the excessive loss of body fluid due to injury and blocks the entry of microbes into the hemocoel [16, 54,55,56]. Three different mechanisms (type A, B and C) of haemolymph coagulation have been described [57,58,59]. According to Tait’s categorization, haemolymph coagulation in shrimp and spiny lobsters follows type C (third category) mechanism and it is characterized by rapid lysis of haemocytes followed by immediate clotting of plasma resulting in low cell aggregation. However, Ghidalia et al. [58] suggested that the three different patterns of coagulation are due to different concentrations of clotting protein (CP) and those species (shrimp) which exhibits type C category possess the highest amount of CP. Later, Hose et al. [59] suggested that the basis of the three categories is related to the proportion of hyaline cells present in the haemolymph. Accordingly, species categorized under type C possess a higher number of hyaline cells (50–70% of total haemocytes). Based on this, Hose et al. [59] proposed that the three categories proposed by Tait [57] actually represent the proportional responses to the percentage of hyaline cells rather than three different mechanisms.
The key components of haemolymph coagulation identified are CP, formerly named as fibrinogen or plasma coagulogen, and transglutaminase (TGase). The CP is a lipoglycoprotein and its subunits can be covalently cross-linked to each other by TGase. The CPs in crustaceans have no structural similarities with fibrinogen from vertebrates or clottable proteins from other arthropods and, therefore, represent a separate group of CPs [16, 32, 60]. TGase is a calcium-dependent enzyme stored in the haemocytes, which helps in the formation of stable clots by mediating the polymerization of CP [60]. Though TGase is primarily involved in coagulation, it is responsible for many other biological processes. TGases involved in haemolymph clotting in crustaceans are stored in an inactive form in the cytoplasm of the cell. It gets activated by the plasma calcium upon getting released from the cell [61, 62]. It is found that unlike vertebrates, the clotting process in crustaceans involve only a single step [63]. Based on the clotting process observed in freshwater crayfish, P. leniusculus, the current model of haemolymph clotting in crustacean has been suggested and, according to this, clotting is initiated by the release of TGase from haemocytes and other tissues and this in turn promote rapid polymerization of plasmatic CP into long and flexible and often branching chains (formation of clot). This process takes place in the presence of calcium ions [16, 60, 64].
2.2.2 Humoral Immune Response
In the humoral immune response, soluble effector molecules synthesized and stored in the haemocytes are secreted to combat pathogens. Major humoral factors consist of proPO, lectins, agglutinins, AMPs etc., and these factors work in coordination with phagocytes to eliminate the microbial pathogens that have overcome the primary barriers of the host [65].
2.2.2.1 Prophenoloxidase System (proPO) and Melanization
The proPO system is the best-studied crustacean immune mechanism and this potent humoral component is involved in melanization, cytotoxic reactions, cell adhesion, encapsulation and phagocytosis [66] and, thereby, helps in wound healing and entrapment of parasites, besides killing of microbes [23]. Semi-granular and granular haemocytes are the repository of proPO system which can be activated by the presence of microbes or microbial components [67]. The proPO system acts upon dihydrophenylalanine, a phenolic substrate and converts it into dopaquinone. Subsequently, melanin, a dark-brown pigment responsible for preventing the spread of foreign particles in the host body as well as for healing cuticle damages, is produced by the non-enzymatic polymerization of dopaquinone. Further, intermediate compounds in the melanin pathway involve in immune reactions, as they have bactericidal properties.
Microbial cell wall components, even in very low quantities, such as lipopolysaccharides (LPS), β-1,3-glucans or peptidoglycans (PGN) etc. can activate the proPO system leading to the formation of melanin [68]. Phenoloxidase (PO) is the main enzyme involved in the cascade and is synthesized as the inactive zymogen (proPO) in the haemocytes and released outside during degranulation. Proteolytic cleavage of inactive proPO can be triggered by the specific recognition of microorganisms by pattern-recognition proteins (PRPs) resulting in the production of active PO. This conversion is mediated by a serine proteinase, prophenoloxidase activating enzyme (ppA). Further, ppA is synthesized and maintained as a zymogen (pro-ppA) and gets activated by proteolytic cleavage in the presence of Ca2+. Activation of PO leads to the production of melanin and toxic reactive intermediates against intruding pathogens. Among crustaceans, the proPO gene was first characterized in crayfish, P. leniusculus [69, 70] and, subsequently, in shrimp, P. monodon [71].
In shrimp (P. monodon), cDNAs of two proPOs, four serine protienase (SP)], three serine proteinase homologues (SPHs) and one PRP have been characterized. In P. monodon, LPS-ß-1,3-glucan binding protein (LGBP) acts as the PRP for the activation of proPO [23]. Similarly, two prophenoloxidase activating enzyme (ppA) genes have also been identified in this species. Based on the available information, a model of the proPO cascade in P. monodon has been suggested by Amparyup et al. [72]. According to this model, PmLGBP acts as a functional PRP for the activation of proPO system as it can bind to LPS and ß-1,3-glucan and, therefore, can play a role in recognizing microbes. The binding of the PRP with the pathogen-associated molecular pattern (PAMP) will activate the clip-SP cascade and results in the conversion of PmPPAE1 and PmPPAE2 into their active forms. This active form of the enzymes will in turn activate the PmproPO1 and PmproPO2 to their active forms, PO1 and PO2, which will finally lead to the production of melanin and reactive oxygen compounds [72] (Fig. 4). Nevertheless, though melanization and activation of proPO system are essential for the immune defence, these cascades are tightly regulated at multiple levels by different inhibitors to prevent the production of excess melanin and other toxic intermediates which can lead to the damage and death of host cells. These include proteinase inhibitors, PO inhibitors, melanization-inhibiting protein (MIP) etc. Although these inhibitors or the negative regulators of proPO system are reported in insects and some crustaceans, information on the inhibitors in penaeid shrimp is lacking [72].
Prophenoloxidase system (proPO) and melanization
2.2.2.2 Antioxidant System
An important defence reaction of haemocytes is the production of antioxidant factors with powerful microbicidal activity. ROIs (O2−, OH− and H2O2) and reactive nitrogen intermediates (RNIs; nitric oxide and peroxynitrite), produced in phagocytic vacuoles, have the potential to cross the cell barrier and destroy the adjoining cells [73]. To mitigate the harmful effects of different ROIs, cells have efficient antioxidant defence strategies consisting of both the enzymatic (catalase, glutathione peroxidase (GPx), superoxide dismutase (SOD), peroxiredoxin (Prx)) and non-enzymatic components (ascorbate, beta-carotene, flavonoids, alpha-tocopherol and vitamin E) [73]. SOD can scavenge the O2− and convert them to H2O2, which is subsequently detoxified to water and oxygen by the action of other antioxidant enzymes [74].
2.2.2.3 Proteinases and Proteinase-Inhibitors
Proteinases and proteinase-inhibitors, which are distributed ubiquitously in all living organisms, play a major role in the innate immune system of shrimp as the important constituents of proPO cascade and apoptosis. On the other hand, proteinase inhibitors regulate these pathways by inhibiting specific proteinases and, thereby, preventing excessive activation of the pathway and subsequent injury to host tissue. Different serine protease-inhibitors such as the Kazal-type serine proteinase-inhibitors (KPIs), Kunitz-type protease-inhibitor (KUPIs), serpins and alpha-2-macroglobulins (A2Ms), have been characterized and their role in the innate immune system of shrimp has been reported [75, 76].
2.2.2.4 Cytokines
The roles of cytokines in the regulation of haematopoiesis and immune responses in vertebrates have been demonstrated; however, only limited information is available on the cytokines of invertebrates [77, 78]. A cytokine-like factor, astakine, containing a prokineticin (PK) domain has been reported for the first time in crayfish, Pacifastacus leniusculus, and shrimp, P. monodon [77] followed by an astakine in L. vannamei (LvAST) [79]. Further, astakine has been demonstrated to play a vital role in promoting haematopoiesis in crustaceans [78, 79]. They are involved in cell proliferation, differentiation and release of mature haemocytes into circulation [77]. In crustaceans, two different astakines (Ast1 and Ast2) have been reported and, while both the variants are present in crayfish, Ast2 shows more similarity with shrimp astakine [24]. Ast1 is secreted by SGCs and is found abundantly in these cells. Further, it is involved in the proliferation of hematopoietic tissue (HPT) cells and induces differentiation of the SGCs. However, Ast2 does not induce proliferation of HPT cells but induces GCs differentiation [24]. These molecules also serve as positive regulators in enhancing immune responses in shrimp against viruses. Administration of recombinant AST in L. vannamei (LvAST) resulted in significant reduction in mortality and longer survival time in WSSV-infected shrimp. Further, silencing of the gene showed enhanced severity of WSSV infection and short survival time in experimentally-infected shrimp [79]. Moreover, astakines play a crucial role in clotting cascade by reducing extracellular TGase activity [80].
2.2.2.5 Antimicrobial Peptides (AMPs)
AMPs are small molecular weight proteins either cationic or anionic, and possess broad-spectrum activity against a diverse range of organisms including viruses, bacteria, protozoa and fungi. The AMPs have been reported in vertebrates as well as invertebrates and these are present in the epithelial cells and liver/fat body [81]. Many AMPs have been reported from shrimp. These include penaeidins, lysozymes, crustins, stylicins and anti-lipopolysaccharide factor (ALF) which are formed and accumulated in haemocytes and their expression is controlled by Toll and IMD pathways [75, 82].
Penaedins are cationic molecules and are divided into four distinct subgroups: PEN2, PEN3, PEN4 and PEN5 [83]. Penaeidin-4 is the most powerful bactericide among the penaeidins, and PmPEN5 serves as antiviral molecule [84]. Crustins, possessing a single whey acidic protein (WAP) domain at the C-terminus [85], are divided into four main types (Types I–IV) based on their domain arrangement [86]. Most crustins found in shrimp belong to Type-II crustins. Type I crustins are mainly found in crabs, lobsters, crayfish and rarely in shrimp. Type III and IV crustins have also been reported from shrimp [87,88,89]. ALF, with a functional LPS-binding domain (LBD), has been reported to display activity against diverse types of pathogens. The ALFs from penaeid shrimp were divided into seven groups (groups A, B, C, D, E, F and G), based on sequence similarities and phylogenetic analysis [90]. ALFPm3 was found to be involved in anti-WSSV immune response by binding to the envelope proteins [91, 92]. Lysozyme is an enzyme that cleaves the peptidoglycan (PG) in the cell wall of both Gram-positive and Gram-negative bacteria resulting in cell lysis. Of the different types of lysozymes reported, only the c-type and i-type lysozymes have been reported in shrimp so far. Stylicins, the first anionic AMP identified in penaeid shrimps, was first reported from L. stylirostris (LsStylicin1) [93]. LsStylicin1 exhibits a strong anti-fungal activity against Fusarium oxysporum. Stylicins from other shrimp species are reported to respond to WSSV [94] and Vibrio [95] infection. Lectins play a key role in immune responses by serving as opsonins and mediating phagocytosis against bacterial pathogens [96]. Their carbohydrate recognition domain (CRD) recognizes and binds with different sugar moieties on the microbial cell surface that leads to their agglutination [97]. PmAV lectin from P. monodon and a mannose-binding C-type lectin from L. vannamei have been discovered and reported to have antiviral activity [74]. Some AMPs such as MjPen-II and MjCru I-1 have been reported to involve in the phagocytosis during microbial infection in shrimp [98, 99].
The relation between clotting system and production of AMPs has been demonstrated, which together form major constituent of humoral innate immune system. In shrimp, activation of clotting cascade mediated by TGase activates the expression of AMP gene and the release of AMPs [99], and the depletion TGase and CP leads to inhibition of AMP expression [100, 101].
2.2.2.6 Double-Stranded RNAs (dsRNA)
dsRNAs are produced during the replication of positive-sense RNA, dsRNA or DNA viruses. It consists of gene fragments of greater than 30 bp and are central component of post-transcriptional gene silencing, which is also termed as RNA interference (RNAi). The inhibition of viral replication through RNAi has been reported in diverse types of invertebrates such as Caenorhabditis elegans, Drosophila, planaria, hydra and trypanosomes [75, 102]. In RNAi, dsRNA is cleaved by the type III endonuclease Dicer into shorter 21–25 bp small interfering RNAs (siRNA), which get incorporated with the RNA-induced silencing complex (RISC) and, that in turn, targets the binding of the siRNA to the homologous mRNA for destruction. Major components of RNAi pathway in shrimp include Dicer1, Dicer-2, HIV-1 transactivating response RNA-binding protein, eukaryotic initiation factor 6 and members of the argonaute family [103, 104].
It has been reported that the administration of artificial dsRNA/siRNA to shrimp can offer effective protection against virus invasion, suggesting that a functional RNAi pathway is an effective strategy for combating viral infection in crustacean [105, 106]. dsRNA injection to shrimp results in specific down-regulation of target gene [107, 108]. Moreover, marked reduction in virus replication could be noticed following injection of sequence-specific dsRNA/siRNA targeting different viral proteins in shrimp [105, 109]. Enhanced expression of immune genes following the administration of dsRNA injection has also been described [110, 111].
2.2.2.7 microRNA (miRNA)
miRNA are small, non-coding RNA molecules, which play important roles in the regulation of immune response by post-transcriptionally targeting the immunity or pathogen-associated genes. The role of different miRNA in virus–host interactions in shrimp has been studied recently, and alterations have been found in the transcript levels of both host and virus miRNA during virus infection. Generally, an individual miRNA possesses multiple target genes. Prevention of virus propagation and subsequent infection by shrimp miR-7 and miR-965 which inhibit the expression of WSSV early genes, wsv477 and wsv240, has been reported [112, 113]. Additionally, the role of miR-965 in promoting the antiviral phagocytosis of shrimp has been reported, which acts on shrimp ATG5 (autophagy-related gene 5). Moreover, shrimp miR-12 (inhibit WSSV replication by targeting the viral wsv024 gene), miR-34 and miR-1000 (targeting wsv191 and wsv407) play crucial roles in antiviral immunity [114,115,116]. The role of miR-1000 in the regulation of apoptotic activity of shrimp against WSSV by targeting the shrimp p53 gene has also been reported [117]. On the other hand, some viral miRNA interact with host genes or other viral genes for promoting viral replication or virus latency. Regulation of Dorsal by two viral miRNAs (WSSV-miR-N13 and WSSV-miR-N23) during WSSV invasion has been reported, thus suppressing the signalling pathway [118]. A viral miRNA (WSSV-miR-22) has been reported to promote WSSV infection by interacting with shrimp STAT [119]. Another viral-encoded miRNA (WSSV-miR-N12) interacts with wsv399 gene, inducing virus latency [120], which is an efficient strategy for virus to escape its host immune responses.
2.2.2.8 Complement System
The complement system, a group of plasma proteins, plays a key role in immune defence against microbial pathogens. Activation of complement leads to a series of events, which culminate in the opsonization and destruction of the pathogen as well as in the generation of the classical inflammatory response through the formation of potent proinflammatory molecules [121]. Three major pathways have been reported to activate the complement system: classical, lectin, and alternative [122]. However, the presence of complement system in shrimps has only been recently reported where a novel complement C3-like gene (Lv-C3L) from L. vannamei has been identified and its transcript level showed significant up-regulation following bacterial and WSSV infection [123].
3 Pathogen Recognition and Signalling Pathways
The recognition of microbial pathogens is achieved through germline-encoded PRRs that are expressed in a variety of cells, which recognize invariable molecular signatures of pathogens known as PAMPs, and certain danger signals associated with cellular stress, known as damage-associated molecular patterns (DAMPs) [124].
LPS from Gram-negative bacteria, PGN from Gram-positive bacteria, double-stranded RNA (dsRNA) from viruses and β-glucans (GLU) from fungi are the major PAMPs. In vertebrates, binding of PRRs with their PAMPs elicits the expression and up-regulation of respective pro-inflammatory cytokines and anti-microbial molecules during the initial stages of infection that minimize the spread of pathogens [125]. Eleven PRR families, such as LPS and β-1,3-glucan binding proteins (LGBPs), C-type lectins (CTLs), galectins, thioester-containing proteins (TEPs), fibrinogen-related proteins (FREPs), scavenger receptors (SRs), Down syndrome cell adhesion molecules (Dscam), Toll-like receptors (TLRs), β-1,3-glucan binding proteins (BGBPs), serine protease homolog (SPHs) and trans-activation response RNA binding protein (TRBPs) have been identified in shrimp [126]. The tissue-level expression of different PRRs and their response to various ligands and microbial pathogens in several crustaceans have been investigated by many researchers, and found ubiquitous expression of most of these PRRs in many tissues and their differential response against potential pathogens including WSSV and bacteria [127,128,129].
Activation of PRRs in invertebrates triggers a sequence of cellular or humoral responses which are controlled by signal transduction pathways and are triggered by the binding of PRRs with specific PAMPs [130]. The triggered cellular and humoral responses include proPO, clotting mechanism, phagocytosis and the release of NF-kB-dependent AMPs. Signalling pathways in shrimp have been categorized into three: Toll pathway, Immune deficiency (IMD) pathway and JAK/STAT pathway. The Toll pathway is responsible for defence against fungi, Gram-positive bacteria, Gram-negative bacteria and viruses. The IMD pathway performs essential role in managing Gram-negative bacterial and viral infections and the JAK/STAT pathway in antiviral immunity [33].
3.1 Toll Pathway
TLR is the most widely studied signalling molecule. While TLRs of vertebrates can directly recognize PAMPs, TLRs of invertebrates, including shrimp, recognize pathogens through the binding with spätzle, a cytokine-like ligand [33, 131]. Following microbial invasions, the spätzle is cleaved by a proteolytic cascade to form a mature form which in turn binds to the Toll receptor, initiating the signalling cascade. TLR signalling pathways are broadly categorized into two classes: Myeloid differentiation factor 88 (MyD88)-dependent signalling and MyD88-independent/TRIF-dependent signalling. Upon activation by distinct PAMPs, TLRs homo- or heterodimerize and this in turn induces recruitment MyD88 (adaptor molecule), via the cytoplasmic TIR (Toll-IL-1R) domain. MyD88 then recruits Tube (Mammalian IL-1R-associated kinases-4 (IRAK-4) homolog) and Pelle (Mammalian IRAK-1 homolog), which phosphorylates Pelle. Tube subsequently activates Pelle by phosphorylation, which in turn gets associated with tumor necrosis factor receptor-associated factor 6 (TRAF6), followed by the phosphorylation and degradation of Cactus (homolog of Ikβ) and freeing of Dorsal (homolog of NF-kβ). Activated Dorsal is subsequently translocated to the nucleus and regulates the expression of AMPs [131]. The Spätzle/Tolls/MyD88/Tube/Pelle/TRAF6/Dorsal signalling pathway has been elucidated in shrimp [33, 132].
3.2 IMD Pathway
The IMD pathway was initially discovered in Drosophila by the identification of a mutation named immune deficiency (IMD), which inhibits the expression of AMPs. IMD pathway has been reported from crustaceans and the pathway regulates AMP expression. IMD codes for a death domain which is identical to that of the Receptor Interacting Protein (RIP) of the tumour necrosis factor receptor (TNF-R) pathway [33]. Relish, a Rel/NF-kB transcription factor, is the key molecule in the IMD pathway that activates the production of AMPs, after its induction by the IMD. Different components of the shrimp IMD pathway have been characterized [133,134,135,136,137,138]. The PmRelish from P. monodon regulates the synthesis of AMPs such as PEN5, PEN3, ALFPm3 and ALFPm6 in response to V. harveyi or yellow head virus infection [138, 139]. Silencing of members of the IMD pathway by dsRNA indicated the regulation of expression of different AMPs in crustaceans [133, 140].
3.3 JAK–STAT Signalling Pathway
The JAK/STAT pathway, consisting of three key cellular components, the transmembrane receptor Domeless, the Janus Kinase (JAK) and the signal transducer and activator of transcription (STAT), involves in the regulation of various immune responses [141]. Although JAK/STAT pathway has been reported to involve in the antiviral response in insects, the first STAT homologue with the typical functional domains from shrimp was reported in P. monodon [142]. The different components of JAK/STAT pathway have been identified and characterized in shrimp such as FcSTAT, PmSTAT, MjSTAT, LvSTAT, LvJAK, LvDOME etc. [142,143,144,145,146]. Further, it has been reported that transcription of STAT gets modulated after WSSV infection in shrimp [142, 143].
3.4 Other Pathways
Mitogen-activated protein kinases (MAPKs), the serine-threonine protein kinases, which are widely conserved across diverse organisms, play critical roles in cellular responses associated with inflammation, environmental stress and microbial attack. MAPKs in mammals have been categorized into three subfamilies: extracellular signal-regulated kinases (ERKs), stress-activated protein kinases/c-Jun N-terminal kinases (SAPK/JNKs) and p38 MAPK [147]. Many components of MAPK pathway have been reported in shrimp [148,149,150,151,152] and their role in the defence against bacterial and viral infections has been investigated.
Besides the pathogen-recognition pathways described above, interferon (IFN) system like antiviral regulatory mechanisms involving the activation of Vago exist in shrimp [153]. Moreover, a cytosolic sensing pathway with the evidence of functionally characterized IFN-activator LvSTING [154] has been reported from shrimp, L. vannaemi. The antiviral immunity of Toll3 from L. vannamei has been elucidated through dsRNA silencing and was found to be involved in the activation of IFN regulatory factor (IRF) expression and its downstream Vago4/5 [155].
4 Existence of Adaptive-Like Immunity in Crustaceans
A characteristic feature of vertebrate immune response is the adaptive or acquired immunity with specificity and immunological memory. T and B cells and antibodies are responsible for this type of immunological memory; however, invertebrates are found to be devoid of these cells. Many immunological studies in invertebrates suggest the existence of alternative adaptive immune response in their innate immune system. Enhancement in phagocytic activity of haemocytes upon re-encountering of foreign antigens following previous exposure has been reported in lobster [156]. Moreover, administration of β-1,3-1,6-glucan to spawners of P. monodon resulted in the transfer of disease resistance against WSSV infection in larvae. The phenomenon of ‘trans-generational immune priming (TIGP)’, which involves the transfer of immune memory to the offspring and to the following generations from a primed parent, has been reported in shrimp, P. monodon [157]. By causing transmissible changes in gene expression profiles, TIGP permits better protection of offspring when encountered with the pathogens inhabiting the same parental environment [158]. However, the molecular mechanism involved in these types of memory is not known.
Adaptive immunity in vertebrates is facilitated by the immunoglobulins (Igs) and T-cell receptors. Immunoglobulin superfamily (IgSF) proteins possess a minimum of one Ig domain and are key in recognizing, binding or adhesion processes of cells and/or pathogens [159]. However, several genes possessing Ig-like domains (IGs) which play critical role in host defence have been reported in invertebrates. Dscams have been implicated in alternative adaptive immunity in several arthropods, including crustaceans, which are capable of generating mRNA variants through alternative splicing [8, 9, 160]. Dscam plays a vital role in immunity through specific recognition of pathogen and formation of pathogen-specific isoforms in response to pathogen challenge [8, 161, 162]. It is a large protein (~220 KDa) having 9 Ig domains followed by 4 fibronectin type (FN) III domains, an Ig domain, 2 FNIII domains, a transmembrane domain and a cytoplasmic tail. However, the tail-less form of Dscam lacking transmembrane domain and cytoplasmic tail also has been reported. Among crustaceans, Dscam was first reported from L. vannamei [8] and subsequently from P. monodon [9]. Both types of Dscam were reported in shrimp [8, 9]. Dscam-mediated immunity is contributed by the hypervariability of both its extracellular and cytoplasmic tail and generation of several Dscam isoforms through alternative splicing, which mediate recognition of diverse pathogens following exposure to immunostimulants and diverse pathogens [11, 12, 161,162,163]. Moreover, cytoplasmic tail of membrane-bound Dscam possesses endocytosis motifs that can elicit phagocytosis [163]. Moreover, the variability in C terminal region of Dscam generating various combinations of transmembrane domains and cytoplasmic tail could form the basis for triggering diverse signalling pathways [163]. The tail-less Dscam are produced either by direct exocytosis or can be cleaved off from membrane-bound Dscam mediated by Type III polyadenylation similar to the production of soluble IgM in vertebrates [12]. The tail-less Dscam mRNA expressions were found to be upregulated in shrimp haemocytes when stimulated with PAMPs, including LPS, PGN, β-1,3-glucans and virus [11]. It is presumed that, when invertebrate hosts are exposed to pathogens, a ‘cloud’ of several isoforms of Dscam with diverse properties and abundance are formed. However, the mechanism of producing specific isoforms of Dscam by host cell after a particular pathogen challenge and the mechanism behind the primed immunity are yet to be understood properly. Functionally, Dscam provides an ‘immunological memory’ and supports a unique immune mechanism, termed ‘innate immunity with specificity’ or ‘immune priming’ which provides adaptive immune characteristics to the innate immune system [161].
Another molecule related to adaptive-like immunity identified is FREPs. These are polymorphic lectin-like molecules involved in various immune responses such as recognition of pathogens, agglutination, lysis of bacteria and defence against parasites [164]. They are characterized by a common C-terminal fibrinogen-related domain (FReD) and variable N-terminal regions [165]. Human ficolin possess N-terminal collagen, whereas molluscan FREPs possess one or two Ig domains in their N-terminus [166]; however, crustacean FREPs lack hypervariable Ig domains. Different categories of FREPs have been reported and named as ficolins, tachylectins and FREPs [167]. The binding abilities of different FREPs towards microbial pathogens vary considerably. Different types of FREPs have been identified in crustaceans that play an important role in the immune response against different pathogens. These proteins showed differential agglutinating properties towards Gram-negative and Gram-positive bacteria and viruses and ligands such as LPS and PGN. They respond differently to bacteria (Vibrio sp.) and virus (WSSV) challenges. MIP has been characterized in crayfish (P. leniusculus) and shrimp (P. monodon) [168, 169], which functions as a regulator of PO-induced melanization. Two ficolin-like proteins reported from crayfish P. leniusculus displayed agglutinating property with Gram-positive and Gram-negative bacteria in the presence of Ca2+; however, bacterial clearance was observed only for Gram-negative bacteria [170]. The FREPs from M. japonicus (MjFREP1) was reported to be up-regulated by challenge with V. anguillarum or WSSV [10] and was able to bind with PGN, LPS and VP28 of WSSV. The two ficolins reported from Macrobrachium rosenbergii could bind to Gram-positive and Gram-negative bacteria as well as to PGN and LPS, besides responding to WSSV or Vibrio challenge [171]. A FREP has been reported from L. vannamei which responded to Vibrio only, but not to WSSV [15]. Subsequently, ten transcripts of FREP have been reported from L. vannmaei [172] which responded differently to bacterial and virus challenge. Three tachylectin-like genes were reported from P. monodon which display agglutinating property with pathogenic vibrios, and RNAi experiment showed marked decline in the survival of the animals following bacterial infection [173, 174].
Hemolin, a specific immune protein belonging to Ig superfamily, has been identified and up-regulation of expression noticed in response to WSSV and V. parahaemolyticus in L. vannamei [14]. Similar to Dscam, hemolin functions as opsonin and can accelerate the phagocytosis and agglutination in the presence of Ca2+. Hemolin consists of seven Ig domains which form a ‘horseshoe’ tertiary structure, which has been reported to function as the site of attachment to bacterial LPS [175]. However, the role of hemolin in adaptive immune response in shrimp has not been elucidated.
5 Summary
In summary, being an invertebrate, shrimps lack a true vertebrate-like adaptive immunity and mainly depend on the well-developed innate immune system consisting of cellular and humoral responses for dealing with the pathogens. The defence mechanisms of shrimp are activated when PAMPs residing on microbial surface are recognized by host-associated PRRs. The binding of PRRs with the specific PAMPs result in the activation of signalling pathways and trigger effector mechanisms (cellular or humoral) leading to the production of AMPs and destruction of invading pathogens. Recent studies on the innate immunity in shrimp suggest the existence of immunological memory and alternative adaptive immunity, though the underlying molecular mechanism is yet to be understood. Nevertheless, these discoveries point to the fact that ‘vaccination’ can be possible in shrimp which provides protection against pathogens. However, it may not be scientifically correct to expect similar responses and patterns of protection as observed in vertebrates.
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K. V., R., K., S., Deepika, A., Kulkarni, A. (2022). Shrimp Immune System and Immune Responses. In: M., M., K.V., R. (eds) Fish immune system and vaccines. Springer, Singapore. https://doi.org/10.1007/978-981-19-1268-9_2
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