Effects of Animal Venoms on Human Innate Immunity: Comparison
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Venoms are products of specialized glands and serve many living organisms to immobilize and kill prey, start digestive processes and act as a defense mechanism. Venoms affect different cells, cellular structures and tissues, such as skin, nervous, hematological, digestive, excretory and immune systems, as well as the heart, among other structures. Components of both the innate and adaptive immune systems can be stimulated or suppressed. Innate immunity is the first line of defense against microorganisms and external stimuli; it is nonspecific and is composed of physical barriers, soluble antimicrobial peptides and molecules, effector cells and phagocytes. Studying the effects on the cells and molecules produced by the immune system has been useful in many biomedical fields. The effects of venoms can be the basis for research and development of therapeutic protocols useful in the modulation of the immunological system, including different autoimmune diseases. 

  • envenomation
  • immunomodulatory
  • immunosuppression
  • innate immune system

1. Introduction

Innate immunity is the first line of defense against microorganisms and external stimuli; it is nonspecific and is composed of physical barriers, soluble antimicrobial peptides and molecules, effector cells and phagocytes [1]. Soluble molecules are useful in opsonization, inflammation and pathogen clearance, while the cellular components are responsible for both elimination and the stimulation of adaptive immunity through antigenic presentation [2][3][4]. This type of immunity can result in a fast and effective response without prior recognition of the stimulus [5].

2. Effects on Phagocytes

Studies have attempted to elucidate the innate immune pathways that are modulated by exposure to venom components, which alter phagocytes mainly by interacting with membrane receptors or intracellular signaling pathways. Diverse venom components interact with receptors on inflammatory cells, activating them and triggering the establishment of a proinflammatory state, which is accompanied by mild anti-inflammatory compensation that attempts to reverse associated local and systemic effects [6].
The initial stimulation of phagocytes is mediated by the recognition of molecules present in the venom by Toll-like receptors (TLRs), especially TLR2 and TLR4. Studies have shown that TLR2 and TLR4 recognize the Ts1 toxin from the venom of the scorpion T. serrulatus [7]. This β-toxin binds to TLR2 and TLR4, inducing the production of cytokines and lipid mediators in a MyD88-dependent manner, leading to the activation of proinflammatory signaling, such as the NF-κB, AP-1 or MAPK pathways (ERK1/2 and MAPK p38) [7]. The greatest toxic effect of Ts1 occurs at the level of sodium channels [8][9][10][11]. MT-III is a group IIA secreted phospholipase A2 (sPLA2) present in Bothrops atrox and Bothrops asper snake venom and is also recognized by TLR2, leading to the production of eicosanoids such as prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), which are potent neutrophil chemoattractants that favor the resolution of the acute response at the injury site [12][13]. Other studies have shown the role of TLR2 in stimulating polymorphonuclear migration and the production of interleukin (IL)-1β and inhibiting the production of IL-6 and mononuclear migration to the injury site in murine models with an intraperitoneal injection of venom from the snake B. atrox [13]. This finding is important because it demonstrates the effect of venoms on proinflammatory signaling pathways through interactions with receptors and their potential use as therapeutic agents.
Crotoxin (CTX) is a major component of the venom of snakes in the genus Crotalus and stimulates receptors such as formylated peptide receptors and muscarinic receptors [14][15]. C. durissus terrificus CTX has been shown to promote anti-inflammatory effects by interfering with leukocyte migration in murine models [14]. Studies have shown that this anti-inflammatory effect of CTX is dependent on its interaction with formylated peptide receptors since the use of antagonists of these receptors, such as Boc-2, inhibited this effect on dendritic cells and macrophages [15][16].
The CTX of C. durissus venom is composed of two subunits: CA, also known as crotapotin, and CB, which is a weakly toxic phospholipase A2 with high enzymatic activity. The CB fraction of CTX can decrease the expression of MHC type II molecules, which are important for antigen presentation to T-lymphocytes, as well as costimulatory molecules such as CD40, CD80 and CD86 [16]. Additionally, the toxin inhibits the production of IL-6, TNF-α and IL-12 by interfering in the phosphorylation of NF-κBp65, ERK1/2 and MAPK p38 [16]. On the other hand, the CB fraction stimulates the production of IL-10, TGF-β, PGE2 and LXA4, thus exerting an anti-inflammatory effect [16][17]. Envenomation by C. durissus, compared to that of other vipers, generates a smaller inflammatory reaction and less pain, which has drawn the attention of researchers looking for anti-inflammatory and analgesic elements of this toxin [6].
In macrophages, the effect of CTX on phagocytic propagation and activity has been characterized, and toxin-mediated alterations in cytoskeletal proteins modulate phagocytosis independent of the receptor involved. The same toxin can stimulate the production of nitric oxide (NO) by activating the enzyme inducible nitric oxide synthase (iNOS) and the NO-GMP pathway [18]. Glucose and glutamine metabolism is also altered by the hyperactivity of hexokinase, glucose 6-phosphate dehydrogenase and glutaminase [18][19]. Enzymatic hyperactivity in macrophages is associated with increased levels of ATP and metabolites from biosynthetic pathways and the stimulation of inflammatory and immune responses, mainly through the production of NADPH [18]. NADPH serves as a substrate for NADPH oxidase, removing electrons from NADPH to reduce O2 to O2-, which is rapidly converted to H2O2 [20]. The effect on macrophages was shown to be prolonged, as it could be detected in circulating macrophages up to 7 days after treatment with CTX [18].
On the other hand, the crude venom of C. durissus terrificus stimulated the production of TNF, IL-6 and interferon (IFN)-γ, which peaked between 24–72 h after intraperitoneal injection in mice [21].
The effects of the fractions and crude venom of some scorpions on macrophages have also been studied. The FII and FIII fractions of Ts1 and Ts6 of T. serrulatus venom dose-dependently stimulated the production of NO and H2O2 in macrophages. These toxins also modulate the inflammatory response by increasing levels of TNF-α, IL-6, IL-1α, IL-1β, IL-8 and GM-CSF, which trigger systemic inflammation and increase the risk of complications [22][23][24][25]. Additionally, Ts2 toxin exerts anti-inflammatory effects through the production of IL-10 [26].
Macrophage differentiation into subpopulations is also modulated by toxins from other animals, such as Androctonus australis hector, a species of scorpion widely distributed in Africa and Asia. Its venom (AahV) has two toxins called AahI and AahII that have regulatory effects on macrophage polarization to the M1 phenotype by stimulating the expression of inflammatory genes such as Il1b, Il23 and nos2 and dysregulating the expression of genes associated with the M2 phenotype, such as Arg1 and Il10 [27].
Venoms can affect the migration of macrophages; pretreatment with Apis mellifera venom has been studied in models of experimental autoimmune encephalitis in which inhibition of the mRNA expression of macrophage chemoattractants such as RANTES, MCP-1 and MIP-1α has been demonstrated [28].
In neutrophils, Loxosceles spider venom causes its indirect activation by an endothelial-mediated mechanism [29]. Loxosceles venom contains phospholipases D, which hydrolyze sphingomyelin and subsequently liberated ceramides act as intermediaries that regulate TNF-α and recruit neutrophils [30]. Inhibition of actin polymerization, tyrosine phosphorylation, and RhoA and Rac1 protein activity has been demonstrated, leading to the inhibition of phagocytosis for up to 14 days after treatment with CTX [31]. Additionally, CTX, the TzII and TzIII toxins of the scorpion T. zulianus and the venom of the snake Calloselasma rhodostoma have positive effects on the production of reactive oxygen species (ROS) and the release of myeloperoxidase, thus contributing to the development of neutrophil effector functions [32].
The venom of aquatic animals has made it possible to modulate the effects of neutrophils on innate immunity; venom isolated from the freshwater ray Potamotrygon cf. henlei induced neutrophilia that depended on TLR/TRIF signaling that was stimulated by the release of IL-33 derived from cells at the site of injury [33]. Likewise, the venom of the saltwater ray Hypanus americanus has been shown to induce strong swelling and leukocyte infiltration in the legs in murine models, which indicates that the venoms of marine animals probably contain molecules or toxins that promote this inflammatory state [34]. The venom of aquatic animals differs in composition from the venom of land animals and is characterized by the presence of phosphatidylcholine-2-acylhydrolase, metalloproteinases and hyaluronidases; these molecules degrade the extracellular matrix and induce the production of IL-33 in epithelial and endothelial cells [33]. The binding of IL-33 to the ST2 receptor stimulates MyD88-dependent MAPK signaling, resulting in the phosphorylation of ERK 1/2, MAPK p38, JNK and NF-κB. This amplification of the innate immune response and the generation of a microenvironment that leads to the accumulation of neutrophils at the injury site promotes tissue damage and necrosis due to the release of ROS, NO, myeloperoxidases such as MMP-9, serine proteases and cathepsin G, among others [33][35]. IL-33 production affects aryl hydrocarbon receptors present on mast cells, which also respond to environmental toxins and endogenous components, and triggers the production of IL-17 and ROS by these cells [36]. Increased IL-17 production is associated with the overexpression of CXCL5, which is a potent neutrophil chemoattractant [37]. Likewise, the venom of T serrulatus (TsV), the CTX of C. durissus terrificus, the batroxase and BatroxPLA2 of B. atrox, and the piratoxin-I, bothropstoxin-I and bothropstoxin-II of Naja mocambica have also been associated with the modulation of cell migration [38].
Regarding the action of venoms on bone marrow and hematopoietic structures, studies are contradictory. In the case of Tityus serrulatus venom, there are conflicting findings in mice studies. Both stimulation [39] and inhibition [40] have been reported. Crotoxin, rattlesnake toxin, down-modulates functions of bone marrow neutrophils and impairs the Syk-GTPase pathway [41]. Extensive studies in this regard are lacking.

3. Effects on Mast Cells

Mast cells are also activated by toxins from animal venoms, which involves excessive activation of the inflammasome and increased expression of caspase 1, which demonstrates a protective effect against the venom [42]. Additionally, mast cells respond to toxins such as LmTx-I from the snake Lachesis muta, which trigger the production of histamine and lipid mediators, favoring inflammation [43]. Mast cell activation and degranulation are also stimulated by CTX of C. durissus terrificus, C. durissus cascavella and C. durissus collilineatus [44]. There is strong evidence of an association between severe anaphylaxis, especially hymenoptera venom-induced anaphylaxis, and mast cell disorders. It has been thought that intrinsic abnormalities in mast cells, including the presence of the activating KIT D816V mutation in mastocytosis or of genetic trait, hereditary alpha-tryptasemia, may influence susceptibility to severe anaphylaxis. The understanding of these mechanisms in susceptible individuals can shed light on the expansion of knowledge on anaphylaxis and its treatment [45].

4. Effects on Complement

Another function of B. atrox is to induce the generation of the complement fractions C3a and C5a, which are potent anaphylatoxins that promote mast cell degranulation and neutrophil chemotaxis and activation [41][46].
The complement system is activated in the presence of toxins from snakes, such as cobras in the Naja genus and the G2 fraction of flavoxobin from Trimeresurus flavoviridis; the former is a source of a protein similar to the C3 protein of complement, which is called cobra venom factor (CVF). This factor gives rise to an enzyme called CVFBb, which is highly stable and has C3/C5 convertase activity, and the second promotes C3a release and the assembly of the membrane attack complex [44][47][48]. The modulation of complement activation pathways has been studied, and the toxins BjussuSP-I from B. jararacussu and BpirSP27 and BpirSP41 from Bothrops pirajai are inhibitors of the classic and lectin pathways and slightly modulate the alternative complement pathway [49].
The study of complement depletion by CVF has allowed elucidation of the behavior of this system in the development of the innate immune response and in the pathogenesis of some inflammatory diseases [6].
A comprehensive review of the effects of the various venoms on the complement system has been published [50].

5. Effects on Cytokines

Inflammation is characterized by redness, swelling, warmth, pain and loss of function in the affected tissue, which are consequences of immune cell responses and the vascular and inflammatory events associated with infection or injury [1][51]. Changes at the circulatory level are related to changes in vascular permeability, leukocyte recruitment and infiltration and the release of inflammatory mediators and cytokines [52].
The immune system responds to tissue damage through the initiation of a chemical signaling cascade to repair the affected tissues. This type of chemical signal is necessary for leukocyte chemotaxis to the site of injury, where activated leukocytes are responsible for resolving the inflammatory response through the production of cytokines, chemokines and lipid mediators [1].
Some cytokines are modulated by toxins. The venom of Centruroides noxius, which is an important scorpion species associated with multiple attacks in Mexico, exerted an important in vivo effect on the secretion of TNF-α, IL-6 and IFN-γ, which was maintained for up to 21 days [53]. After 21 days, there is an increase of IL-10, suggesting the modulation from an anti-inflammatory profile of other components of the venom [53].
The venom of A. australis hector and the toxins Bl-PLA2 and Bbill-TX from snakes B. leucurus and B. billilineata have been shown to increase the levels of proinflammatory cytokines such as IL-4, IL-6, IL-12, TNF-α and IL-1β, which are associated with hemolytic activity and leukocytosis due to neutrophilia and eosinophilia [54][55][56][57]. The cytokines IL-1, IL-6 and IL-12 have multiple functions and act synergistically to establish acute inflammation in tissues and modulate the function and differentiation of T- and B-lymphocytes [55].
Modulation of the anti-inflammatory profile has been evaluated in models of envenomation with the venom of Crotalus durissus collilineatus, Daboia russelii, C. durissus terrificus and species of Bothrops spp., and the results showed an increase in the production of IL-10 [58][59][60].
The gene expression of cytokines has been studied in response to venoms from other animals, such as that of the viper Vipera ammodytes ammodytes, and it was shown that the venom of this snake stimulates the expression of proinflammatory genes such as Il1a, Il1b, Ifna2 and Ifnb1 [61]. The same venom is capable of downregulating the production of IL-12 and IL-18, which are potent stimulators of IFN-γ release [61]. IL-12- and IL-18-induced production of IFN-γ is important for inducing the cytotoxic activity of innate immune cells, as well as for the development and maintenance of the Th1 response [62]. Similarly, the venoms of V. ammodytes ammodytes, B. billilineata and Calloselasma rhodostoma stimulate the gene expression of IL-8 by neutrophils, which is a powerful chemoattractant of polymorphonuclear cells, CD4+ and CD8+ T-lymphocytes and NK cells [31][63].
The urine of mice that were intraperitoneally injected with C. durissus terrificus venom showed increased concentrations of TNF-α, IL-10, IL-5, IL-6 and IFN-γ 15 min to 4 h after inoculation, and these levels decreased in urine after 4 h [64][65]. These findings were associated with kidney damage characterized by proteinuria and elevated serum creatinine levels [65]. The renal alterations are related to the accumulation of proinflammatory cytokines, which induce the rupture and desquamation of the tubular epithelium, favoring the development of proteinuria and the loss of renal function [65][66].
The effects of toxins isolated from the venom of bees and snakes have on the progression and development of symptoms in inflammatory and autoimmune disorders such as rheumatoid arthritis (RA) [67], acute intestinal inflammation [68], systemic lupus erythematosus (SLE) [69] and systemic inflammatory syndrome [70] have been evaluated. Thus, many modulatory effects have been studied, including the modulatory effects of cytokines.
Cobratoxin, cardiotoxin and neurotoxin derived from N. naja atra venom exert anti-inflammatory responses by reducing the levels of TNF-α and IL-1β and the enzymatic activities of myeloperoxidase (MPO) and iNOS [71][72]. This anti-inflammatory effect has also been demonstrated by the poisons of Apis mellifera and the cobra Naja naja atra, which have been evaluated as possible treatments for rheumatoid arthritis since the administration of different concentrations of these agents in murine models reduced edema in the legs, as well as the arthritis index and inflammatory pain [73]. In addition, bee venom contains PLA2, melittin and hyaluronidases, among other factors. Bee venom is useful in decreasing serum levels of rheumatoid factor, PCR, anti-streptolysin O and proinflammatory cytokines such as TNF-α, IFN-γ, IL-6 and IL-1β [67][74]. The excretion of hydroxyproline and glucosamine in urine, as well as serum levels of acid phosphatase and alkaline phosphatase, was also decreased in RA models treated with Naja kouthia venom, indicating the protective and anti-inflammatory effect on cartilage degeneration and destruction [75]. The action of diverse components of venoms on the extracellular matrix (both in the damage and in the reparative processes) is a fascinating field of research that can contribute to the knowledge of the pathogenesis and possible treatment of connective tissue diseases and cancer [76]. This field of knowledge is outside the scope of this work, but it must be taken into account.
CTX has also been shown to be effective in dysregulating acute intestinal inflammation in BALB/c mouse models of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis through toxin-mediated inhibition of IL-17A and IFN-γ secretion by innate lymphoid cells (ILC) 1 and ILC3 located in the intestinal mucosa [68]. The effect of the venom of the Naja naja atra cobra on systemic lupus erythematosus was evidenced by the decrease in lymphadenopathy, skin erythema, proteinuria and tissue lesions in MRL/lp mice. In addition, the production of TNF-α and IL-6 and the levels of anti-dsDNA antibodies decreased [69]. The decrease in this type of antibody is important due to its association with renal deterioration and the activation of dendritic cells and, thus, the development of the adaptive immune response [77].

6. Effects on Inflammasomes

The inflammasome is a multiprotein complex that participates in the inflammatory response against venoms through the production of the cytokines IL-1β and IL-18, tissue repair and pyroptosis [78][79]. The ability of Apis mellifera venom to activate the NLRP3 inflammasome has been demonstrated both in vivo and in vitro, and its effect is mainly attributed to melittin in the venom, which forms pores in the cells, generating a signal that is recognized by the immune system and activates the inflammasome [42].

7. Effects on Transcription Factors

It is important to consider that the inflammatory response is regulated by various transcription factors; in physiological conditions, NF-κB binds to the inhibitory protein IκB (IκB-α, IκB-β, IκB-ε, etc.) in the cytoplasm [80]. Under inflammatory conditions, some cytokines, such as TNF-α and IL-1β, promote the phosphorylation of kinases of IκB proteins, which are degraded and release NF-κBp65 to translocate to the nucleus and initiate the transcription of proinflammatory cytokine genes [80][81]. Cobratoxin from Naja naja atra decreased the levels of phosphorylated IKK-α and phosphorylated IκB-α, blocking the translocation of NF-κBp65 to the nucleus [82]. Cobratoxin from other snakes, inhibited the NF-κB pathway by binding with high affinity to the IKK proteins in the canonical pathway; these proteins are involved in the phosphorylation and degradation of IκB, blocking the release of NF-κB dimers and subsequent nuclear translocation [83]. In addition, the venom of other animals, such as the parasitoid wasp Nasonia vitripennis, suppresses the inhibitors IκBα and A20, inhibiting negative feedback and the activity of NF-κB [84]. In addition, venom stimulates the transcription of glucocorticoid-regulated genes such as GILZ and MKP1, which inhibit NF-κB by interacting with p65 and dephosphorylating and inactivating JNK and p38 [85][86][87][88]. The effect of the venom was also evidenced in the prolongation of JNK activation in the MAPK pathway in LPS-induced macrophages, which could lead to the development of a cytotoxic response in the cell when high concentrations of the venom were administered [84]. The inhibitory effect of other poisons, such as the Apis mellifera venom and the N. naja atra venom, on inflammatory intracellular signaling decrease the release of IL-17 by reducing the phosphorylation of p38 in the MAPK pathway, as well as reducing the activation and translocation of NF-κB to the nucleus [28][71].

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