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

The Middle East and Northern Africa, collectively known as the MENA region, are inhabited by a plethora of venomous animals that cause up to 420,000 bites and stings each year. To understand the resultant health burden and the key variables affecting it, this review describes the epidemiology of snake, scorpion, and spider envenomings primarily based on heterogenous hospital data in the MENA region and the pathologies associated with their venoms. In addition, we discuss the venom composition and the key medically relevant toxins of these venomous animals, and, finally, the antivenoms that are currently in use to counteract them. Unlike Asia and sub-Saharan Africa, scorpion stings are significantly more common (approximately 350,000 cases/year) than snakebites (approximately 70,000 cases/year) and present the most significant contributor to the overall health burden of envenomings, with spider bites being negligible. However, this review also indicates that there is a substantial lack of high-quality envenoming data available for the MENA region, rendering many of these estimates speculative. Our understanding of the venoms and the toxins they contain is also incomplete, but already presents clear trends. For instance, the majority of snake venoms contain snake venom metalloproteinases, while sodium channel–binding toxins and potassium channel–binding toxins are the scorpion toxins that cause most health-related challenges. There also currently exist a plethora of antivenoms, yet only few are clinically validated, and their high cost and limited availability present a substantial health challenge. Yet, some of the insights presented in this review might help direct future research and policy efforts toward the appropriate prioritization of efforts and aid the development of future therapeutic solutions, such as next-generation antivenoms.

Co-option of the same ancestral gene family gave rise to mammalian and reptilian toxins

Background Evolution can occur with surprising predictability when organisms face similar ecological challenges. For most traits, it is difficult to ascertain whether this occurs due to constraints imposed by the number of possible phenotypic solutions or because of parallel responses by shared genetic and regulatory architecture. Exceptionally, oral venoms are a tractable model of trait evolution, being largely composed of proteinaceous toxins that have evolved in many tetrapods, ranging from reptiles to mammals. Given the diversity of venomous lineages, they are believed to have evolved convergently, even though biochemically similar toxins occur in all taxa. Results Here, we investigate whether ancestral genes harbouring similar biochemical activity may have primed venom evolution, focusing on the origins of kallikrein-like serine proteases that form the core of most vertebrate oral venoms. Using syntenic relationships between genes flanking known toxins, we traced the origin of kallikreins to a single locus containing one or more nearby paralogous kallikrein-like clusters. Additionally, phylogenetic analysis of vertebrate serine proteases revealed that kallikrein-like toxins in mammals and reptiles are genetically distinct from non-toxin ones. Conclusions Given the shared regulatory and genetic machinery, these findings suggest that tetrapod venoms evolved by co-option of proteins that were likely already present in saliva. We term such genes ‘toxipotent’—in the case of salivary kallikreins they already had potent vasodilatory activity that was weaponized by venomous lineages. Furthermore, the ubiquitous distribution of kallikreins across vertebrates suggests that the evolution of envenomation may be more common than previously recognized, blurring the line between venomous and non-venomous animals.

Neglected Venomous Animals and Toxins: Underrated Biotechnological Tools in Drug Development

Among the vast repertoire of animal toxins and venoms selected by nature and evolution, mankind opted to devote its scientific attention—during the last century—to a restricted group of animals, leaving a myriad of toxic creatures aside. There are several underlying and justifiable reasons for this, which include dealing with the public health problems caused by envenoming by such animals. However, these studies became saturated and gave rise to a whole group of animals that become neglected regarding their venoms and secretions. This repertoire of unexplored toxins and venoms bears biotechnological potential, including the development of new technologies, therapeutic agents and diagnostic tools and must, therefore, be assessed. In this review, we will approach such topics through an interconnected historical and scientific perspective that will bring up the major discoveries and innovations in toxinology, achieved by researchers from the Butantan Institute and others, and describe some of the major research outcomes from the study of these neglected animals.

Poisoning in Children and adolescents assisted during the COVID-19 pandemic at the Toxicological Information and Assistance Center in Federal District, Brazil (CIATOX -DF): Descriptive, Cross-sectional, and Analytical study with 1.037 patients

Exogenous poisonings are one of the principal accidents involving children and adolescents. The social isolation promoted by the COVID-19 pandemic raises concerns about the possibility of an increase in poisoning among children since most cases of poisoning occur in home environments. Therefore, the present study evaluated exogenous poisonings in children under ten years of age and adolescents aged 11 to 20 years old through data recorded at the Toxicological Information and Assistance Center in the Federal District (CIATOX-DF) from January to September 2020. The results showed a change in the number of notifications, with 1.037 poisonings registered in patients under 20 years of age. Registrations of poisoning by venomous animals, medications, and household cleaning products in children tend to be higher in months of vacation. This study demonstrated poisoning notifications by non-venomous animals in March and April and household cleaning products as the second leading cause of exogenous poisoning, demonstrating a clear temporal association among social isolation, increased use of household cleaning products, and exposure to these products. The multivariate analysis methodology managed to show the significant characteristics of the studied sample, contributing to creating local actions that aim to reduce the number of preventable cases of poisonings.

Pectoral-fin glands and delivery apparatus in the catfish genus Brachyrhamdia Myers, 1927 (Siluriformes: Heptapteridae)

The Siluriformes, popularly known as catfishes, are probably the vertebrate group with the highest diversity of venomous animals, even though only approximately a hundred venomous catfishes are reported to date. Venomous catfishes might present a delivery system apparatus, formed by an unbranched ray at the leading edge of pectoral and dorsal fins (spine), which can be stiffened and pungent, while venom glands can be present at the surface of such spines and/or the axillary region. This work investigated the presence, morphology and distribution of glands and pectoral-fin delivery apparatus in the heptapterid Brachyrhamdia genus. Pectoral-fin spine external morphology was compared across all valid species in the genus, histological sections of the pectoral-fin spine and axillary regions of B. heteropleura and B. marthae were produced, and dissections of the pectoral girdle region of the mentioned species were analyzed. The histological sections confirmed the presence of pectoral-fin glands at the surface of the pectoral-fin spine of Brachyrhamdia species, and cellular morphology indicates these glands are probably venomous. Also, we found a piriform gland at the axillary region, whose cell morphology is like the reported for other catfishes. However, we cannot currently confirm or deny axillary gland participation in the venom delivery apparatus. This work constitutes the first report of venom glands in Brachyrhamdia, and the first description of Heptapteridae axillary glands.

The genome of the venomous snail Lautoconus ventricosus sheds light on the origin of conotoxin diversity

Background Venoms are deadly weapons to subdue prey or deter predators that have evolved independently in many animal lineages. The genomes of venomous animals are essential to understand the evolutionary mechanisms involved in the origin and diversification of venoms. Results Here, we report the chromosome-level genome of the venomous Mediterranean cone snail, Lautoconus ventricosus (Caenogastropoda: Conidae). The total size of the assembly is 3.59 Gb; it has high contiguity (N50 = 93.53 Mb) and 86.6 Mb of the genome assembled into the 35 largest scaffolds or pseudochromosomes. On the basis of venom gland transcriptomes, we annotated 262 complete genes encoding conotoxin precursors, hormones, and other venom-related proteins. These genes were scattered in the different pseudochromosomes and located within repetitive regions. The genes encoding conotoxin precursors were normally structured into 3 exons, which did not necessarily coincide with the 3 structural domains of the corresponding proteins. Additionally, we found evidence in the L. ventricosus genome for a past whole-genome duplication event by means of conserved gene synteny with the Pomacea canaliculata genome, the only one available at the chromosome level within Caenogastropoda. The whole-genome duplication event was further confirmed by the presence of a duplicated hox gene cluster. Key genes for gastropod biology including those encoding proteins related to development, shell formation, and sex were located in the genome. Conclusions The new high-quality L. ventricosus genome should become a reference for assembling and analyzing new gastropod genomes and will contribute to future evolutionary genomic studies among venomous animals.

Risky Business: The Function of Play in a Venomous Mammal—The Javan Slow Loris (Nycticebus javanicus)

Immature mammals require opportunities to develop skills that will affect their competitive abilities and reproductive success as adults. One way these benefits may be achieved is through play behavior. While skills in developing use of tusks, antlers, and other weapons mammals have been linked to play, play in venomous animals has rarely been studied. Javan slow lorises (Nycticebus javanicus) use venom to aid in intraspecific competition, yet whether individuals use any behavioral mechanisms to develop the ability to use venom remains unclear. From April 2012 to December 2020, we recorded 663 play events and studied the factors influencing the frequency of play and the postures used during play in wild Javan slow lorises. Regardless of the presence of siblings, two thirds of play partners of young slow lorises were older and more experienced adults. Young lorises engaged in riskier behaviors during play, including using more strenuous postures and playing more in riskier conditions with increased rain and moonlight. We found that play patterns in immature lorises bear resemblance to venom postures used by adults. We suggest that play functions to train immature lorises to deal with future unexpected events, such as random attacks, as seen in other mammalian taxa with weapons. Given the importance of venom use for highly territorial slow lorises throughout their adult lives and the similarities between venom and play postures, we cannot rule out the possibility that play also prepares animals for future venomous fights. We provide here a baseline for the further exploration of the development of this unique behavior in one of the few venomous mammals.

The parallel origins of vertebrate venoms

Evolution can occur with surprising predictability when faced with similar ecological challenges. How and why this repeatability occurs remains a central question in evolutionary biology, but the complexity of most traits makes it challenging to answer. Reptiles and mammals independently evolved oral venoms that consist of proteinaceous cocktails which allow straightforward mapping between genotype and phenotype. Although biochemically similar toxins can occur as major venom components across many taxa, whether these toxins evolved via convergent or parallel means remains unknown. Most notable among them are kallikrein-like serine proteins, which form the core of most vertebrate venoms, and are employed by all venomous snake families. Here we used a combination of comparative genomics and phylogenetics to investigate whether serine protease recruitment into the venom occurred independently or in parallel across the different tetrapod lineages. Using syntenic relationships between genes flanking known toxins, we traced the origin of kallikreins to a single locus containing one or more nearby paralogous kallikrein-like clusters. Independently, phylogenetic analysis of vertebrate serine proteases revealed that the same gene cluster gave rise to toxins in mammals and reptiles. Given the shared regulatory and genetic machinery underlying venom evolution, these findings suggest a unified model underlying vertebrate venom evolution by exaptation of homologous ancestral kallikreins. Furthermore, the ubiquitous distribution of kallikreins across vertebrates suggests that the evolution of envenomation may be more common than previously recognized, blurring the line between venomous and non-venomous animals.