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Terrestrial venomous animals, the envenomings they cause, and treatment perspectives in the Middle East and North Africa

['Timothy P. Jenkins', 'Department Of Biotechnology', 'Biomedicine', 'Technical University Of Denmark', 'Kongens Lyngby', 'Shirin Ahmadi', 'Matyas A. Bittenbinder', 'Naturalis Biodiversity Center', 'Leiden', 'The Netherlands']

Date: 2022-01 

2.1. Snakes

There are over 731 different venomous snake species spread across the world (snakedb.org). However, the burden that these snakes cause to regions and communities is not evenly distributed. The highest burden is felt in sub-Saharan Africa and Southeast Asia, in part, due to the high number of highly venomous species found in these regions [17]. Consequently, these regions have so far received most of the international attention and resources. Conversely, the MENA region has been largely overlooked, despite numerous venomous species inhabiting this region. Indeed, according to the World Health Organization (WHO), a total of 16 Category I medically important snake species (i.e., highly venomous snakes that are prevalent in the respective country and cause numerous bites, leading to mortality or morbidity) are spread across North Africa and the Middle East (Fig 1A) [1]. Based on a literature review and modeling study performed by Kasturiratne and colleagues [17], North Africa was estimated to have between 463 and 36,208 snakebite incidences with a death toll between 20 and 29 individuals each year; the Middle East had similar figures, with 2,306 to 31,417 incidences and between 15 and 33 deaths annually. However, these statistics are very broad estimations seen from a global perspective and are expected to be significantly underestimated due to the lack of medical information in most of the assessed countries [17]. In the last 25 years, no reliable data involving snakebites exist from Algeria, Libya, Tunisia, Qatar, Syria, and Kuwait. This significantly skews the data for the whole MENA region and, in particular, North Africa, as only Egypt and Morocco are providing the epidemiological data for the entire region. As it remains, the actual number of incidences and deaths in this region will not be fully known until the lack of data from many countries is resolved. The available epidemiological data from the MENA countries reveal many similarities consistent across incidences involving snakebites. Numerous data reports show that most snakebite cases occur in rural farmable areas [18–24]. Specifically, multiple studies conducted in Egypt, Iran, Iraq, Morocco, and Saudi Arabia found that 70% or more of cases were reported from rural farming areas. Furthermore, males constitute more than 50% of snakebite incidences in many MENA countries [18,22,24–32]. Mortality rates from these countries range significantly and are largely dependent on the amount of available data. Epidemiological data from Egypt, Iran, Jordan, Morocco, Saudi Arabia, and Yemen have shown mortality rates ranging from 0.13% up to 4.8% [18,19,22–24,26,29,32]. Disturbingly, a study conducted on snakebite incidences in Iraq found a mortality rate of 7% to 15% among adults [27].

Responsible for this morbidity and mortality are the snakes’ toxins. Notably, while a great diversity in venom composition exists between and within different snake species, the key protein components that are present in these toxin cocktails often remain similar: Elapid venoms typically predominantly consist of three-finger toxins (3FTxs) and phospholipase A 2 s (PLA 2 s), whereas viper venoms often contain a substantial amount of snake venom metalloproteases (SVMPs), snake venom serine proteases (SVSPs), as well as PLA 2 s [7,33]. Currently, proteomics or transcriptomic data exist for half of the medically important snake species (nine out of 18), and based on that, SVMPs are the most prominent (average relative abundance of 41.9%) toxins in the MENA snakes, followed by C-type lectins (CTLs; 9.7%), PLA 2 s (9%), disintegrins (DISs; 8.5%), 3FTxs (7.5%), and SVSPs (6.4%; Fig 1B). SVMPs are important compounds of most viperid and crotalid venoms. The highest relative abundances of these toxins in the MENA snakes are found in the genera Echis, Cerastes, and Macrovipera (Fig 1B). They are known to cause hemorrhagic and local effects in victims through different mechanisms including disrupting extracellular matrix (ECM) of capillary endothelial cells, which, in turn, results into escaping of blood from capillaries. The second most abundant toxin family in the MENA snakes, i.e., snake venom CTLs (lectin-like proteins) [34]. CTLs are frequently found in the vipers and target clotting factors and various receptors on platelets, endothelial, and immune cells. CTL-related proteins can cause disseminated intravascular coagulopathies or severe bleedings, which both are life-threatening situations in viper envenomings [35]. Notably, PLA 2 s are another group of abundant toxins in MENA snakes, but their relative abundance varies greatly between different species, with the highest percentages observed in Echis pyramidum (20.6%) and Cerastes cerastes (19.1%) and the lowest in Naja haje (4%, Fig 1B). Besides affecting the blood coagulation cascade, PLA 2 s can have both neurotoxic and cytotoxic activities, resulting in systemic and local symptoms [36,37]. DISs constitute another group of abundant toxins in the MENA snakes and are frequently found in vipers and rattlesnakes and closely related to SVMPs. They are either produced from the proteolysis of a SVMP precursor or synthesized from mRNAs that have lost their metalloprotease-coding region [38]. DISs induce their toxicity through interacting with integrins on platelets, which are responsible for cell–ECM interactions and intercellular signaling [39], hence interfering with clot formation. Furthermore, while 3FTxs are only found in Naja species, they comprise more than half of their venom, e.g., Naja nubiae [40] and N. haje venom contains 70.9% and 60% of these toxins, respectively (Fig 1B). They are highly toxic and despite significant homology in sequence and structure, 3FTxs demonstrate a wide range of activities, from highly specific ion channel inhibition (neurotoxicity) to nonspecific membrane disruption (cytotoxicity). Finally, SVSPs are found in all viper species in the MENA region, with Bitis arietans presenting the highest relative abundance (19.5%; Fig 1B). In general, different SVSPs are able to both specifically activate the blood components that play a role in coagulation, fibrinolysis, and platelet aggregation (coagulant effect) and enzymatically degrade them (anticoagulant effect) [41].

The following presents an overview of all medically relevant snakes in the MENA region (see also [28]), their key toxins (Fig 1), and the role these toxins play in inducing envenoming symptoms.

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TIFF original image Download: Fig 1. Medically relevant Category I snakes in North Africa and the Middle East. (A) Phylogeny and geographic distribution and (B) reported toxicity and available venom proteome or transcriptome (+) data are shown. Specifically, the table presents the genera, species, the origin of the reference proteome or transcriptome, and the median lethal dose in mice (LD 50 ; mg/kg) [42–46]. It also illustrates the relative abundance of 3FTxs, PLA 2 s, SVMPs, SVSPs, LAAOs, KSPIs, CRiSPs, DISs, NPs, and CTLs. All components are represented as relative wet weight abundance in %. Notably, snake venom composition may vary depending on region. 3FTx, three-finger toxin; CRiSP, cysteine-rich secretory protein; CTL, C-type lectin; DIS, disintegrin; KSPI, kunitz-type serine protease inhibitor; LAAO, L-amino acid oxidase; NP, natriuretic peptide; PLA 2 s, phospholipase A 2 s; SVMP, snake venom metalloprotease; SVSP, snake venom serine protease. https://doi.org/10.1371/journal.pntd.0009880.g001

2.1.1. Elapidae family. Elapids have short, hollow, and fixed fangs [47], with venoms that are predominantly neurotoxic and characterized by progressive symptoms of paralysis and respiratory failure [48]. In the MENA countries, the Elapidae family is only represented by one genus, Naja, otherwise known as true cobras, that contains three species of Category I and one (N. nubiae) of Category II (potentially dangerous, but insufficient epidemiological data) medically important venomous snakes. Naja genus. The genus Naja contains over 30 species of highly venomous snakes [49], of which three have been identified within the MENA region. WHO considers Naja arabica, N. haje, and Naja oxiana as Category I venomous snakes. While N. arabica is found across Oman, Saudi Arabia, and Yemen, where it especially is a problem [1], N. oxiana is only located in Iran. Meanwhile, N. haje is distributed across North Africa and is known to be highly problematic in Algeria, Egypt, Libya, and Morocco (Fig 1A) [1]. Like many cobras, N. haje bites result in potentially lethal neurotoxic symptoms, as well as local swelling and pain at the bite site; these effects are primarily caused by neurotoxins (NTxs) and cytotoxins (CTxs) [42,50] from the 3FTx family. The NTxs mostly act by binding to the postsynaptic nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction to produce clinically significant and potentially lethal skeletal muscle paralysis [51]. Notably, in the MENA region, snake venom 3FTxs are only found in Naja species and have never been identified in the venoms of other MENA snakes. Yet, in the Naja genus, 3FTxs constitute a significant proportion of the whole venom and the majority of the venom’s toxicity. Indeed, proteomics data, which are only available for N. haje, reveals that 3FTxs (60%; Fig 1B) constitute the main venom component of these snakes. In addition to 3FTxs, PLA 2 s likely also play a role in inducing some of the N. haje envenoming symptoms. Indeed, PLA 2 s and CTxs from sub-Saharan African Naja species have been shown to act synergistically [52] and to be the primary components behind permanent tissue loss and the resultant amputations in Naja snakebite envenomings [53].

2.1.2. Viperidae family. Besides elapids, another family of highly venomous snakes can be found in the MENA region, i.e., the family Viperidae, more commonly known as vipers. Vipers are characterized by their long, hollow, and retractable fangs [47] and often possess myotoxic and hemotoxic venom that can cause symptoms of local or systemic bleeding in the affected limbs, coagulopathy, and extensive edema [50]. This family also encompasses 12 of the 16 species identified by WHO as Category I snakes in the MENA region. These 12 species are spread across six genera, which are further discussed below. 2.1.2.1. Bitis. The Bitis genus is widespread across the African continent and the southern Arabian Peninsula and consists of 17 species [49]. However, only one species, B. arietans, can be found within the MENA region. This species is known to inhabit Algeria and Morocco, but its distribution also extends to the Arabian Peninsula, including Oman, Saudi Arabia, and Yemen (Fig 1A) [49]. A study conducted by Eljaoudi and colleagues [50] found that B. arietans is responsible for approximately 17% of all recorded snakebites in Morocco. Notably, the large amounts of venom injected during an average bite (typically between 150 and 350 mg), alongside its toxicity, renders this species highly dangerous [54]. The venom of B. arietans can induce severe local and systemic clinical manifestations, including bleeding, swelling, necrosis, compartment syndrome, and hypotension [54]. Furthermore, based on proteomics data, B. arietans possesses the highest relative abundance (19.5%; Fig 1B) of SVSPs among all MENA snakes. SVSPs can generally be found in viper venoms and are known to affect the blood coagulation cascade at different levels, resulting in the inactivation of blood clotting factors, inhibition of platelet aggregation, and a decrease in blood pressure by acting as a hypotensive agent [42,46,55]. Besides SVSPs, CTLs make up a significant amount of Bitis venoms. These toxins (e.g., bitiscetin) are hemostasis disruptive and consequently prevent blood clotting by interfering with platelet aggregation and the coagulation cascade [35]. 2.1.2.2. Cerastes. One of the most widely distributed viper genera across the Sahara and Arabian Peninsula is the genus Cerastes, which consists of only three distinct species [56]. Two, i.e., C. cerastes and Cerastes gasperettii, are considered medically relevant. These species are dispersed across the MENA region (Fig 1A) and are responsible for many snakebite incidences. In particular, a study conducted by Al-Sadoon over the period from 2005 to 2010 found that in the Riyadh Province of Saudi Arabia, C. gasperettii was responsible for 886 snakebite cases, accounting for 86.9% of all incidences in this area [32]. In southern Morocco, C. cerastes is considered the most dangerous snake species [57]. A C. gasperetti envenoming causes local pain, swelling, edema, and tenderness in most patients [32]. Similarly, the danger from C. cerastes can be attributed to its venom causing mild to severe local effects, hypotension, and arterial thrombosis [50,58]. Currently, proteomics data are only available for C. cerastes; this suggests that SVMPs and PLA 2 s are the main constituents of its venom. SVMPs are capable of damaging ECM components, such as proteoglycans [59], collagen, laminin, and fibronectin [60]. Thus, SVMPs are mainly involved in edema, inflammation, swelling, blistering, skin damage, tissue necrosis, myonecrosis, and cardiovascular shock. In addition, they have procoagulant, anticoagulant, and platelet aggregation inhibitory effects [60]. In the MENA region, Cerastes, together with Echis and Macrovipera (see Sections 2.1.2.4, 2.1.2.5, and Fig 1B), possesses the highest relative abundances of SVMPs. 2.1.2.3. Daboia. Like Cerastes, the genus Daboia only contains two medically relevant species within the MENA region, Daboia mauritanica and Daboia palaestinae. The former can be found within Algeria, Morocco, and Tunisia, whereas the latter is distributed across Israel, Jordan, Lebanon, Palestine, and Syria (Fig 1A). D. mauritanica, in particular, has been suggested to be responsible for most of the snakebite incidences within North Africa [49]. This species was linked to 69.4% of all the snakebite incidences that Eljaoudi and colleagues identified in Morocco [50]. Epidemiological data are scarce for D. palaestinae, but it has been reported that bites are associated with a death rate of 6.2% in Israel and Jordan [49]. Notably, the venom of D. palaestinae is cytotoxic and can induce hematuria, swelling, bleeding at the site of the bite, and significant hemorrhage [49]. Similarly, the venom of D. mauritanica is primarily cytotoxic and is characterized by mild to severe local effects, hypotension, and coagulopathy [50]. Proteomics data are only available for D. mauritanica (Fig 1B) and demonstrates that its venom predominantly contains SVSPs and DISs that inhibit platelet aggregation and integrin-dependent cell adhesion. 2.1.2.4. Echis. Echis constitutes another genus of vipers in the MENA region and is one of the most taxonomically problematic Viperidae genera. The number of currently recognized species ranges from 8 to 12, and potentially 20 subspecies, depending on the literature [61]. Five of these species can be found in the MENA countries: Echis burkini, Echis carinatus, and Echis omanensis, which are predominantly located across the Middle Eastern countries, as well as E. pyramidum and Echis coloratus, which are mainly found in Egypt but also in the ME (Fig 1A). Indeed, a bite from this genus, without antivenom treatment, has an estimated mortality rate of up to 20% [45]. E. coloratus, in particular, is one of the key species contributing to this high mortality rate. It was identified as the primary species causing snakebite-related deaths in two different studies in Saudi Arabia. The first study found that E. coloratus accounted for 67% of all the Riyadh Province’s identifiable snakebite cases [18], yet this statistic did not hold true in a later study that demonstrated that C. gasperettii was the primary cause of death. The second one focused on snakebites among children in the Al-Baha region and found that this species accounted for 10.8% of the identifiable cases [20]. Furthermore, E. carinatus was responsible for up to 9% of snakebites in Oman, and alongside E. omanensis, it is thought to be the primary cause for snakebites in this country [31]. E. carinatus has also been identified as the species which causes highest mortality and morbidities in Iran [22]. General symptoms of Echis bites include local swelling at the bite site, local blistering, necrosis, incoagulable blood, and spontaneous systemic bleeding. The proteomics data available for E. carinatus, E. coloratus, and E. pyramidum offer a possible reason. Venom from these snakes predominantly contains SVMPs and CTLs. Besides local effects, SVMPs together with CTLs, have anticoagulant and platelet-modulating activities [62]. 2.1.2.5. Macrovipera. The genus Macrovipera, a smaller and taxonomically simpler genus than Echis, currently contains just three species and five subspecies [63]. Macrovipera lebetina is the most prominent species from this genus, with an extensive geographic range from the Middle East extending throughout central Asia (Fig 1A) [64,65]. In addition, it is the only species from this genus that is considered as a Category I medically important species by WHO. On the Iranian plateau (i.e., Afghanistan, Azerbaijan, Iran, Iraq, Pakistan, and Turkmenistan), this species is considered one of the most venomous snakes [64]. It is noteworthy that Macrovipera razii has recently been separated from M. lebetina as a new species that is endemic to Iran; however, its epidemiologic data are still not available [63]. The venom of M. lebetina is known to cause significant local tissue damage, necrosis, edema, and hemorrhage [64]. Nevertheless, the primary cause of death by this species has been attributed to acute renal failure [64]. The underlying toxin(s) that induce acute renal failure have not been identified. However, the venom of M. lebetina was found to be dominated by SVMPs (Fig 1B) that have been hypothesized to cause nephrotoxicity through secondary effects, including hypotension, hemolysis, and rhabdomyolysis [64]. 2.1.2.6. Pseudocerastes. Finally, the genus Pseudocerastes was given its name due to its phenotypic similarity to the Cerastes genus, despite a lack of genetic relatedness. Pseudocerastes contains three species with a geographical distribution ranging from Egypt to Iran and extending to the southeastern part of the Arabian Peninsula (Fig 1A) [49]. Nonetheless, Pseudocerastes persicus is the only clinically relevant species recognized within the MENA region. This species’ venom is thought to be highly coagulopathic, but little is known about its symptomatic effects in humans [66]. Pseudocerastes fieldi inhabits a similar geographic range as P. persicus and is classified as a Category II species by WHO. Notably, its venom substantially differs from P. persicus and is thought to possess neurotoxic properties [66]. This neurotoxicity is attributed to a novel PLA 2 complex that creates an irreversible neuromuscular blockade at the presynaptic site [66].

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